Cyanamide: a convenient building block to synthesize 4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine systems via a multicomponent reaction

Article abstract of DOI:10.1016/j.tet.2008.01.087

4-Aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine derivatives were prepared using a multicomponent reaction by reacting a mixture of arene or heteroarenecarbaldehyde, 1,3-dicarbonyl compounds, and cyanamide under acidic conditions. The novelty of this approach derives from its use of cyanamide as a building block in a four-component Biginelli-type reaction. Varying the reaction conditions led to the formation of either N-(2-imino-6-phenyl-1,3,5-oxadiazinan-4-ylidene) cyanamide or 3,4-dihydropyrimidin-2(1H)-one. The type of heterocycle skeleton synthesized depends on the nature of the acid catalyst as well as the reaction conditions employed.

Full text of DOI:10.1016/j.tet.2008.01.087

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3372e3380
www.elsevier.com/locate/tet
Cyanamide: a convenient building block to synthesize
4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine
systems via a multicomponent reaction
a
a
a
a
a
R. Hulme a,b, , O.D.P. Zamora , E.J. Mota , M.A. Pasten , R. Contreras-Rojas , R. Miranda ,
*
I. Valencia-Hernandez , J. Correa-Basurto , J. Trujillo-Ferrara , F. Delgado
´
b
b
b
c,
*
´
a Departamento de Ciencias Quimicas, Facultad de Estudios Superiores Cuautitla´n, Universidad Nacional Auto´noma de Me´xico,
Avenida 1ro de Mayo s/n, Cuautitla´n Izcalli, Estado de Me´xico, CP 54740, Mexico
b Escuela Superior de Medicina-IPN, Plan de San Luis y D´ıaz Miro´n, Col. Santo Toma´s, Me´xico, D.F., CP 11340, Mexico
c Departamento de Qu´ımica Orga´nica, Escuela Nacional de Ciencias Biolo´gicas, Instituto Polite´cnico Nacional,
Prolongacio´n Carpio y Plan de Ayala, Casco de Santo Toma´s, Me´xico, D.F., CP 11340, Mexico
Received 19 December 2007; received in revised form 21 January 2008; accepted 24 January 2008
Available online 31 January 2008
Abstract
4-Aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine derivatives were prepared using a multicomponent reaction by reacting a mixture of arene
or heteroarenecarbaldehyde, 1,3-dicarbonyl compounds, and cyanamide under acidic conditions. The novelty of this approach derives from its
use of cyanamide as a building block in a four-component Biginelli-type reaction. Varying the reaction conditions led to the formation of either
N-(2-imino-6-phenyl-1,3,5-oxadiazinan-4-ylidene) cyanamide or 3,4-dihydropyrimidin-2(1H)-one. The type of heterocycle skeleton synthesized
depends on the nature of the acid catalyst as well as the reaction conditions employed.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cyanamide; Building block; Multicomponent reaction; 4-Aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine
1. Introduction
an interesting reaction is the four-component approach, recently
reported by Orru and et al., to synthesize DHPMs that are prop-
erly functionalized at the N-3 position, providing a pool of
structurally diverse compounds of biological interest.5 Many
of these derivative compounds have emerged as a class of ther-
apeutic drugs with important pharmacological roles in medici-
nal chemistry, such as hexahydrotriazaacenaphthalenes (1),6
SQ 32926 (2),7 and HAP-1 (3).8
Although this reaction has been intensely explored, the con-
struction of 4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine
(aryl-CIDHPM) compounds (4) that are chemically analogous
to the Biginelli compounds has not yet been reported. Interest-
ingly, the above molecules possess the N-cyanoguanidinyl moi-
ety in their structure, which is found in other biologically active
molecules such as the potentially antimycotic agent N-cyano-
iminopyrimidine (5),9 pinacidil (6), a KATP channel activator10
(Fig. 1), and other compounds containing the cyanoimino
In recent years, multicomponent reactions (MCRs) have
emerged as a powerful strategy to construct structurally com-
plex molecules from simple starting materials.1 Molecules
synthesized by this method continue attracting the attention
of medicinal and synthetic chemists.2 One of the most cited
MCRs is the Biginelli reaction, which leads to the formation
of 3,4-dihydropyrimidin-2(1H)-one (DHPM) derivatives using
benzaldehyde, ethyl acetoacetate, and urea as starting mate-
rials.3 This reaction has been widely extended to include varia-
tions in all of its components,4 allowing access to a large
number of multifunctionalized DHPM derivatives. For example,
* Corresponding authors.
E-mail addresses: hulmerg@yahoo.com (R. Hulme), fdelgado@
woodward.encb.ipn.mx (F. Delgado).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.087

R. Hulme et al. / Tetrahedron 64 (2008) 3372e3380
3373
building blocks.13 Therefore, the application of this approach
to prepare aryl-CIDHPMs, its scope and limitations via system-
atic variation of arene or heteroarenecarbaldehyde and 1,3-di-
ketone components, and the influence of catalyst nature in the
absence or presence of solvents are reported.
F
O2N
O
Cl
O
O
O
R3O2C
R2
CO2R
R1
N
i-PrO
N
NH2 EtO
N
N
H
N
H
N
H
N
H
N
H
N
2. Results and discussion
3
1
2
The initial efforts to synthesize aryl-CIDHPMs were based
on the preparation of N-arylidenecyanoguanidine, a Michael
acceptor that was chemically convenient to replace a-tosyl-
substituted N-cyanoguanidines, the key intermediate in the
synthesis of alkyl-CIDHPMs. In agreement with the accepted
Biginelli mechanism,14 this species may form in situ under
the Biginelli three-component reaction (B-3CR) conditions
through the initial reaction of a mixture of arenecarbaldehyde
and cyanoguanidine. The subsequent formation of the aryl-
CIDHPMs theoretically could have been achieved by reacting
the N-arylidenecyanoguanidine with an appropriate 1,3-dicar-
bonylic compound. Unfortunately, we were unable to prepare
this compound using this method.
However, recently Fischer et al. reported the synthesis of
2-arylaminopyrimidine derivatives through N-arylguanidine.
This intermediate was appropriately synthesized from a mix-
ture of cyanamide and aryl amines under strongly acidic con-
ditions.15 The chemical explanation behind this process led us
to attempt to form N-arylidenecyanoguanidine under similar
conditions by replacing cyanoguanidine with 2 equiv of
cyanamide in the presence of 1 equiv of arenecarbaldehyde,
yielding the title compound after a subsequent reaction with a
1,3-dicarbonyl compound. The result was the development of
a novel one-pot multicomponent reaction via a four-compo-
nent approach to prepare aryl-CIDHPMs.
O
Aryl
CN
NH
CN
H
N
N
N
N
R2
N
CN
N
N
H
N
H
R3
N
H
6
5
4
Figure 1. Biginelli-type and cyanoguanidine compounds with pharmacological
activity.
functional group that have been found in pharmacologically
active products.11
The most promising method to construct aryl-CIDHPMs
is through the synthesis reported by Shutalev et al. for the
obtention of 4-alkyl-2-cyanoimino-3,4-dihydro-1H-pyrimidines
(alkyl-CIDHPMs).12 This approach implies the preparation of
a-tosyl-substituted N-cyanoguanidines i. A subsequent reaction
with potassium enolates of ethyl acetoacetate results in 5-eth-
oxycarbonyl-2-cyanimino-4-hydroxyhexahydropyrimidines ii,
which yield the alkyl-CIDHPMs iii after dehydration under
acidic conditions (Scheme 1). However, some of the drawbacks
of this approach involve a relatively long synthetic pathway,
lengthy reaction times, and purification steps that considerably
reduce the efficiency of the reaction and overall yields of these
compounds.
R
In this multicomponent approach, an exploratory reaction
composed of benzaldehyde 7a, ethyl acetoacetate 8a, and cyan-
amide 9 (50% in water) were reacted in a 1:1:2 molar ratio, re-
spectively, in the presence of concd hydrochloric acid (pH w2)
at reflux conditions (EtOH, 4 h). The desired 2-cyanoimino-5-
ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydro-1H-pyrimidine
10a was obtained, although in very low yields (5%, Scheme 2,
method a).
R
O
H2N
H
O
O
O
OH
/ KOH
2-4 day
water, rt
OEt
6-7 h, rt
Ts
H2N
NH
S
CN
+
N
CN
H2N
N
63-94%
i
O
R
O
R
H
N
R= Me, Et, Pr
EtO
N
H
N
The result may be rationalized by considering the substan-
tial formation of cyanamidium cations and its corresponding
hydrolysis to urea, according to the following equation:16
EtO
HO
TsOH/EtOH
1-2 h, reflux
CN
N
H
CN
N
H
N
46-73%
51-80%
O
H
H2O
ii
iii
H3N
N
9
CO2 + 2NH2
H2N
NH2
Scheme 1. Shutalev synthesis of alkyl-CIDHPMs.
This reaction is known to occur at pH <8.17 Therefore,
weak acidic conditions that shift the equilibrium toward the
cyanamide would inhibit ureide formation and probably im-
prove the yield.
Thus, the next catalytic system explored was a mixture of
AcONa (1 equiv) and concd hydrochloric acid (in catalytic
amount) at pH w5, which substantially improved the overall
yield (40%, Scheme 2, method b). Since this process implies
the in situ formation of AcOH, the possibility of better yields
More relevant to the present work is the novel methodology
employed to synthesize aryl-CIDHPMs by a four-component
Biginelli-type reaction based on replacing the cyanoguanidine
with 2 equiv of cyanamide. It is worth mentioning that this pro-
tocol explored the use of cyanamide as a precursor of new urea-
type building blocks to obtain structurally diverse Biginelli
compounds, whereas most of the previously reported Biginelli
reactions involve urea, thiourea, isourea, or guanidine as

3374
R. Hulme et al. / Tetrahedron 64 (2008) 3372e3380
H
O
N
CN
HN
N
H
N
i= 50%
11
Method
i
7a
O
O
O
H
N
H
N
H
O
Methods
g, h
Methods
a, b, c d, e, f
O
EtO
N
EtO
N
2
CN
+
EtO
N
H
N
H
NH2
O
12
10a
8a
9
a= 5%, b= 40 %, c= 34 %
d= 0%, e= 11 %, f= 15%
g= 59%, h= 61%
Scheme 2. Synthesis of compounds 10a, 11, and 12 through the 4-CR protocol using diverse reaction conditions. Reagents and conditions: method a: HCl/EtOH,
method b: HCl/AcONa/EtOH, method c: AcOH/EtOH, method d: AcONa/EtOH, method e: acetate buffer (AcOH/AcONa/HCl, pH 5), method f: HCl/AcONa/
H2O, method g: TsOH/NH4Cl/EtOH, method h: AlCl3/EtOH, and method i: HCl/AcONa.
using AcOH alone was considered. However, the yield with
AcOH was lower (34%, Scheme 2, method c) than that with
method b, whereas no product was formed when the reaction
was carried out in the absence of either AcOH or concd hydro-
chloric acid (0%, Scheme 2, method d). Since these experimen-
tal results show that the reaction is pH dependent, an acetate
buffer was considered to be more appropriate. However, the
yield of 10a did not improve (11%, Scheme 2, Method e),
and unwanted by-products were observed, perhaps due to a
competing acid-catalyzed hydrolysis of cyanamide to urea,
known to happen under acetate buffer conditions.18
On the other hand, when the reaction was promoted with
pure cyanamide using the conditions of method b, the overall
yield was not improved (30%) and the corresponding product
was not observed as a precipitate at the end of the reaction
(similar to the results from method b). To obtain the desired
compound, it was necessary to concentrate and cool the mix-
ture for 24 h at 0 ꢀC.
To further improve the yield, other solvents, such as water
and methyl sulfoxide, were used without obtaining better re-
sults. When EtOH was substituted with water, the yields were
substantially lower (15%, Scheme 2, method f), which was
probably a consequence of a lack of reagent solubility and the
hydrolysis of cyanamide to urea, known to be more effective
in hydrochloric acid aqueous solution,18 while the reaction
with methyl sulfoxide led to no detectable production of 10a.
In an attempt to gain more complete understanding on the
behavior of this reaction, we employed modified conditions,
such as the use of TsOH/NH4Cl or AlCl3 as catalytic agent,
as well as solventless conditions in the presence of concd hy-
drochloric acid and AcONa. In the former case, the Biginelli
product, 5-ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyr-
imidin-2(1H)-one 12, was obtained at 59% with TsOH and
61% with AlCl3 (Scheme 2, methods g and h). This compound
was spectroscopically identical to a sample prepared through
the typical B-3CR protocol.3c When concd hydrochloric
acid/AcONa and solventless conditions were used, the iso-
lated product was N-(2-imino-6-phenyl-1,3,5-oxadiazinan-4-
ylidene) cyanamide 11 (50%, Scheme 2, method i). The
proposed structure was consistent with the spectroscopic data
1
obtained on the basis of NMR and MS experiments. The H
NMR spectrum showed the presence of four magnetically dif-
ferent protons that appear as two singlet signals at 10.47 and
9.68 ppm and two doublet signals at 8.63 (3J6,5¼2.4 Hz) and
5.63 (3J5,6¼2.4 Hz) ppm. These signals were appropriately as-
signed to the NH groups bonded to C-2, NH-3, NH-5, and H-6,
respectively. The multiple signals observed between 7.45 and
7.34 ppm were attributed to the five protons of the phenyl moi-
ety on C-6. The 13C NMR spectrum showed signals assigned to
two nonequivalent C]N groups at 156.6 (C-4) and 150.6 (C-
2) ppm; carbons observed at 140.4 (C-10), 128.9 (C-40), 128.8
(C-30), and 125.9 (C-20) ppm were appropriately assigned to
the phenyl group, and the signal that appeared at 63.3 ppm
was attributed to the methine carbon (C-6).
Comparing the reaction conditions summarized in Scheme
2, it is clear that method b constitutes the most efficient
method to prepare aryl-CIDHMs, while chemoselectivity
depends on the reaction conditions.
In order to explore the scope and limitations of this novel pro-
tocol, as well as to identify the effect induced by other substrates
on the formation of the aryl-CIDHPM, the reactions were per-
formed using various arenecarbaldehyde, heteroarenecarbalde-
hyde, arenedicarbaldehydes, aliphatic aldehydes, b-ketoesters,
and cyclicb-diketones, under the conditionsofmethod b (Table 1).
A similar behavior was observed in the reactions of arene-
carbaldehyde or heteroarenecarbaldehydes, 7beu, with the

R. Hulme et al. / Tetrahedron 64 (2008) 3372e3380
3375
Table 1
Synthesis of 4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine derivates
(10aeu)a
To determine the structural attributes of these products, sev-
eral spectroscopic experiments were performed (NMR, MS,
and IR). All the data are consistent with the aryl-CIDHPMs
10aeu structure. Thus, only the most important signals of
the 2-cyanoimino-3,4-dihydro-1H-pyrimidine fragment, which
is common to all aryl-CIDHPMs, are described. The 1H NMR
spectrum of 10b (taken as an example) showed two D2O-
exchangeable protons at d 10.30 and 9.24 ppm. The former
signal appeared as a doublet (3J1,3¼1.4 Hz) and was assigned
to NH-1, whereas the latter signal was observed as a doublet
of doublets (3J¼1.4 and 3.6 Hz) and was assigned to NH-3.
The doublet signal (3J4,3¼3.6 Hz) observed at 5.37 ppm was
assigned to H-4. The 13C NMR spectrum displayed signals
at 154.6, 116.2, and 53.0 ppm due to the imino, cyano, and
methine, as well as at 100.1 and 147.1 ppm due to the carbons
C-5 and C-6, respectively.
Further confirmation of the structure of this fragment is
provided by gHMBC. Long-range correlations were observed
between the carbon atom at 101.1 ppm (C-5) and the protons
at 10.36 (H-1), 9.24 (H-3), 2.32 (CH3), and 5.37 (H-4) ppm. In
conclusion, the spectroscopic data lead to the unambiguous
identification of 4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimi-
dine as tautomer A and rule out the other two possible tauto-
meric forms B or C (Fig. 2).
O
R2
8a-c
O
R1
R3
+
O
H
N
R2
N
N
R1
HCl / AcONa / EtOH
78 °C / 4 h
2
CN
R3
N
H
O
H
NH2
10a-u
7a-l, n-r
9
Entry R1
R2
R3
Product Yieldb (%)
1
C6H5
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
10a
10b
10c
10d
10e
10f
40
68
68
33
38
25
40
35
30
45
50
63
50
45
20
39
34
36
36
25
26
2
4-NO2eC6H4
2-NO2eC6H4
3-FeC6H4
3
4
5
2-CleC6H4
Piperonyl
6
7
4-BreC6H4
2-(CF3)eC6H4
3-(CF3)eC6H4
10g
10h
10i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
a
4-(OCHF2)eC6H4
2-(OCHF2)eC6H4
10j
10k
10l
5-NO2e2-(OCHF2)eC6H3 C2H5O
4-(NO2)eC6H4
CH3O
10m
10n
10o
10p
10q
10r
c
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
d
NO2
NO2
NO2
4-Pyridinyl
2-Furanyl
2-Thienyl
4´
6´
2´
O
O
O
C6H5
4-(NO2)eC6H4
2-(NO2)eC6H4
R2/R3¼(CH2)3 10s
R2/R3¼(CH2)3 10t
R2/R3¼(CH2)3 10u
H
N
H
H
N
N
EtO
N
EtO
EtO
3
5
CN
CN
CN
N
H
N
H
N
1
N
N
H
Reaction conditions: 7 (24 mmol), 8 (24 mmol), 9 (48 mmol), AcONa
H
(24 mmol), EtOH (20 mL), reflux, 4 h.
b
Overall yields.
4-[4-(2-Cyanoimino-5-ethoxycarbonyl-6-methyl-3,4-dihydro-1H-pyrimidin-
A
B
C
c
Figure 2. Possible tautomeric forms of 10b.
4-yl)-phenyl].
d
4-[3-(2-Cyanoimino-5-ethoxycarbonyl-6-methyl-3,4-dihydro-1H-pyrimidin-
4-yl)-phenyl].
Finally, a reasonable and appropriate mechanism is sug-
gested for this MCR, as outlined in Scheme 3. The cyclocon-
densation reaction of 7aeu and 8aec with 9 that produces the
aryl-CIDHPM derivatives 10aeu probably involves N-arylide-
necyanoguanidinium IIb as the key intermediate. The nucleo-
philic addition of cyanamide to the arenecarbaldehyde leads to
the aryl cyanoimino compound I, which forms the arylcyano-
iminium species Ia after protonation. A subsequent reaction
with a second molecule of cyanamide generates the intermedi-
ate II, which is in equilibrium with IIa. The cationic interme-
diate IIb may now undergo nucleophilic attack by the 1,
3-dicarbonyls 8aec, probably under its enol form, to yield
the intermediate III, which finally cyclizes to the aryl-
CIDHPMs 10aeu.
The proposed mechanism assumes the presence of cyan-
amide as a nucleophile in a pH range of 5e6 and rules out
the cyanamide hydrolysis to urea. This latter conclusion is
supported by 13C NMR experiments, as the 13C signal of cyan-
amide at 116.5 ppm remains unchanged. If hydrolysis occurs,
the carbon signal of the urea at 164.7 ppm would gradually ap-
pear. Also implicit in the proposed mechanism is that the
1,3-dicarbonylic compounds 8aec in the presence of cyan-
amide 9. The overall yields obtained for the corresponding
products 10beu range from modest to good (Table 1, entries
2e21). The highest yields of aryl-CIDHPMs corresponded to
the reactions between arenecarbaldehyde containing electron-
withdrawing substituents with ethyl acetoacetate (Table 1, en-
tries 2 and 3). However, when cyclohexane-1,3-dione was
used, the corresponding aryl-CIDHPMs 10teu yields were
rather poor (Table 1, entries 20 and 21). Conversely, when the
sterically more demanding isophthalaldehyde was used as reac-
tant, the yield of 10o was low (Table 1, entry 15). The use of
aliphatic aldehydes failed to give useful yields of the desired
products (data not shown). The reactivity trends found with
the cyclic and acyclic 1,3-dicarbonylic compounds are most
likely explained by their ketoeenol tautomeric content. In
this sense, ethyl acetoacetate is more easily enolized than cyclo-
hexane-1,3-dione because the former is stabilized by a very
favorable intramolecular hydrogen bond within a six-mem-
bered ring.

3376
R. Hulme et al. / Tetrahedron 64 (2008) 3372e3380
NH2CN
9
NH2CN
9
R1
R1
H
R1
R1
R1
R1
CN
H
H
N
O
H
N
H
OH
H
N
H
N
CN
CN
C
NH
H2N
N
HN
N
H
7a-l, n-r
Ia
IIa
I
II
OH
R2
R3
8a-c
R1
O
R1
O
R1
R1
O
O
H
H
H
R2
N
R2
N
H
N
NH
R2
H
CN
CN
CN
CN
N
R3
N
H
N
R3
HO
N
H
N
HN
N
H
R3
O
H2N
III
IIb
IIIa
10a-u
Scheme 3. Proposed mechanism to obtain aryl-CIDHPMs.
presence of the enol form of 1,3-dicarbonyl favors a conjugate
attack on either the N-arylidenecyanoguanidine species IIa or
the carbocationic form IIb to subsequently yield the corre-
sponding aryl-CIDHPMs. In this regard, the postulation of
IIb as an intermediate would also account for the lack of re-
activity observed with aliphatic aldehydes. Compared to aro-
matic aldehydes, aliphatic aldehydes are less efficient in
stabilizing the intermediate carbocation IIb, which ultimately
results in a less efficient cyclocondensation reaction to gener-
ate aliphatic-CIDHPMs.
One important feature of the present protocol is the ability to
tolerate variation in two of the four components, making it an
MCR of moderate variability. Furthermore, cyclic b-diketone
and aromatic aldehyde can also be employed as substrates, in
addition to the b-ketoester and aryl dialdehyde or heterocyclic
aldehyde, without causing a substantial decrease in the overall
yield of aryl-CIDHPM. Interestingly, all aromatic aldehydes
that carry either electron-donating or electron-withdrawing
substituents reacted under this 4-CR protocol, allowing the pro-
duction of aryl-CIDHPM in high purity and at low to moderate
yields. An additional feature of this procedure is the tolerance
of acid-sensitive aldehydes (e.g., furfural 7q) and functional
groups (e.g., acetal 7f). Finally, many of the pharmacologically
relevant substitution patterns on the 4-phenyl ring can be intro-
duced with high efficiency.
4. Experimental section
4.1. General
Melting points (uncorrected) were determined with a Fishere
Johns apparatus. IR spectra were recorded on a PerkineElmer
1600 spectrophotometer. 1H, 13C, DEPT, COSY, HETCOR,
and gHMBC spectra were recorded on a Varian Mercury 300 in-
strument in DMSO-d6. Mass spectra (MS) and high-resolution
mass spectrometry (HRMS) were obtained on an MStation
JMS-700 JEOL spectrometer. Analytical thin-layer chromatog-
raphy (TLC) was performed using Kieselgel 60 F254 silica gel
plates (Merck, Darmstadt, Germany). All reagents, except 2-di-
fluoromethoxy-5-nitrobenzaldehyde that was prepared accord-
ing to protocols described previously,10a as well as solvents
wereofreagent gradefromAldrichandwereusedwithout further
treatment.
4.2. General procedures
4.2.1. 2-Cyanoimino-dihydro-1H-pyrimidines (10aeu)
A suspension of the corresponding arenecarbaldehydes
7ael, ner (24 mmol), 1,3-dicarbonyls 8aec (24 mmol), cyan-
amide 9 (50% in water, 48 mmol), sodium acetate (24 mmol),
and concd hydrochloric acid (37%, 0.5 mL) in ethanol
(20 mL) was stirred and heated at reflux for 4 h. After, the
solvent was removed under vacuum, the crude product was
filtered and the solid obtained was recrystallized from ethanol
to give the pure products.
3. Conclusion
A novel synthesis based on a four-component Biginelli-
type reaction has been described. The novelty of this multi-
component reaction is the use of cyanamide as a convenient
building block to obtain Aryl-CIDHPMs in a very simple
and practical way. Furthermore, mild reaction conditions, tol-
erance of acid-sensitive functional groups, facile purification,
moderate overall yields, and flexibility make this method an
attractive tool to synthesize molecules featuring 2-cyanoi-
mino-3,4-dihydro-1H-pyrimidinic moieties, which might be
useful synthons in organic chemistry or important scaffolds
in the synthesis of more elaborate compounds with interesting
pharmacological properties.
4.2.1.1. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-phenyl-
3,4-dihydro-1H-pyrimidine (10a). Yield 40%; mp 259e
261 ꢀC; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.09 (t,
J¼7.0 Hz, 3H), 2.30 (s, 3H), 4.01 (q, J¼7.0 Hz, 2H), 5.25
(s, 1H), 7.23e7.40 (m, 5H), 9.14 (s, 1H), 10.16 (s, 1H); 13C
NMR (75 MHz, DMSO-d6/TMS): d 14.0, 17.3, 53.2, 59.7,
101.2, 116.5, 126.4, 127.9, 128.7, 143.2, 146.0, 154.8,
164.7; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N),
3297 (NH) cmꢁ1; MS m/z 284; HRMS (EI, 70 eV) found:
284.1282, calcd for C15H16O2N4: 284.1273.

R. Hulme et al. / Tetrahedron 64 (2008) 3372e3380
3377
4.2.1.2. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(4-nitro-
phenyl)-3,4-dihydro-1H-pyrimidine (10b). Yield 68%; mp
263e265 ꢀC; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.08 (t,
J¼7.0 Hz, 3H), 2.32 (s, 3H), 4.0 (m, J¼7.0 Hz, 2H), 5.37 (d,
J¼3.6 Hz, 1H), 7.53 (d, J¼8.7 Hz, 2H), 8.24 (d, J¼8.7 Hz,
2H), 9.23 (dd, J¼3.0, 2.1 Hz, 1H), 10.31 (d, J¼1.5 Hz, 1H);
13C NMR (75 MHz, DMSO-d6/TMS): d 14.0, 17.4, 53.0,
59.9, 100.1, 116.2, 124.1, 128.0, 147.1, 150.1, 154.6, 164.4;
IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297
(NH) cmꢁ1; MS m/z 329; HRMS (EI, 70 eV) found:
329.1127, calcd for C15H15O4N5: 329.1124.
(C]O), 2174 (C^N), 3297 (NH) cmꢁ1; MS m/z 328; HRMS
(EI, 70 eV) found: 328.1177, calcd for C16H16O4N4: 328.1172.
4.2.1.7. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(4-bromo-
phenyl)-3,4-dihydro-1H-pyrimidine (10g). Yield 40%; mp
1
264e265 ꢀC; H NMR (300 MHz, DMSO-d6/TMS): d 1.08
(t, J¼7.0 Hz, 3H), 2.30 (s, 3H), 4.10 (q, J¼7.0 Hz, 2H), 5.23
(s, 1H), 7.19 (d, J¼8.4 Hz, 2H), 7.57 (d, J¼8.0 Hz, 2H),
9.17 (br s, 1H), 10.07 (br s, 1H); 13C NMR (75 MHz,
DMSO-d6/TMS): d 14.0, 17.3, 52.8, 59.8, 100.6, 116.3,
121.0, 128.7, 131.6, 142.5,146.4, 154.6, 164.5; IR (KBr)
1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cmꢁ1
;
4.2.1.3. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-nitro-
phenyl)-3,4-dihydro-1H-pyrimidine (10c). Yield 68%; mp
205e207 ꢀC; 1H NMR (300 MHz, DMSO-d6/TMS): d 0.93 (t,
J¼7.0 Hz, 3H), 2.32 (s, 3H), 3.87 (q, J¼7.0 Hz, 2H), 6.04 (d,
J¼2.7 Hz, 1H), 7.50e7.60 (m, 2H), 7.76 (ddd, J¼8.7, 7.8,
1.2 Hz, 1H), 7.95 (dd, J¼8.4, 1.2 Hz, 1H), 9.16 (d, J¼2.7 Hz,
1H), 10.27 (s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS):
d 13.7, 17.3, 48.6, 59.7, 100.1, 115.9, 124.4, 129.3, 129.4,
134.3, 137.8,147.0, 147.4, 153.9, 164.1; IR (KBr) 1641
(C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cmꢁ1; MS
m/z 329; HRMS (EI, 70 eV) found: 329.1198, calcd for
C15H15O4N5: 329.1124.
MS m/z 362; HRMS (EI, 70 eV) found: 362.0381, calcd for
C15H15O2N4Br: 362.0378.
4.2.1.8. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-trifluo-
romethylphenyl)-3,4-dihydro-1H-pyrimidine
(10h). Yield
35%; mp 210e211 ꢀC; 1H NMR (300 MHz, DMSO-d6/TMS):
d 0.91 (t, J¼7.2 Hz), 2.38 (s, 3H,), 3.89 (q, J¼7.2 Hz, 2H),
5.70 (s, 1H), 7.46e7.58 (m, 2H), 7.66e7.76 (m, 2H), 8.61 (s,
1H), 10.28 (s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS):
d 13.6, 17.8, 50.7, 60.5 101.4, 115.2, 124.2 (1JCF¼272.1 Hz),
126.5 (3JCF¼5.7 Hz), 127.1 (2JCF¼30.6 Hz), 128.3, 128.9,
133.3, 139.2, 145.5, 154.2, 164.0; IR (KBr) 1641 (C]N),
1679 (C]O), 2174 (C^N), 3297 (NH) cmꢁ1; MS m/z 352;
HRMS (EI, 70 eV) found: 352.1140, calcd for C16H15O2N4F3:
352.1147.
4.2.1.4. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(3-fluro-
phenyl)-3,4-dihydro-1H-pyrimidine (10d). Yield 33%; mp
1
270e272 ꢀC; H NMR (300 MHz, DMSO-d6/TMS): d 1.08
(t, J¼7.2 Hz, 3H), 2.30 (s, 3H), 4.10 (q, J¼7.2 Hz, 2H), 5.27
(s, 1H), 7.19 (d, J¼8.4 Hz, 2H), 7.57 (d, J¼8.0 Hz, 2H),
9.33 (br s, 2H); 13C NMR (75 MHz, DMSO-d6/TMS):
d 14.0, 17.3, 52.8, 59.8, 100.5, 113.3 (2JCF¼21.6 Hz), 114.7
(2JCF¼20.4 Hz), 116.3, 122.4, 130.8 (3JCF¼7.9 Hz), 145.9,
146.7, 154.7, 163.7 (1JCF¼275.0 Hz), 164.5; IR (KBr) 1641
(C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cmꢁ1; MS
m/z 302; HRMS (EI, 70 eV) found: 302.1197, calcd for
C15H15O2N4F: 302.1179.
4.2.1.9. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(3-trifluo-
romethylphenyl)-3,4-dihydro-1H-pyrimidine (10i). Yield 30%;
mp 267e268 ꢀC; 1H NMR (300 MHz, DMSO-d6/TMS):
d 1.05(t, J¼7.0 Hz, 3H), 2.32 (s, 3H,), 3.99 (q, J¼7.0 Hz,
2H), 5.35 (s, 1H), 7.50e7.71 (m, 4H), 9.22 (br s, 1H), 10.15
(br s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 13.8,
17.3, 53.1, 59.8, 100.3, 116.2, 123.5 (3JCF¼4.5 Hz), 124.1
(3JCF¼3.45 Hz), 129.0 (2JCF¼31.7 Hz), 130.1, 130.4, 144.5,
146.8, 154.6, 164.4; IR (KBr) 1641 (C]N), 1679 (C]O),
2174 (C^N), 3297 (NH) cmꢁ1; MS m/z 352; HRMS (EI,
70 eV) found: 352.1134, calcd for C16H15O2N4F3: 352.1147.
4.2.1.5. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-chloro-
phenyl)-3,4-dihydro-1H-pyrimidine (10e). Yield 38%; mp
1
243e245 ꢀC; H NMR (300 MHz, DMSO-d6/TMS): d 1.02
4.2.1.10. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(4-difluo-
(t, J¼7.0 Hz, 3H), 2.31 (s, 3H), 3.93 (q, J¼7.0 Hz, 2H), 5.68
(d, J¼0.9 Hz, 1H), 7.25e7.53 (m, 5H), 9.28 (br s, 2H); 13C
NMR (75 MHz, DMSO-d6/TMS): d 13.9, 17.2, 51.4, 59.6,
79.2, 100.0, 116.2, 127.8, 129.7, 129.8, 131.9, 140.3, 146.5,
154.0, 164.4; IR (KBr) 1641 (C]N), 1679 (C]O), 2174
romethoxyphenyl)-3,4-dihydro-1H-pyrimidine
(10j). Yield
1
45%; mp 209e211 ꢀC; H NMR (300 MHz, DMSO-d6/TMS):
d 1.02 (t, J¼6.9 Hz, 3H), 2.31 (s, 3H), 4.01 (q, J¼7.0 Hz, 2H),
5.26 (br s, 1H), 7.18 (d, J¼8.7 Hz, 2H), 7.22 (t, 2JHF¼74.1 Hz,
1H), 7.29 (d, J¼8.7 Hz, 2H), 9.14 (br s, 1H), 10.20 (s, 1H); 13
C
(C^N), 3297 (NH) cmꢁ1
; HRMS (EI, 70 eV) found:
318.0875, calcd for C15H15O2N4Cl: 318.0884.
NMR (75 MHz, DMSO-d6/TMS): d 14.0, 17.3, 52.6, 59.8,
1
100.9, 116.3 (t, JCF¼256.2 Hz), 116.4, 118.9, 128.2, 140.1,
146.3, 150.5, 154.7, 164.6; IR (KBr) 1641 (C]N), 1679
(C]O), 2174 (C^N), 3297 (NH) cmꢁ1; MS m/z 350; HRMS
(EI, 70 eV)found:350.1197, calcdforC16H16O3N4F2:350.1190.
4.2.1.6. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-piperon-
yl-3,4-dihydro-1H-pyrimidine (10f). Yield 25%; mp 264e
266 ꢀC; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.09 (t,
J¼7.0 Hz, 3H), 2.30 (s, 3H), 4.01 (q, J¼7.0 Hz, 2H), 5.17 (s,
1H), 6.00 (s, 1H), 6.68e6.90 (m, 3H), 9.08 (s, 1H), 10.15 (s,
1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 14.0, 17.3, 52.9,
59.7, 101.1, 101.2, 106.8, 108.2, 116.5, 119.7, 137.0, 146.1,
146.9, 147.4, 154.6, 164.7; IR (KBr) 1641 (C]N), 1679
4.2.1.11. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-difluo-
romethoxyphenyl)-3,4-dihydro-1H-pyrimidine
(10k). Yield
50%; mp 247e249 ꢀC; 1H NMR (300 MHz, DMSO-d6/
TMS): d 1.04 (t, J¼6.9 Hz, 3H), 2.28 (s, 3H), 3.93 (q,
J¼7.0 Hz, 2H), 5.54 (s, 1H), 7.15e7.41 (m, 4H), 7.21 (dd,

3378
R. Hulme et al. / Tetrahedron 64 (2008) 3372e3380
2JHF¼75.0, 72.9 Hz, 1H), 8.95 (br s, 1H), 10.14 (br s, 1H); 13
C
4.2.1.16. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(4-pyri-
NMR (75 MHz, DMSO-d6/TMS): d 13.8, 17.2, 49.9, 59.6,
dinyl)-3,4-dihydro-1H-pyrimidine (10p). Yield 39%; mp
1
1
99.5, 116.4, 116.5 (t, JCF¼255.1 Hz), 117.3, 125.0, 129.6,
249e251 ꢀC; H NMR (300 MHz, DMSO-d6/TMS): d 1.10
130.1, 133.3, 146.3, 149.0, 154.2, 164.5; IR (KBr) 1641
(C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cmꢁ1; MS
m/z 350; HRMS (EI, 70 eV) found: 350.1176, calcd for
C16H16O3N4F2: 350.1190.
(t, J¼7.0 Hz, 3H), 2.30 (s, 3H), 4.10 (q, J¼7.0 Hz, 2H), 5.26
(s, 1H), 7.23 (d, J¼4.8 Hz, 2H), 8.57 (d, J¼4.8 Hz, 2H),
9.24 (s, 1H), 10.30 (s, 1H); 13C NMR (75 MHz, DMSO-d6/
TMS): d 14.0, 17.4, 52.3, 59.9, 99.9, 116.2, 121.4, 147.2,
150.2, 151.1, 154.9, 164.5; IR (KBr) 1641 (C]N), 1679
(C]O), 2174 (C^N), 3297 (NH) cmꢁ1; MS m/z 285;
HRMS (EI, 70 eV) found: 285.1215, calcd for C14H15O2N5:
285.1226.
4.2.1.12. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-difluo
romethoxy-5-nitrophenyl)-3,4-dihydro-1H-pyrimidine
(10l).
1
Yield 63%; mp 249e250 ꢀC; H NMR (300 MHz, DMSO-
d6/TMS): d 1.02 (t, J¼6.9 Hz, 3H), 2.27 (s, 3H), 3.91 (q,
J¼7.0 Hz, 2H), 5.59 (s, 1H), 7.43 (d, J¼9.0 Hz, 1H), 7.50
4.2.1.17. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-fura-
nyl)-3,4-dihydro-1H-pyrimidine (10q). Yield 34%; mp 244e
245 ꢀC; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.12 (t,
J¼7.0 Hz, 3H), 2.25 (s, 3H), 4.08 (q, J¼7.0 Hz, 2H), 5.30
(d, J¼2.7 Hz, 1H), 6.16 (d, J¼3.3 Hz, 1H), 6.37 (dd, J¼3.3,
1.8 Hz, 1H), 7.58 (dd, J¼1.8, 0.6 Hz, 1H), 9.15 (d,
J¼2.7 Hz, 1H), 10.22 (s, 1H); 13C NMR (75 MHz, DMSO-
d6/TMS): d 14.1, 17.3, 47.0, 59.8, 98.8, 106.4, 110.5, 116.3,
142.8, 147.0, 154.2, 155.3, 164.4; IR (KBr) 1641 (C]N),
1679 (C]O), 2174 (C^N), 3297 (NH) cmꢁ1; MS m/z 274;
HRMS (EI, 70 eV) found: 274.1052, calcd for C13H14O3N4:
274.1066.
2
(dd, JHF¼73.5, 72.9 Hz, 1H), 8.08 (d, J¼3.0 Hz, 1H), 8.29
(dd, J¼9.0, 2.7 Hz, 1H), 8.97 (br s, 1H), 10.28 (br s, 1H);
13C NMR (75 MHz, DMSO-d6/TMS): d 13.6, 17.1, 51.1,
1
59.5, 97.7, 115.7 (t, JCF¼257.3 Hz), 116.1, 117.0, 125.2,
125.9, 133.6, 143.1, 147.2, 153.9, 154.1, 164.1; IR (KBr)
;
1641 (C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cmꢁ1
MS m/z 395; HRMS (EI, 70 eV) found: 395.1041, calcd for
C16H15O5N5F2: 395.1041.
4.2.1.13. 2-Cyanoimino-5-methoxycarbonyl-6-methyl-4-(4-nitro-
phenyl)-3,4-dihydro-1H-pyrimidine (10m). Yield 50%; mp
1
238e240 ꢀC; H NMR (300 MHz, DMSO-d6/TMS): d 2.32
(s, 3H), 3.55 (s, 3H), 5.38 (s, 1H), 7.52 (d, J¼8.4 Hz, 2H),
8.23 (d, J¼8.7 Hz, 2H), 9.27 (s, 1H), 10.34 (s, 1H); 13C
NMR (75 MHz, DMSO-d6/TMS): d 17.4, 51.3, 52.8, 99.9,
116.2, 124.1, 127.9, 147.1, 147.3, 149.9, 154.7, 164.9; IR
(KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N), 3297
(NH) cmꢁ1; MS m/z 315; HRMS (EI, 70 eV) found:
315.0954, calcd for C14H13O4N5: 315.0968.
4.2.1.18. 2-Cyanoimino-5-ethoxycarbonyl-6-methyl-4-(2-thien-
yl)-3,4-dihydro-1H-pyrimidine (10r). Yield 36%; mp 255e
256 ꢀC; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.15 (t,
J¼7.0 Hz, 3H), 2.28 (s, 3H), 4.08 (q, J¼7.0 Hz, 2H), 5.52
(s, 1H), 6.92 (d, J¼3.6 Hz, 1H), 6.97 (dd, J¼4.8, 3.6 Hz,
1H), 7.42 (d, J¼4.5 Hz, 1H), 9.31 (s, 1H), 10.31 (s, 1H);
13C NMR (75 MHz, DMSO-d6/TMS): d 14.1, 17.2, 48.5,
59.9, 101.7, 116.3, 124.3, 125.5, 127.0, 146.5,146.7, 155.0,
164.4; IR (KBr) 1641 (C]N), 1679 (C]O), 2174 (C^N),
3297 (NH) cmꢁ1; MS m/z 290; HRMS (EI, 70 eV) found:
290.0840, calcd for C13H14O2N4S: 290.0837.
4.2.1.14. 2-Cyanoimino-4-[4-(2-cyanoimino-5-ethoxycarbonyl-
6-methyl-3,4-dihydro-1H-pyrimidin-4-yl)-phenyl]-5-ethoxycar-
bonyl-6-methyl-3,4-dihydro-1H-pyrimidine (10n). Yield 45%;
mp 303e305 ꢀC; 1H NMR (300 MHz, DMSO-d6/TMS):
d 1.08 (t, J¼7.2 Hz, 3H), 1.09 (t, J¼7.2 Hz, 3H), 2.29 (s,
6H), 4.01 (q, J¼7.2 Hz, 4H), 5.23 (s, 2H), 7.23 (s, 4H), 9.08
(s, 2H), 10. 13 (s, 2H); 13C NMR (75 MHz, DMSO-d6/
TMS): d 14.6, 18.0, 53.7, 59.4, 101.7, 117.0, 143.5, 146.7,
155.4, 165.3; IR (KBr) 1641 (C]N), 1679 (C]O), 2174
(C^N), 3297 (NH) cmꢁ1; MS m/z 490; HRMS (EI, 70 eV)
found: 490.2079, calcd for C24H26O4N8: 490.2077.
4.2.1.19. [5-Oxo-4-phenyl-3,4,5,6,7,8-hexahydroquinazolin-
1
2(1H)-ylidene]cyanamide (10s). Yield 36%; mp 300 ꢀC; H
NMR (300 MHz, DMSO-d6/TMS): d 1.72e206 (m, 2H),
2.20e2.40 (m, 2H), 2.45e2.65 (m, 2H), 5.26 (d, J¼3.6 Hz,
1H), 7.19e7.36 (m, 5H), 9.12 (d, J¼3.6 Hz, 1H), 10.46 (s,
1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 20.4, 25.4,
36.2, 50.9, 109.5, 116.2, 126.4, 127.7, 128.6, 143.0, 152.1,
154.7, 193.6; IR (KBr) 1641 (C]N), 1679 (C]O), 2174
(C^N), 3297 (NH) cmꢁ1; MS m/z 266; HRMS (EI, 70 eV)
found: 266.1173, calcd for C15H14ON4: 266.1168.
4.2.1.15. 2-Cyanoimino-4-[3-(2-cyanoimino-5-ethoxycarbonyl-
6-methyl-3,4-dihydro-1H-pyrimidin-4-yl)-phenyl]-5-ethoxycar-
bonyl-6-methyl-3,4-dihydro-1H-pyrimidine (10o). Yield 20%;
mp 315e320 ꢀC; 1H NMR (300 MHz, DMSO-d6/TMS):
d 1.05 (t, J¼7.2 Hz, 3H), 1.09 (t, J¼7.2 Hz, 3H), 2.29 (s,
6H), 3.99 (q, J¼7.2 Hz, 4H), 5.23 (s, 2H), 7.23 (s, 4H), 9.12
(s, 2H), 10.15 (s, 2H); 13C NMR (75 MHz, DMSO-d6/TMS):
d 14.0, 17.2, 53.2, 59.7, 101.1, 116.4, 124.3, 124.5, 126.0,
128.9, 143.7, 146.1, 154.7, 154.8, 164.5; IR (KBr) 1641
(C]N), 1679 (C]O), 2174 (C^N), 3297 (NH) cmꢁ1; MS
m/z 490; HRMS (EI, 70 eV) found: 490.2069, calcd for
C24H26O4N8: 490.2077.
4.2.1.20. [4-(4-Nitrophenyl)-5-oxo-3,4,5,6,7,8-hexahydroquin-
azolin-2(1H)-ylidene]cyanamide (10t). Yield 25%; mp
1
300 ꢀC; H NMR (300 MHz, DMSO-d6/TMS): d 1.65e2.05
(m, 2H), 2.10e2.40 (m, 2H), 2.45e2.70 (m, 2H), 5.39 (s,
1H), 7.51 (d, J¼9.0 Hz, 2H), 8.21 (d, J¼8.7 Hz, 2H), 9.22
(s, 1H), 10.59 (s, 1H); 13C NMR (75 MHz, DMSO-d6/TMS):
d 20.3, 25.5, 36.1, 50.9, 108.5, 115.9, 123.9, 127.9, 146.9,
150.0, 152.8, 154.6, 193.5; IR (KBr) 1641 (C]N), 1679
(C]O), 2174 (C^N), 3297 (NH) cmꢁ1; MS m/z 311;

R. Hulme et al. / Tetrahedron 64 (2008) 3372e3380
3379
HRMS (EI, 70 eV) found: 311.1006, calcd for C15H13O3N5:
311.1018.
References and notes
1. (a) Domling, A. Chem. Rev. 2006, 106, 17e89; (b) Tietze, L. F.; Rackel-
¨
mann, N. Pure Appl. Chem. 2004, 11, 1967e1983; (c) Weber, L.; Illgen,
4.2.1.21. [4-(2-Nitrophenyl)-5-oxo-3,4,5,6,7,8-hexahydroquin-
azolin-2(1H)-ylidene]cyanamide (10u). Yield 26%; mp 270e
275 ꢀC; 1H NMR (300 MHz, DMSO-d6/TMS): d 1.65e2.0
(m, 2H), 2.05e2.35 (m, 2H), 2.41e2.65 (m, 2H), 6.01 (s,
1H), 7.19e7.36 (m, 5H), 9.13 (s, 1H), 10.56 (s, 1H); 13C
NMR (75 MHz, DMSO-d6/TMS): d 20.4, 25.4, 36.0, 47.5,
108.5, 115.7, 124.1, 129.0, 129.7, 133.8, 137.2, 147.8,
152.4, 153.9, 193.4; IR (KBr) 1641 (C]N), 1679 (C]O),
2174 (C^N), 3297 (NH) cmꢁ1; MS m/z 312; HRMS (EI,
70 eV) found: 312.1100, calcd for C15H14O3N5: 311.2954.
K.; Almstetter, M. Synlett 1999, 366e374; (d) Domling, A.; Ugi, I.
¨
Angew. Chem., Int. Ed. 2000, 39, 3168e3210; (e) Tietze, L. F. Chem.
Rev. 1996, 96, 115e136; (f) Domling, A.; Ugi, I.; Horl, W. Endeavour
¨
¨
1994, 18, 115e122; (g) Kolb, J.; Beck, B.; Almstetter, M.; Heck, S.;
Herdtweck, E.; Domling, A. Mol. Divers. 2003, 6, 297e313; (h) Heath-
¨
cock, C. H. Angew. Chem., Int. Ed. Engl. 1992, 31, 665e681; (i) Domling,
¨
A.; Ugi, I.; Werner, B. Molecules 2003, 8, 53e66.
2. (a) Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1e82; (b) Radzis-
zewski, B. Ber. Dtsch. Chem. Ges. 1882, 15, 1499; (c) Bon, R. S.; Vliet,
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Benzaldehyde 7a (24 mmol), cyanamide 9 (50% in water,
48 mmol), sodium acetate (24 mmol), and concd hydrochloric
acid (37%, 0.5 mL, pH w5e6) were stirred and heated in the
absence of solvent at 90 ꢀC for 2 h. After being concentrated
under vacuum, the residue was filtered, resuspended in hot eth-
anol, and cooled. The precipitate was filtered to yield the pure
product: yield 50%; mp 300 ꢀC; 1H NMR (300 MHz, DMSO-
d6/TMS): d 5.63 (d, J¼2.4 Hz, 1H), 7.30e7.47 (m, 5H), 8.63
(d, J¼2.4 Hz, 1H), 9.68 (br s, 1H), 10.47 (br s, 1H); 13C NMR
(75 MHz, DMSO-d6/TMS): d 63.3, 115.7, 125.9, 128.8, 128.9,
140.4, 150.6, 156.6; MS m/z 215; HRMS (EI, 70 eV) found:
215.0809, calcd for C10H9ON5: 215.0807.
´
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Benzaldehyde 9a (24 mmol), cyanamide 9 (50% in water,
48 mmol), ammonium chloride (24 mmol), and p-toluenesul-
fonic acid (24 mmol) in ethanol (20 mL) were stirred and heated
to reflux for 2 h. Subsequently, ethyl acetate 8a (24 mmol) was
added to the mixture, which was heated and stirred for 3 h, and
then concentrated, cooled, and filtered. The residue was washed
with either isopropyl alcohol or ethanol and ether. The solid was
suspended in acetone and filtered. The product was collected
after elimination of acetone and recrystallized from ethanol
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1
obtaining the pure product: yield 59%; mp 203e205 ꢀC; H
NMR (300 MHz, DMSO-d6/TMS): d 1.08 (t, J¼6.9 Hz, 3H),
2.24 (s, 3H), 3.97 (q, J¼7.2 Hz, 2H), 5.13 (d, J¼3.3 Hz, 1H),
7.0e7.50 (m, 5H), 7.77 (dd, J¼3.3 and 2.1 Hz, 1H), 9.22 (d,
J¼1.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6/TMS): d 14.1,
17.8, 53.9, 59.2, 99.2, 126.2, 127.3, 128.4, 144.8, 148.4,
152.1, 165.3; MS (EI, 70 eV) m/z 260.2908.
Acknowledgements
F.D. would like to acknowledge CONACyT (Grant 44038-
Q) and SIP/IPN (Grant 20060055, 20070617) for financial
support. R.H. is grateful to CONACyT for a graduate scholar-
ship and a Research Fellowship IN1-69, FESC-UNAM. I.V.-H.
is a fellow of the EDI/IPN and COFAA/IPN programs. The au-
thors are grateful to Ms. Ana P. Contreras Rojas (McGill Uni-
versity, Montreal Canada) for reviewing the manuscript.
12. Shutalev, A. D. Fourth International Electronic Conference Synthetic
Organic Chemistry ECSO-4, 2000; pp 1e30.
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