Reactivity of the pyrimidine nitrogen atom toward an acetal moiety: Formation of 3-ethoxy-2,3-dihydroimidazo[1,2-c ]pyrimidines by intramolecular cyclization of n -(2,2-diethoxyethyl)pyrimidine-4-amines

Article abstract of DOI:10.1055/s-0033-1339350

A new protocol was developed for the synthesis of 2,3-dihydroimidazo[1,2-c] pyrimidines, based on an intramolecular reaction between a pyrimidine nitrogen atom and an acetal moiety in the presence of boron trifluoride etherate. The method was expanded to permit the synthesis of the triheterocyclic imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine system.

Full text of DOI:10.1055/s-0033-1339350

2438▌
PAPER
paper
Reactivity of the Pyrimidine Nitrogen Atom toward an Acetal Moiety:
Formation of 3-Ethoxy-2,3-dihydroimidazo[1,2-c]pyrimidines by Intramole-
cular Cyclization of N-(2,2-Diethoxyethyl)pyrimidine-4-amines
Intramolecular Cyclization of N-(2,2-Diethoxyethyl)pyrimidine-4-amines
Robertas Juskenas, Viktoras Masevicius, Sigitas Tumkevicius*
Department of Organic Chemistry, Vilnius University, Naugarduko 24, 03225 Vilnius, Lithuania
Fax +370(5)2330987; E-mail: sigitas.tumkevicius@chf.vu.lt
Received: 03.04.2013; Accepted after revision: 13.06.2013
erocycles containing N,O-acetal fragments. This reaction
Abstract: A new protocol was developed for the synthesis of 2,3-
should unlock a potential for further functionalization of
dihydroimidazo[1,2-c]pyrimidines, based on an intramolecular re-
the newly formed ring. However, only a few examples of
action between a pyrimidine nitrogen atom and an acetal moiety in
the presence of boron trifluoride etherate. The method was expand-
this type of reaction have been described.12 Here, we re-
ed to permit the synthesis of the triheterocyclic imidazo[1,2-c]pyr- port a novel method for the synthesis of 2,3-dihydroimid-
azolo[4,3-e]pyrimidine system.
azo[1,2-c]pyrimidines by the intramolecular reaction
between the pyrimidine nitrogen atom and the acetal
group in N-(2,2-diethoxyethyl)pyrimidine-4-amines.
Key words: acetals, cyclizations, heterocycles, polycycles, pyrimi-
dines, imidazoles
Generally, we introduced an acetal moiety by nucleophilic
substitution of chlorine in chloropyrimidines by (2,2-
diethoxyethyl)amine. Thus, pyrimidine 2a, prepared from
the dichloropyrimidine 1, was treated with dimethylamine
to afford the dimethylamino derivative 2b, whereas the
methoxy analogue 2c was similarly prepared from pyrim-
idine 3. Treatment of pyrimidines 2a and 2c with boron
trifluoride etherate in dichloromethane, followed by a
work-up with an aqueous sodium bicarbonate solution
gave the corresponding aldehydes 4a and 4c. Spectro-
scopic (NMR and HRMS) and elemental analyses of these
compounds were consistent with the proposed structures.
In the IR spectra of 4a and 4c, instead of one strong ab-
sorption band for the carbonyl group, two absorption
bands of medium intensity were observed in the region
1710−1750 cm−1. Under the same reaction conditions, the
dimethylamino derivative 2b gave the desired 2,3-dihy-
droimidazo[1,2-c]pyrimidine 5b (Scheme 1). We found
that 2.5 equivalents of boron trifluoride etherate were re-
quired to achieve full conversion of compounds 2a−c in
the two reactions. In an attempt to prevent the formation
of aldehydes, we examined a variety of nonaqueous work-
up conditions using bases as such as carbonates, potassi-
um phosphate, or amines, but with no success.
The chemistry of heterocycles can be very useful, and it
has long been studied in detail. As a result of the extensive
use of various heterocyclic derivatives in pharmacology,1
in light-emitting technologies,2 or as dyes,3 there is great
interest in this branch of chemistry. A search for novel,
more efficient, synthetic paths to heterocycles and their
functionalized derivatives is crucial for the development
of the aforementioned technologies and of heterocyclic
chemistry itself.
Fused heterocyclic systems containing the 2,3-dihydro-
imidazo[1,2-c]pyrimidine scaffold exhibit a diversity of
biological activities. Such compounds are known to dis-
play antipsychotic,4 antidepressant,5 antihypertensive,6
and antiparasitic7 activities, and they are useful as adenos-
ine receptors antagonists8 or for treatment of cancer.9 Re-
cently, 2,3-dihydroimidazo[1,2-c]pyrimidine derivatives
have been found to exhibit antimycobacterial activities.10
The main method that is used for the synthesis of these
compounds involves the intramolecular cyclization of 4-
[(2-hydroxyethyl)amino]pyrimidines in the presence of a
chlorinating agent.5,10,11 Other methods4,6 for the forma-
tion of a 2,3-dihydroimidazole ring on an existing pyrim-
idine framework are scarce and they are limited to the
formation of derivatives bearing alkyl or aryl groups on
the carbon atoms of the imidazole ring.
To determine whether the aldehydes 4a−c were formed
during the isolation procedure or whether, in fact, no
cyclization involving a pyrimidine nitrogen atom had
occurred, we attempted to isolate the 2,3-dihydroimid-
azo[1,2-c]pyrimidinium salt intermediates. The reaction
conditions for the reactions of 2a−c with boron trifluoride
were the same as those described above. After the cycliza-
tion had occurred (as determined by thin-layer chroma-
tography), the solvent was removed and salts 6a−c were
precipitated with diethyl ether (Scheme 2). NMR spectra
of these compounds were recorded in acetonitrile-d3, as
they were unstable in DMSO-d6. The presence of two
peaks at −151.69 ppm and −151.75 ppm in the 19F NMR
spectra of 6a−c suggested that the counterion was tetra-
The acetal scaffold is usually used in organic synthesis as
means of protecting a carbonyl group or as a precursor of
this group. In the absence of an external nucleophile, how-
ever, an acetal group can participate in intramolecular cy-
clization reactions. If an acetal group is present on a side
chain in a position adjacent to a pyridine-type nitrogen
atom, a cyclization reaction can occur to afford fused het-
SYNTHESIS 2013, 45, 2438–2446
Advanced online publication: 22.07.2013
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DOI: 10.1055/s-0033-1339350; Art ID: SS-2013-T0249-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Intramolecular Cyclization of N-(2,2-Diethoxyethyl)pyrimidine-4-amines
2439
CN
Cl
CN
N,O-acetals, should be stable, as it is known that electron
acceptors, such as acyl groups, on the nitrogen atom sta-
bilize N,O-acetals.14
CN
H
N
H
R2
N
Cl
Cl
i
N
N
N
N
CH(OEt)2
N
N
CHO
Treatment of pyrimidines 2e−i with boron trifluoride gave
the corresponding 2,3-dihydroimidazo[1,2-c]pyrimidini-
um salts 6e−i in good to excellent yields (Scheme 3, Table
1). Attempts to isolate the 7-chloro-3-ethoxy-5-(methyl-
sulfanyl)-8-nitro-2,3-dihydroimidazo[1,2-c]pyrimidin-1-
ium salt formed in the reaction of 2d with boron trifluo-
ride resulted in a complex mixture of compounds. Never-
theless, workup with aqueous sodium hydroxide without
isolation of the salt gave 3-ethoxy-5-(methylsulfanyl)-8-
nitro-2,3-dihydroimidazo[1,2-c]pyrimidin-7-ol (5d) in
low yield. The target compounds 5e−h can therefore be
SMe
SMe
74%
1
2a
SMe
4a,c
a R2 = Cl 76%
c R2 = OMe 55%
iv
v
ii
or
CN
CN
CN
H
N
MeO
Cl
R1
Me2N
N
iii
N
N
N
N
CH(OEt)2
N
N
3
2b,c
SMe
86%
SMe
OEt
SMe
74%
5b
b R1 = NMe2 79%
c R1 = OMe 82%
Scheme 1 Reagents and conditions: (i) NH2CH2CH(OEt)2, Na2CO3,
MeOH, r.t., 1 h; (ii) MeOH, Na2CO3, r.t., 2 h; (iii) NH2CH2CH(OEt)2, obtained either from the isolated 2,3-dihydroimidazo[1,2-
Et3N, MeOH, r.t., 20 h; (iv) Me2NH, i-PrOH, r.t., 1.5 h; (v) BF3·OEt2,
CH2Cl2; then aq NaHCO3.
c]pyrimidinium salts 6e−h or directly from the pyrimi-
dines 2e−h. Note that 2,3-dihydroimidazo[1,2-c]pyrimi-
dines 5e−h were obtained in better yields (for example, 5b
was isolated in a 12% greater yield) when they were syn-
fluoroborate. The isotope shift was 60 ppb, and the ratio
thesized without isolation of the intermediate salts. How-
of the intensities of the two peaks was 4:1. The presence
ever, all attempts to isolate 3-ethoxy-N,N-dimethyl-5-
(methylsulfanyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-7-
amine by normal- or reverse-phase chromatography or by
crystallization resulted in failure.
of isotopomers of tetrafluoroborate has been reported in
some earlier cases.13 Treatment of salts 6a−c with a non-
aqueous base (DBU, Et3N, K3PO4, or a carbonate) led to
the formation of the corresponding 2,3-dihydroimid-
azo[1,2-c]pyrimidines 5a−c. However, pure compounds
R1
R1
could not be obtained by using this isolation procedure.
Trituration of solutions of these compounds with water
appeared to be essential for the isolation of pure substances.
Because workup of the reaction mixtures with aqueous so-
dium bicarbonate gave aldehydes in some cases, strongly
alkaline solutions were used to deprotonate the 2,3-dihy-
droimidazo[1,2-c]pyrimidinium salts in the workup
phase. This procedure led to the isolation of the required
2,3-dihydroimidazo[1,2-c]pyrimidines 5a−c in good
yields. The basicity of the workup solutions therefore ap-
pears to be the key factor in determining the course of the
reaction.
H
Cl
Cl
Cl
N
i
N
N
N
N
CH(OEt)2
vi
R1
H
N+
R2
SMe
SMe
7 R1 = NO2
2d,g 44 and 90%
8 R1 = H
N
N
iv or v
OEt
ii
SMe
vi
R1
NO2
6e–i 74–96%
H
R2
N
MeO
Cl
iii
N
N
N
N
CH(OEt)2
vii
SMe
SMe
9 64%
2e,f,h,i 68–92%
R1 R2
R1
NO2
R2
HO
N
N
d
e
f
g
h
i
NO2
NO2 OMe
NO2 NMe2
H
H
H
CN
CN
CN
or
H
N+
H
N
N
N
N
R
R
R
N
N
ii
i
OEt
OEt
SMe
5e–h 45–87%
SMe
N
N
N
N
N
N
CH(OEt)2
OMe
NMe2
5d 29%
OEt
OEt
–
SMe
5a–c 76–81%
SMe
6a–c 87–94%
SMe
BF4
Reagents and conditions: (i) for R1 = NO2:
2a–c
Scheme
3
NH2CH2CH(OEt)2, Na2CO3, i-PrOH, r.t., 5 min; for R1 = H:
NH2CH2CH(OEt)2, Et3N, i-PrOH, 60−65 °C, 3 h; (ii) MeOH,
Na2CO3, r.t., 5 h; (iii) NH2CH2CH(OEt)2, Et3N, i-PrOH, r.t. (iv)
NaOMe, MeOH, 100 °C, 16 h; (v) for R1 = NO2: Me2NH, i-PrOH, r.t.,
15 min; for R1 = H: Me2NH, 1,4-dioxane, 100 °C, 6 h; (vi) BF3·OEt2,
CH2Cl2; (vii) 5% aq NaOH.
a R = Cl
b R = OMe
c R = NMe2
Scheme 2 Reagents and conditions: (i) BF3·OEt2, CH2Cl2; (ii)
BF3·OEt2, CH2Cl2; then 5% aq NaOH.
To explore the scope of the reaction, we synthesized a se-
ries of N-(2,2-diethoxyethyl)pyrimidin-4-amines 2d−i
(Scheme 3, Table 1). Nitro-group-containing pyrimidines
2d−f were chosen for several reasons. As an electron-
withdrawing substituent, the nitro group should reduce the
reactivity of the pyrimidine nitrogen atom. Also, interme-
diate salts were expected to be less stable. On the other
hand, the target 2,3-dihydroimidazo[1,2-c]pyrimidines, as
The nature of the substituent at the 6-position of the py-
rimidine had a marked effect on the reaction time. Com-
pounds containing a chlorine group reacted within several
minutes, whereas full conversion of pyrimidines bearing a
dimethylamino group required two hours (Table 1, entries
2, 6, 9). These results were opposite to those expected. It
appears that the pyrimidine nitrogen atom in the dimeth-
ylamino derivatives is not only more nucleophilic than
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2438–2446

2440
R. Juskenas et al.
PAPER
R2
R2
Table 1 Preparation of N-(2,2-Diethoxyethyl)pyrimidine-4-amines
2a−i and 2,3-Dihydroimidazo[1,2-c]pyrimidines 5a−h and Their
Salts 6a−c and 6e−i
R1
N
N
H
H
N
N
Cl
N
Me
N
Me
i
N
N
ii
N
N
CH(OEt)2
N
R1
R1
N
N
CH(OEt)2
R1
H
H
R2
N
CH(OEt)2
OEt
R2
R2
N+
SMe
2j R2 = H 71%
2k R2 = NH2 65%
SMe
N
SMe
–
BF4
10 R1 = CHO
2a R1 = CN
5j R2 = H 82%
N
N
N
N
N
N
5k R2 = NH2 89%
OEt
OEt
SMe
2a–k
SMe
5a–c,e–h,j,k
SMe
6a–c,e–i
Scheme 4 Reagents and conditions: (i) MeNHNH2, i-PrOH, 30 min;
(ii) BF3·OEt2, CH2Cl2, 2 h; then 5% aq NaOH.
Entry R1
R2
Yield (%) Yield (%) Yield (%) Time (for 5
of 2
of 5
of 6
and 6)
In summary, we have developed a novel method for the
synthesis of 2,3-dihydroimidazo[1,2-c]pyrimidines by in-
tramolecular cyclization of N-(2,2-diethoxyethyl)pyrimi-
din-4-amines. The use of strongly basic aqueous solutions
in the reaction workup is essential for the deprotonation of
intermediate 2,3-dihydroimidazo[1,2-c]pyrimidinium tet-
rafluoroborate salts. The reaction can also be used in the
synthesis of tricyclic heterocycles containing imidazopy-
rimidine moieties.
1
2
3
4
5
6
7
8
9
CN Cl
2a 74
5a 81
5b 76
5c 79
5d 29
5e 87
5f 78
5g 50
5h 45
−
6a 94
6b 97
6c 87
−
10 min
2 h
CN NMe2 2b 79
CN OMe 2c 82
1.5 h
5 min
1 h
NO2 Cl
2d 44
NO2 OMe 2e 69
NO2 NMe2 2f 68
6e 96
6f 96
6g 96
6h 74
6i 95
2 h
Melting points were determined in open capillaries by using a digi-
tal melting point apparatus (IA9100 Series; Electrothermal) and are
uncorrected. IR spectra were recorded on a FTIR spectrophotometer
(Spectrum BX II; PerkinElmer) in KBr unless stated otherwise. 1H
NMR and 13C NMR spectra were recorded on a Varian Unity Inova
spectrometer at 300 MHz and 75 MHz, respectively, for all com-
pounds except 4a and 4c; residual solvents signals were used as in-
H
H
H
Cl
2g 90
10 min
1 h
OMe 2h 72
NMe2 2i 92
2 h
1
ternal standard. H NMR and 13C NMR spectra for compounds 4a
and 4c were recorded on a Bruker Ascend 400 spectrometer (400
MHz and 100 MHz, respectively) with residual solvent signals as
internal standards. All reactions and purities of the synthesized
compounds were monitored by TLC on silica gel 60 F254-coated
aluminum plates (Merck) with visualization by UV radiation. Ele-
mental analyses were performed on a Thermo Scientific FLASH
2000 apparatus. HRMS data were obtained with an Agilent 6230
TOF mass spectrometer (ESI).
that in the chloro compounds, but also more basic, so that
its interaction with boron trifluoride retards the reaction.
On the other hand, substituents at the 5-position of the py-
rimidine did not have a significant effect on the reaction
time; however, lower yields of the 2,3-dihydroimid-
azo[1,2-c]pyrimidines 5g and 5h were obtained from the
5-unsubstituted pyrimidines 2g and 2h (Table 1, entries 7,
8).
4-Chloro-6-[(2,2-diethoxyethyl)amino]-2-(methylsulfanyl)py-
rimidine-5-carbonitrile (2a)
Note that 2,3-dihydroimidazo[1,2-c]pyrimidines 5a−h are
unstable when stored at room temperature. Decomposi-
tion occurs within hours or days, depending on the struc-
ture of the particular compound. Because of this low
stability of the synthesized 2,3-dihydroimidazo[1,2-c]py-
rimidines, we decided to use another heterocyclic scaffold
in the reaction. On the basis of our previous work,15 we
synthesized two pyrazolo[3,4-d]pyrimidines 2j and 2k
containing a (2,2-diethoxyethyl)amino group at the 4-po-
sition of the pyrazolopyrimidine moiety by the reaction of
the corresponding 6-chloropyrimidines 2a and 10 with an
excess of methylhydrazine (Scheme 4). The conversion of
2j and 2k into the corresponding dihydroimidazo[1,2-
c]pyrazolo[4,3-e]pyrimidines 5j and 5k was carried out
under the same reaction conditions as those used for the
synthesis of compounds 5a−h. In contrast to the 2,3-dihy-
droimidazo[1,2-c]pyrimidines 5a−h, compounds 5j and
5k appeared to be stable for weeks or more when stored at
room temperature.
A suspension of pyrimidine 116 (0.5 g, 2.27 mmol) in MeOH (25
mL) was treated by dropwise addition of a soln of 2,2-diethoxy-
ethylamine (395 μL, 23 mmol) in MeOH (5 mL). Na2CO3 (0.29 g,
2.73 mmol) was added and the mixture was stirred at r.t. for 1 h.
H2O (100 mL) was then added and the resulting precipitate was col-
lected by filtration, dried, and crystallized (hexane) to give a color-
less solid; yield: 0.53 g (74%); mp 74–75 °C.
IR (KBr): 3332 (NH), 2222 (CN) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.28 (t, J = 6.9 Hz, 6 H, 2 × CH3),
2.56 (s, 3 H, SCH3), 3.60 (dq, 2J = 9.6 Hz, 3J = 6.9 Hz, 2 H,
2 × CHAHBCH3), 3.70–3.84 (m, 4 H, NCH2 and 2 × CHAHBCH3),
4.64 (t, J = 5.4 Hz, 1 H, OCH), 5.89 (t, J = 5.4 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 14.7, 15.6, 44.0, 63.5, 86.1, 100.2,
113.8, 161.2, 161.5, 176.3.
Anal. Calcd for C12H17ClN4O2S: C, 45.49; H, 5.41; found: C, 45.62;
H, 5.57.
4-[(2,2-Diethoxyethyl)amino]-6-(dimethylamino)-2-(methylsul-
fanyl)pyrimidine-5-carbonitrile (2b)
40% aq Me2NH (748 μL, 6.0 mmol) was added to a suspension of
pyrimidine 2a (0.76 g, 2.4 mmol) in i-PrOH (20 mL), and the mix-
ture was stirred at r.t. for 1.5 h. H2O (100 mL) was added and the
precipitate was collected by filtration, dried, and crystallized (hex-
ane) to give a colorless solid; yield: 0.45 g (79%); mp 86–87 °C.
Synthesis 2013, 45, 2438–2446
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Intramolecular Cyclization of N-(2,2-Diethoxyethyl)pyrimidine-4-amines
2441
IR (KBr): 3326, 3300 (NH), 2204 (CN) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.27 (t, J = 6.9 Hz, 6 H, 2 × CH3),
2.55 (s, 3 H, SCH3), 3.60 (dq, 2J = 9.3 Hz, 3J = 6.9 Hz, 2 H,
2 × CHAHBCH3), 3.72–3.83 (m, 4 H, NCH2 and 2 × CHAHBCH3),
4.09 (s, 3 H, OCH3), 4.68 (t, J = 5.4 Hz, 1 H, OCH), 8.84 (br s, 1 H,
NH).
1H NMR (300 MHz, CDCl3): δ = 1.26 (t, J = 7.2 Hz, 6 H, 2 × CH3),
2.48 (s, 3 H, SCH3), 3.31 [s, 6 H, N(CH3)2], 3.59 (dq, 2J = 9.6 Hz,
3J = 7.2 Hz, 2 H, 2 × CHAHBCH3), 3.66 (t, J = 5.7 Hz, 2 H, NCH2),
2
3
3.76 (dq, J = 9.6 Hz, J = 7.2 Hz, 2 H, 2 × CHAHBCH3), 4.60 (t,
J = 5.7 Hz, 1 H, OCH), 5.66 (t, J = 5.7 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 14.8, 15.6, 44.3, 55.7, 63.2, 100.5,
113.5, 156.6, 163.8, 174.6.
13C NMR (75 MHz, CDCl3): δ = 14.3, 15.6, 39.7, 43.8, 63.2, 65.5,
101.0, 119.1, 161.2, 163.9, 173.3.
Anal. Calcd for C12H20N4O5S: C, 43.36; H, 6.07. Found: C, 43.68;
H, 6.11.
Anal. Calcd for C14H23N5O2S: C, 51.67; H, 7.12. Found: C, 52.09;
H, 7.15.
N′-(2,2-Diethoxyethyl)-N,N-dimethyl-2-(methylsulfanyl)-5-ni-
tropyrimidine-4,6-diamine (2f)
4-[(2,2-Diethoxyethyl)amino]-6-methoxy-2-(methylsulfanyl)py-
rimidine-5-carbonitrile (2c)
40% aq Me2NH (340 μL, 2.73 mmol) was added to a suspension of
pyrimidine 2d (0.40 g, 1.19 mmol) in i-PrOH (15 mL), and the mix-
ture was stirred at r.t. until the starting compound has dissolved
(~15 min). H2O (50 mL) was added and the product was extracted
with CH2Cl2 (2 × 50 mL). The organic layers were combined,
washed with H2O (2 × 20 mL), dried (Na2SO4), and concentrated.
The crude product was crystallized from hexane at –15 °C to give a
yellow solid; yield: 0.28 g (68%); mp 46–47 °C.
2,2-Diethoxyethylamine (505 μL, 3.48 mmol) and Et3N (485 μL,
3.48 mmol) were added to a soln of pyrimidine 3 (0.5 g, 2.32 mmol)
in MeOH (25 mL), and the mixture was stirred at r.t. for 20 h. H2O
(100 mL) was added and the precipitate was collected by filtration,
dried, and crystallized (hexane) to give a colorless solid; yield: 0.62
g (82%); mp 84–85 °C.
IR (KBr): 3320 (NH), 2220 (CN) cm–1.
IR (KBr): 3368 (NH) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.26 (t, J = 6.9 Hz, 6 H, 2 × CH3),
2.53 (s, 3 H, SCH3), 3.58 (dq, 2J = 9.6 Hz, 3J = 6.9 Hz, 2 H,
2 × CHAHBCH3), 3.69 (t, J = 5.4 Hz, 2 H, NCH2), 3.76 (dq, 2J = 9.6
Hz, 3J = 6.9 Hz, 2 H, 2 × CHAHBCH3), 4.02 (s, 3 H, OCH3), 4.61 (t,
J = 5.4 Hz, 1 H, OCH), 5.65 (t, J = 5.4 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 14.5, 15.6, 43.8, 54.9, 63.3, 70.6,
100.7, 114.7, 162.8, 169.7, 175.6.
1H NMR (300 MHz, CDCl3): δ = 1.27 (t, J = 6.9 Hz, 6 H, 2 × CH3),
2.51 (s, 3 H, SCH3), 3.10 [s, 6 H, N(CH3)2], 3.61 (dq, 2J = 9.3 Hz,
3J = 6.9 Hz, 2 H, 2 × CHAHBCH3), 3.71–3.82 (m, 4 H, NCH2 and
2 × CHAHBCH3), 4.67 (t, J = 5.4 Hz, 1 H, OCH), 8.60 (br s, 1 H,
NH).
13C NMR (75 MHz, CDCl3): δ = 14.7, 15.6, 40.6, 44.1, 63.1, 100.8,
111.7, 156.5, 158.2, 172.5.
Anal. Calcd for C13H20N4O3S: C, 49.98; H, 6.45. Found: C, 50.08;
H, 6.59.
Anal. Calcd for C13H23N5O4S: C, 45.20; H, 6.71. Found: C, 45.30;
H, 6.67.
6-Chloro-N-(2,2-diethoxyethyl)-2-(methylsulfanyl)-5-nitropy-
rimidin-4-amine (2d)
6-Chloro-N-(2,2-diethoxyethyl)-2-(methylsulfanyl)pyrimidin-
4-amine (2g)
2,2-Diethoxyethylamine (430 μL, 2.95 mmol) and Na2CO3 (0.285
g, 2.69 mmol) were added to a stirred soln of pyrimidine 717 (0.645
g, 2.69 mmol) in i-PrOH (20 mL). After 5 min, H2O (50 mL) was
added and the product was extracted with CH2Cl2 (2 × 50 mL). The
organic layers were combined, washed with H2O (2 × 20 mL), dried
(Na2SO4), and concentrated. The residue was purified by flash chro-
matography [silica gel, hexane–benzene (1:1); Rf = 0.15] to give a
yellow solid; yield: 0.40 g (44%); mp 71.5–73.5 °C.
2,2-Diethoxyethylamine (3.35 mL, 23 mmol) and Et3N (3.2 mL, 23
mmol) were added to a suspension of pyrimidine 818 (3.0 g, 15.4
mmol) in i-PrOH (50 mL), and the mixture was heated in the sand
bath at 60–65 °C for 3 h. H2O (200 mL) was added and the precip-
itate was collected by filtration, dried, and crystallized (hexane) to
give a colorless solid; yield: 4.05 g (90%); mp 76–77 °C.
IR (KBr): 3324 (NH) cm–1.
IR (KBr): 3364 (NH) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.26 (t, J = 6.9 Hz, 6 H, 2 × CH3),
2.53 (s, 3 H, SCH3), 3.45–3.64 (m, 4 H, NCH2 and 2 × CHAHBCH3),
3.75 (dq, J = 9.6 Hz, J = 6.9 Hz, 2 H, 2 × CHAHBCH3), 4.62 (t,
J = 5.1 Hz, 1 H, OCH), 5.21 (br s, 1 H, NH), 6.11 (s, 1 H, Ar-H).
1H NMR (300 MHz, CDCl3): δ = 1.28 (t, J = 7.2 Hz, 6 H, 2 × CH3),
2.58 (s, 3 H, SCH3), 3.61 (dq, 2J = 9.3 Hz, 3J = 7.2 Hz, 2 H,
2 × CHAHBCH3), 3.73–3.85 (m, 4 H, NCH2 and 2 × CHAHBCH3),
4.69 (t, J = 5.4 Hz, 1 H, OCH), 8.17 (br s, 1 H, NH).
2
3
13C NMR (75 MHz, DMSO-d6): δ = 14.1, 16.0, 43.5, 62.5, 99.9,
100.5, 157.3, 163.3, 171.9.
13C NMR (75 MHz, DMSO-d6): δ = 14.5, 15.7, 44.3, 62.3, 99.8,
124.6, 152.6, 154.6, 173.0.
Anal. Calcd for C11H18ClN3O2S: C, 45.28; H, 6.22. Found: C,
45.48; H, 6.52.
Anal. Calcd for C11H17ClN4O4S: C, 39.23; H, 5.09. Found: C,
39.21; H, 5.07.
N-(2,2-Diethoxyethyl)-6-methoxy-2-(methylsulfanyl)pyrimi-
din-4-amine (2h)
N-(2,2-Diethoxyethyl)-6-methoxy-2-(methylsulfanyl)-5-nitro-
pyrimidin-4-amine (2e)
A mixture of pyrimidine 2g (0.4 g, 1.37 mmol), NaOMe (0.37 g,
6.85 mmol), and MeOH (10 mL) was heated at 100 °C in a closed
pressure vessel for 16 h, then cooled to r.t. H2O (40 mL) was added
and the product was extracted with CH2Cl2 (2 × 20 mL). The com-
bined organic layers were washed with H2O (2 × 20 mL), dried
(Na2SO4), and concentrated. The product was purified by flash
chromatography [silica gel, PE–EtOAc (9:1); Rf = 0.46] to give a
pinkish oil; yield: 0.28 g (72%).
2,2-Diethoxyethylamine (470 μL, 3.23 mmol) was added to a sus-
pension of pyrimidine 9 (0.63 g, 2.67 mmol) in i-PrOH (30 mL), and
the mixture was stirred at r.t. until the starting compound has dis-
solved. Et3N (560 μL, 4.0 mmol) was then added and the mixture
was stirred for a further 45 min. H2O (50 mL) was added and the
product was extracted with CH2Cl2 (2 × 50 mL). The organic layers
were combined, washed with H2O (2 × 20 mL), dried (Na2SO4), and
concentrated. The residue was purified by flash chromatography
(silica gel, CH2Cl2; Rf = 0.42) to give a yellow solid; yield: 0.61 g
(69%); mp 65.5–67.5 °C.
IR (CH2Cl2 film): 3383 (NH) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.24 (t, J = 6.9 Hz, 6 H, 2 × CH3),
2.52 (s, 3 H, SCH3), 3.42 (t, J = 5.4 Hz, 2 H, NCH2), 3.57 (dq,
IR (KBr): 3380 (NH) cm–1.
2J = 9.6 Hz, J = 6.9 Hz, 2 H, 2 × CHAHBCH3), 3.73 (dq, J = 9.6
3
2
© Georg Thieme Verlag Stuttgart · New York
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R. Juskenas et al.
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Hz, 3J = 6.9 Hz, 2 H, 2 × CHAHBCH3), 3.91 (s, 3 H, OCH3), 4.62 (t,
J = 5.4 Hz, 1 H, OCH), 5.08 (br s, 1 H, NH), 5.42 (s, 1 H, Ar-H).
Anal. Calcd for C13H22N6O2S: C, 47.83; H, 6.79. Found: C, 47.85;
H, 6.79.
13C NMR (75 MHz, CDCl3): δ = 14.2, 15.6, 44.2, 53.8, 63.0, 81.3,
100.9, 163.9, 170.1, 170.9.
HRMS (ESI): m/z [M + H]+ calcd for C12H22N3O3S: 288.1376;
found: 288.1385.
4-Chloro-6-methoxy-2-(methylsulfanyl)pyrimidine-5-carboni-
trile (3)
Et3N (1.79 mL, 1.30 g, 11.87 mmol) was added dropwise to a sus-
pension of pyrimidine 1 (2.5 g, 11.4 mmol) in MeOH (40 mL), and
the mixture was stirred at r.t. for 2 h. H2O (200 mL) was added and
the precipitate was collected by filtration, dried, and crystallized (i-
PrOH) to give a colorless solid; yield: 2.10 g (86%); mp 123–124.5
°C.
IR (KBr): 2229 (CN) cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.61 (s, 3 H, SCH3), 4.14 (s, 3 H,
N′-(2,2-Diethoxyethyl)-N,N-dimethyl-2-(methylsulfanyl)pyrim-
idine-4,6-diamine (2i)
A mixture of pyrimidine 2g (0.5 g, 1.71 mmol), 40% aq Me2NH (3
mL, 24 mmol), and 1,4-dioxane (8 mL) was heated at 100 °C in a
closed pressure vessel for 6 h. H2O (40 mL) was added and the re-
sulting precipitate was collected by filtration and dried to give an
analytically pure colorless solid; yield: 0.47 g (92%); mp 94.5–96
°C.
OCH3).
13C NMR (75 MHz, DMSO-d6): δ = 14.6, 56.0, 90.7, 112.0, 162.5,
169.1, 176.8.
IR (KBr): 3271 (NH) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.26 (t, J = 6.9 Hz, 6 H, 2 × CH3),
2.51 (s, 3 H, SCH3), 3.07 [s, 6 H, N(CH3)2], 3.42 (t, J = 5.4 Hz, 2 H,
Anal. Calcd for C7H6ClN3OS: C, 38.99; H, 2.80. Found: C, 39.15;
H, 2.68.
2
3
NCH2), 3.59 (dq, J = 9.3 Hz, J = 6.9 Hz, 2 H, 2 × CHAHBCH3),
2
3
4-Substituted 2-(Methylsulfanyl)-6-[(2-oxoethyl)amino]pyrimi-
dine-5-carbonitriles 4a and 4c; General Procedure
3.75 (dq, J = 9.3 Hz, J = 6.9 Hz, 2 H, 2 × CHAHBCH3), 4.65 (t,
J = 5.4 Hz, 1 H, OCH), 4.76 (br s, 1 H, NH), 5.12 (s, 1 H, Ar-H).
13C NMR (75 MHz, CDCl3): δ = 14.1, 15.6, 33.3, 44.3, 63.8, 76.8,
101.2, 163.0 (C-4, C-6, from HMBC data), 169.9.
BF3·OEt2 (95 μL, 0.75 mmol) was added to a soln of pyrimidine 2a
or 2c (0.30 mmol) in CH2Cl2 (5 mL), and the mixture was stirred at
r.t. for 5 min (2a) or 2 h (2c). The mixture was then washed succes-
sively with 5% aq NaHCO3 (5 mL) and H2O (2 × 5 mL). The organ-
ic layers were combined, dried (Na2SO4) and, without removal of
the solvent, purified by flash chromatography.
Anal. Calcd for C13H24N4O2S: C, 51.97; H, 8.05. Found: C, 52.01;
H, 8.05.
N-(2,2-Diethoxyethyl)-1-methyl-6-(methylsulfanyl)-1H-pyrazo-
lo[3,4-d]pyrimidin-4-amine (2j)
4-Chloro-2-(methylsulfanyl)-6-[(2-oxoethyl)amino]pyrimidine-
5-carbonitrile (4a)
Colorless solid: yield: 55 mg (76%); mp 140 °C (dec.); Rf = 0.1
(CH2Cl2).
MeNHNH2 (1.25 mL, 23.6 mmol) was added to a soln of pyrimidine
10 (3.0 g, 9.38 mmol) in i-PrOH (100 mL), and the mixture was
stirred at r.t. for 30 min. The solvent was evaporated under reduced
pressure, and the product was extracted with CH2Cl2 (30 mL). The
soln was washed with H2O (2 × 20 mL), dried (Na2SO4), and
flushed through a 1-cm-thick layer of silica gel with CH2Cl2. After
a removal of the solvent, the residue was crystallized (hexane) to
give a colorless solid; yield: 2.07 g (71%); mp 81–82.5 °C.
IR (KBr): 3330 (NH), 2846, 2728 (CHO), 2220 (CN), 1735, 1715
(CO) cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.52 (s, 3 H, SCH3), 4.45 (d,
J = 5.2 Hz, 2 H, CH2), 6.42 (br s, 1 H, NH), 9.74 (s, 1 H, CH).
13C NMR (100 MHz, CDCl3): δ = 14.5, 51.4, 86.2, 113.3, 161.10,
161.17, 176.5, 195.0.
IR (KBr): 3302 (NH) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.27 (t, J = 6.9 Hz, 6 H, 2 × CH3),
2.61 (s, 3 H, SCH3), 3.62 (dq, 2J = 9.3 Hz, 3J = 6.9 Hz, 2 H,
2 × CHAHBCH3), 3.72–3.84 (m, 4 H, NCH2 and 2 × CHAHBCH3),
3.98 (s, 3 H, NCH3), 4.72 (t, J = 5.1 Hz, 1 H, OCH), 5.60 (br s, 1 H,
NH), 7.81 (s, 1 H, Ar-H).
Anal. Calcd for C8H7ClN4OS: C, 39.59; H, 2.91. Found: C, 39.89;
H, 3.03.
HRMS (ESI): m/z [M + H]+ calcd for C8H7ClN4OS: 243.0102;
found: 243.0108.
13C NMR (75 MHz, CDCl3): δ = 14.4, 15.6, 33.9, 43.4, 63.2, 98.7,
100.8, 130.5, 154.5, 156.1, 169.7.
4-Methoxy-2-(methylsulfanyl)-6-[(2-oxoethyl)amino]pyrimi-
dine-5-carbonitrile (4c)
Colorless solid: yield: 39 mg (55%); mp 160 °C (dec.); Rf = 0.15
(CH2Cl2).
Anal. Calcd for C13H21N5O2S: C, 50.14; H, 6.80. Found: C, 50.37;
H, 6.68.
IR (KBr): 3332 (NH), 2848, 2741 (CHO), 2213 (CN), 1747, 1713
(CO) cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.49 (s, 3 H, SCH3), 4.04 (s, 3 H,
OCH3), 4.37 (d, J = 5.2 Hz, 2 H, CH2), 6.22 (br s, 1 H, NH), 9.71 (s,
1 H, CH).
13C NMR (100 MHz, CDCl3): δ = 14.2, 51.4, 54.9, 70.7, 114.1,
162.5, 169.4, 175.8, 196.5.
N4-(2,2-Diethoxyethyl)-1-methyl-6-(methylsulfanyl)-1H-pyr-
azolo[3,4-d]pyrimidine-3,4-diamine (2k)
MeNHNH2 (126 μL, 2.34 mmol) was added to a suspension of py-
rimidine 2a (0.30 g, 0.95 mmol) in i-PrOH (10 mL), and the mixture
was refluxed for 30 min. H2O (40 mL) was then added and the re-
sulting precipitate was collected by filtration, dried, and crystallized
(MeOH) to give a colorless solid; yield: 0.20 g (65%); mp 179–180
°C.
Anal. Calcd for C9H10N4O2S: C, 45.37; H, 4.23. Found: C, 45.03; H,
4.22.
HRMS (ESI): m/z [M + H]+ calcd for C9H10N4O2S: 239.0597;
IR (KBr): 3422, 3382, 3300, 3208 (NH, NH2) cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 1.13 (t, J = 6.9 Hz, 6 H,
2 × CH3), 2.48 (s, 3 H, SCH3), 3.48–3.56 (m, 4 H, NCH2 and
2 × CHAHBCH3), 3.57 (s, 3 H, NCH3), 3.68 (dq, 2J = 9.6 Hz, 3J = 6.9
Hz, 2 H, 2 × CHAHBCH3), 4.73 (t, J = 5.4 Hz, 1 H, CH), 5.69 (s, 2
H, NH2), 7.46 (t, J = 5.4 Hz, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): δ = 14.3, 16.3, 33.2, 44.1, 62.8,
88.4, 101.0, 147.9, 154.5, 156.4, 168.8.
found: 239.0605.
3-Ethoxy-2,3-dihydroimidazo[1,2-c]pyrimidines 5a–h, 5j, and
5k; General Procedure
BF3·OEt2 (95 μL, 0.75 mmol) was added to a soln of the appropriate
4-(2,2-diethoxyethyl)aminopyrimidine 2a–k (0.30 mmol) in
CH2Cl2 (5 mL), and the mixture was stirred at r.t. for 10 min to 2 h
(TLC monitoring). The mixture was then washed successively with
Synthesis 2013, 45, 2438–2446
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Intramolecular Cyclization of N-(2,2-Diethoxyethyl)pyrimidine-4-amines
2443
5% aq NaOH (5 mL) and H2O (2 × 5 mL). The organic layers were
combined, dried (Na2SO4) and, without removal of a solvent, puri-
fied by flash chromatography. Impurities were eluted with CH2Cl2,
and the product was eluted with a mixture of CH2Cl2 and acetone in
the ratio given below.
2J = 12.6 Hz, 3J = 6.9 Hz, 1 H, NCHAHBCH), 5.91 (dd, 3J = 6.9 Hz
3J = 1.8 Hz, 1 H, CH), 9.88 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): δ = 14.0, 15.3, 50.6, 62.4, 86.4, 111.4,
154.0, 159.5, 159.8.
HRMS (ESI): m/z [M + H]+ calcd for C9H12N4O4S: 273.0652;
7-Chloro-3-ethoxy-5-(methylsulfanyl)-2,3-dihydroimidazo[1,2-
c]pyrimidine-8-carbonitrile (5a)
Reaction time: 10 min. Yellowish oil; yield: 66 mg (81%); Rf = 0.4
(CH2Cl2–acetone, 9:1).
found: 273.0657.
3-Ethoxy-7-methoxy-5-(methylsulfanyl)-8-nitro-2,3-dihydro-
imidazo[1,2-c]pyrimidine (5e)
Reaction time: 1 h. Yellow oil; yield: 78 mg (87%); Rf = 0.25
(CH2Cl2–acetone, 3:1).
IR (KBr): 2224 (CN) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.26 (t, J = 6.9 Hz, 3 H, CH3),
2.65 (s, 3 H, SCH3), 3.47 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
CHAHBCH3), 3.59 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3),
1H NMR (300 MHz, CDCl3): δ = 1.22 (t, J = 6.9 Hz, 3 H, CH3),
2.65 (s, 3 H, SCH3), 3.43 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
CHAHBCH3), 3.57 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3),
2
3
3.95 (dd, J = 16.2 Hz, J = 3.3 Hz, 1 H, NCHAHBCH), 4.05 (dd,
2J = 16.2 Hz, 3J = 7.5 Hz, 1 H, NCHAHBCH), 5.70 (dd, 3J = 7.5 Hz,
3J = 3.3 Hz, 1 H, CH).
2
3
4.03 (dd, J = 16.5 Hz, J = 2.7 Hz, 1 H, NCHAHBCH), 4.08–4.15
(m, 4 H, NCHAHBCH and OCH3), 5.66 (dd, 3J = 6.9 Hz 3J = 2.7 Hz,
1 H, CH).
13C NMR (75 MHz, CDCl3): δ = 14.4, 15.3, 59.9, 61.9, 88.0, 90.3,
112.9, 150.9, 159.8, 165.5.
HRMS (ESI): m/z [M + H]+ calcd for C10H12ClN4OS: 271.0415;
found: 271.0420.
13C NMR (75 MHz, CDCl3): δ = 14.2, 15.1, 56.1, 60.3, 61.2, 87.3,
112.9, 148.6, 161.7, 164.8.
HRMS (ESI): m/z [M + H]+ calcd for C10H14N4O4S: 287.0809;
found: 287.0815.
7-(Dimethylamino)-3-ethoxy-5-(methylsulfanyl)-2,3-dihydro-
imidazo[1,2-c]pyrimidine-8-carbonitrile (5b)
Reaction time: 2 h. Yellowish solid; yield: 66 mg (79%); mp 60 °C
(dec.); Rf = 0.25 (CH2Cl2–acetone, 1:1).
3-Ethoxy-N,N-dimethyl-5-(methylsulfanyl)-8-nitro-2,3-dihy-
droimidazo[1,2-c]pyrimidin-7-amine (5f)
Reaction time: 2 h. Yellow solid; yield: 68 mg (78%); mp 72 °C
(dec.); Rf = 0.25 (CH2Cl2–acetone, 1:1).
IR (KBr): 2199 (CN) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.17 (t, J = 6.9 Hz, 3 H, CH3),
2.53 (s, 3 H, SCH3), 3.15 [s, 6 H, N(CH3)2], 3.38 (dq, 2J = 9.0 Hz,
3J = 6.9 Hz, 1 H, CHAHBCH3), 3.51 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
CHAHBCH3), 3.98 (dd, 2J = 16.5 Hz, 3J = 2.7 Hz, 1 H, NCHAHBCH),
1H NMR (300 MHz, CDCl3): δ = 1.22 (t, J = 6.9 Hz, 3 H, CH3),
2.54 (s, 3 H, SCH3), 3.35–3.44 [m, 7 H, CHAHBCH3 and N(CH3)2],
2
3
3.54 (dq, J = 9.0 Hz, J = 6.9 Hz, 1 H, CHAHBCH3), 3.86 (dd,
2J = 15.9 Hz, J = 2.7 Hz, 1 H, NCHAHBCH), 4.03 (dd, J = 15.9
Hz, J = 7.2 Hz, 1 H, NCHAHBCH), 5.64 (dd, J = 7.2 Hz J = 2.7
4.06 (dd, J = 16.5 Hz, J = 6.6 Hz, 1 H, NCHAHBCH), 5.57 (dd,
3
2
2
3
3
3
3
3J = 6.6 Hz 3J = 2.7 Hz, 1 H, CH).
Hz, 1 H, CH).
13C NMR (75 MHz, CDCl3): δ = 14.2, 15.3, 31.1, 41.3, 60.7, 61.1,
87.1, 108.7, 149.5, 157.2, 160.5.
13C NMR (75 MHz, CDCl3): δ = 13.9, 15.3, 40.6, 59.2, 60.6, 61.9,
87.4, 118.4, 155.5, 159.8, 160.7.
HRMS (ESI): m/z [M + H]+ calcd for C12H18N5OS: 280.1227;
HRMS (ESI): m/z [M + H]+ calcd for C11H18N5O3S: 300.1125;
found: 300.1130.
found: 280.1232.
7-Chloro-3-ethoxy-5-(methylsulfanyl)-2,3-dihydroimidazo[1,2-
c]pyrimidine (5g)
Reaction time: 10 min. Yellowish oil; yield: 37 mg (50%); Rf = 0.15
(CH2Cl2–acetone, 9:1).
Anal. Calcd for C12H17N5OS: C, 51.59; H, 6.13. Found: C, 51.37; H,
6.23.
3-Ethoxy-7-methoxy-5-(methylsulfanyl)-2,3-dihydroimid-
azo[1,2-c]pyrimidine-8-carbonitrile (5c)
Reaction time: 90 min. Yellowish solid; yield: 61 mg (76%); mp 73
°C (dec.); Rf = 0.1 (CH2Cl2–acetone, 9:1).
1H NMR (300 MHz, CDCl3): δ = 1.24 (t, J = 6.9 Hz, 3 H, CH3),
2.59 (s, 3 H, SCH3), 3.42 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
CHAHBCH3), 3.53 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3),
2
3
3.85 (dd, J = 16.5 Hz, J = 3.0 Hz, 1 H, NCHAHBCH), 3.94 (dd,
2J = 16.5 Hz, 3J = 7.2 Hz, 1 H, NCHAHBCH), 5.64 (dd, 3J = 7.2 Hz
3J = 3.0 Hz, 1 H, CH), 6.14 (s, 1 H, Ar-H).
IR (KBr): 2216 (CN) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.25 (t, J = 6.9 Hz, 3 H, CH3),
2.64 (s, 3 H, SCH3), 3.42 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
CHAHBCH3), 3.57 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3),
13C NMR (75 MHz, CDCl3): δ = 13.9, 15.3, 59.3, 60.9, 86.9, 103.3,
153.1, 154.6, 161.0.
HRMS (ESI): m/z [M + H]+ calcd for C9H13ClN3OS: 246.0462;
found: 246.0472.
2
3
3.93 (dd, J = 16.2 Hz, J = 2.7 Hz, 1 H, NCHAHBCH), 3.98–4.08
(m, 4 H, NCHAHBCH and OCH3), 5.68 (dd, 3J = 7.2 Hz 3J = 2.7 Hz,
1 H, CH).
13C NMR (75 MHz, CDCl3): δ = 14.1, 15.3, 55.7, 59.7, 61.1, 69.3,
87.6, 113.9, 153.1, 165.5, 169.1.
HRMS (ESI): m/z [M + H]+ calcd for C11H15N4O2S: 267.0910;
found: 267.0916.
3-Ethoxy-7-methoxy-5-(methylsulfanyl)-2,3-dihydroimid-
azo[1,2-c]pyrimidine (5h)
Reaction time: 1 h. Yellowish oil; yield: 32 mg (45%); Rf = 0.1
(MeOH).
1H NMR (300 MHz, CDCl3): δ = 1.22 (t, J = 6.9 Hz, 3 H, CH3),
2.56 (s, 3 H, SCH3), 3.39 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
CHAHBCH3), 3.52 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3),
3.78–3.87 (m, 4 H, NCHAHBCH and OCH3), 3.92 (dd, 2J = 16.2 Hz,
3J = 7.2 Hz, 1 H, NCHAHBCH), 5.31 (s, 1 H, Ar-H), 5.63 (dd,
3J = 7.2 Hz 3J = 2.4 Hz, 1 H, CH).
3-Ethoxy-5-(methylsulfanyl)-8-nitro-2,3-dihydroimidazo[1,2-
c]pyrimidin-7-ol (5d)
Reaction time: 5 min. Yellow solid; yield: 24 mg (29%); mp 160 °C
(dec.); Rf = 0.1 (CH2Cl2–acetone, 7:1).
IR (KBr): 3259 (OH), 1649 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.16 (t, J = 6.9 Hz, 3 H, CH3),
2.52 (s, 3 H, SCH3), 3.57 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
CHAHBCH3), 3.65 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3),
13C NMR (75 MHz, CDCl3): δ = 13.5, 15.2, 55.0, 59.0, 60.1, 79.2,
86.5, 157.1, 160.2, 166.3.
2
3
3.81 (dd, J = 12.6 Hz, J = 1.8 Hz, 1 H, NCHAHBCH), 3.98 (dd,
© Georg Thieme Verlag Stuttgart · New York
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R. Juskenas et al.
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2
3
2
HRMS (ESI): m/z [M + H]+ calcd for C10H16N3O2S: 242.0958;
found: 242.0967.
(dq, J = 9.0 Hz, J = 6.9 Hz, 1 H, CHAHBCH3), 3.79 (dq, J = 9.0
Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3), 3.92 (dd, 2J = 12.6 Hz, 3J = 2.4
2
3
Hz, 1 H, NCHAHBCH), 4.08 (dd, J = 12.6 Hz, J = 7.2 Hz, 1 H,
NCHAHBCH), 6.02 (dd, 3J = 7.2 Hz 3J = 2.4 Hz, 1 H, CH), 7.90 (br
s, 1 H, NH).
13C NMR (75 MHz, CD3CN): δ = 14.1, 14.5, 40.7, 49.8, 62.5, 63.8,
88.0, 114.2, 157.8, 159.2, 162.7.
HRMS (ESI): m/z [M+] calcd for C12H18N5OS: 280.1227; found:
3-Ethoxy-7-methyl-5-(methylsulfanyl)-2,7-dihydro-3H-imid-
azo[1,2-c]pyrazolo[4,3-e]pyrimidine (5j)
Reaction time: 2 h. Yellowish solid; yield: 65 mg (82%); mp 123.5–
125 °C; Rf = 0.15 (CH2Cl2–acetone, 2:1).
1H NMR (300 MHz, CDCl3): δ = 1.23 (t, J = 6.9 Hz, 3 H, CH3),
2.65 (s, 3 H, SCH3), 3.39 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
CHAHBCH3), 3.54 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3),
3.90–3.99 (m, 4 H, NCHAHBCH and NCH3), 4.04 (dd, 2J = 16.2 Hz,
3J = 6.9 Hz, 1 H, NCHAHBCH), 5.72 (dd, 3J = 2.7 Hz 3J = 6.9 Hz, 1
H, CH), 7.87 (s, 1 H, Ar-H).
280.1244.
8-Cyano-3-ethoxy-7-methoxy-5-(methylsulfanyl)-2,3-dihydro-
imidazo[1,2-c]pyrimidin-1-ium Tetrafluoroborate (6c)
Reaction time: 90 min. Colorless solid; yield: 92 mg (87%); mp 156
°C (dec.).
13C NMR (75 MHz, CDCl3): δ = 13.9, 15.4, 34.3, 59.6, 60.4, 86.5,
98.5, 134.1, 150.0, 150.3, 158.3.
IR (KBr): 3276 (NH), 2233 (CN) cm–1.
Anal. Calcd for C11H15N5OS: C, 49.79; H, 5.70. Found: C, 49.93; H,
5.68.
1H NMR (300 MHz, CD3CN): δ = 1.27 (t, J = 6.9 Hz, 3 H, CH3),
2.84 (s, 3 H, SCH3), 3.69 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
CHAHBCH3), 3.83 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3),
4.03 (dd, J = 12.9 Hz, J = 2.7 Hz, 1 H, NCHAHBCH), 4.16 (dd,
2J = 12.9 Hz, 3J = 7.2 Hz, 1 H, NCHAHBCH), 4.29 (s, 3 H, OCH3),
6.00 (dd, 3J = 7.2 Hz 3J = 2.7 Hz, 1 H, CH), 8.59 (br s, 1 H, NH).
13C NMR (75 MHz, CD3CN): δ = 14.4, 14.7, 50.0, 52.6, 58.2, 64.2,
88.9, 110.3, 158.2, 169.6, 170.2.
HRMS (ESI): m/z [M+] calcd for C11H15N4O2S: 267.0910; found:
267.0924.
3-Ethoxy-7-methyl-5-(methylsulfanyl)-2,7-dihydro-3H-imid-
azo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-amine (5k)
Reaction time: 2 h. Yellowish solid; yield: 75 mg (89%); mp 104–
106 °C; Rf = 0.1 (acetone).
2
3
IR (KBr): 3402, 3308, 3302 (NH2) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.23 (t, J = 6.9 Hz, 3 H, CH3),
2.62 (s, 3 H, SCH3), 3.39 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
CHAHBCH3), 3.53 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3),
2
3
3.72 (s, 3 H, NCH3), 3.73 (dq, J = 15.9 Hz, J = 2.1 Hz, 1 H,
NCHAHBCH), 3.89 (dd, 2J = 15.9 Hz, 3J = 6.9 Hz, 1 H, NCHAHBCH),
5.06 (s, 2 H, NH2), 5.65 (dd, 3J = 6.9 Hz 3J = 2.1 Hz, 1 H, CH).
3-Ethoxy-7-methoxy-5-(methylsulfanyl)-8-nitro-2,3-dihydro-
imidazo[1,2-c]pyrimidin-1-ium Tetrafluoroborate (6e)
Reaction time: 1 h. Yellowish solid; yield: 111 mg (96%); mp 170
°C (dec.).
13C NMR (75 MHz, CDCl3): δ = 13.7, 15.1, 33.2, 59.1, 60.0, 85.8,
86.0, 149.3, 149.5, 150.6, 158.0.
IR (KBr): 3327 (NH) cm–1.
Anal. Calcd for C11H16N6OS: C, 47.13; H, 5.75. Found: C, 47.28; H,
5.72.
1H NMR (300 MHz, CD3CN): δ = 1.28 (t, J = 6.9 Hz, 3 H, CH3),
2.87 (s, 3 H, SCH3), 3.73 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
CHAHBCH3), 3.86 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3),
4.14 (dd, J = 12.6 Hz, J = 2.7 Hz, 1 H, NCHAHBCH), 4.29 (dd,
2J = 12.6 Hz, 3J = 7.2 Hz, 1 H, NCHAHBCH), 4.37 (s, 3 H, OCH3),
6.02 (dd, 3J = 7.2 Hz 3J = 2.7 Hz, 1 H, CH), 9.29 (br s, 1 H, NH).
13C NMR (75 MHz, CD3CN): δ = 14.4, 14.9, 50.9, 58.7, 64.3, 84.4,
88.9, 153.5, 163.5, 169.2.
HRMS (ESI): m/z [M+] calcd for C10H15N4O4S: 287.0809; found:
287.0817.
3-Ethoxy-2,3-dihydroimidazo[1,2-c]pyrimidin-1-ium Tetra-
fluoroborates 6a–c and 6e–i; General Procedure
2
3
BF3·OEt2 (95 μL, 0.75 mmol) was added to a soln of the appropriate
N-(2,2-diethoxyethyl)pyrimidin-4-amine 2a–i (0.30 mmol) in
CH2Cl2 (5 mL), and the mixture was stirred at r.t. for 10 min to 2 h.
The solvent was evaporated to give an oily residue that solidified on
shaking with Et2O (15 mL) to give a product that was collected by
filtration.
7-Chloro-8-cyano-3-ethoxy-5-(methylsulfanyl)-2,3-dihydro-
imidazo[1,2-c]pyrimidin-1-ium Tetrafluoroborate (6a)
Reaction time: 10 min. Colorless solid; yield: 101 mg (94%); mp
156 °C (dec.).
7-(Dimethylamino)-3-ethoxy-5-(methylsulfanyl)-8-nitro-2,3-di-
hydroimidazo[1,2-c]pyrimidin-1-ium Tetrafluoroborate (6f)
Reaction time: 2 h. Yellow solid; yield: 109 mg (96%); mp 138 °C
(dec.).
IR (KBr): 3341, 3220 (NH) cm–1.
1H NMR (300 MHz, CD3CN): δ = 1.27 (t, J = 6.9 Hz, 3 H, CH3),
IR (KBr): 3168 (NH), 2233 (CN) cm–1.
1H NMR (300 MHz, CD3CN): δ = 1.25 (t, J = 6.9 Hz, 3 H, CH3),
2.80 (s, 3 H, SCH3), 3.70 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
CHAHBCH3), 3.84 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3),
2.75 (s, 3 H, SCH3), 3.11 (s, 3 H, NCH3), 3.53 (s, 3 H, NCH3), 3.68–
2
3
3.90 (m, 2 H, CH2CH3), 4.05 (dd, J = 13.2 Hz, J = 2.1 Hz, 1 H,
NCHAHBCH), 4.19 (dd, 2J = 13.2 Hz, 3J = 7.2 Hz, 1 H, NCHAHBCH),
6.02 (dd, 3J = 7.2 Hz 3J = 2.1 Hz, 1 H, CH), 8.93 (br s, 1 H, NH).
2
3
4.10 (dd, J = 13.8 Hz, J = 3.0 Hz, 1 H, NCHAHBCH), 4.23 (dd,
2J = 13.8 Hz, 3J = 7.8 Hz, 1 H, NCHAHBCH), 6.23 (dd, 3J = 7.8 Hz
3J = 3.0 Hz, 1 H, CH), 9.21 (br s, 1 H, NH).
13C NMR (75 MHz, CD3CN): δ = 14.47, 14.52, 40.6, 43.2, 51.2,
64.3, 87.8, 108.1, 153.5, 155.1, 161.7.
HRMS (ESI): m/z [M+] calcd for C11H18N5O3S: 300.1125; found:
300.1133.
13C NMR (75 MHz, CD3CN): δ = 14.2, 14.7, 50.0, 64.6, 87.2, 89.6,
109.9, 156.5, 164.7, 168.8.
HRMS (ESI): m/z [M+] calcd for C10H12ClN4OS: 271.0415; found:
271.0424.
7-Chloro-3-ethoxy-5-(methylsulfanyl)-2,3-dihydroimidazo[1,2-
c]pyrimidin-1-ium Tetrafluoroborate (6g)
Reaction time: 10 min. Colorless solid; yield: 96 mg (96%); mp 130
°C (dec.).
8-Cyano-7-(dimethylamino)-3-ethoxy-5-(methylsulfanyl)-2,3-
dihydroimidazo[1,2-c]pyrimidin-1-ium Tetrafluoroborate (6b)
Reaction time: 2 h. Yellowish solid; yield: 107 mg (97%); mp 170
°C (dec.).
IR (KBr): 3252 (NH), 2212 (CN) cm–1.
1H NMR (300 MHz, CD3CN): δ = 1.26 (t, J = 6.9 Hz, 3 H, CH3),
IR (KBr): 3253 (NH) cm–1.
1H NMR (300 MHz, CD3CN): δ = 1.27 (t, J = 6.9 Hz, 3 H, CH3),
2.75 (s, 3 H, SCH3), 3.67 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
2.71 (s, 3 H, SCH3), 3.43 (s, 3 H, NCH3), 3.56 (s, 3 H, NCH3), 3.66
Synthesis 2013, 45, 2438–2446
© Georg Thieme Verlag Stuttgart · New York

PAPER
Intramolecular Cyclization of N-(2,2-Diethoxyethyl)pyrimidine-4-amines
2445
CHAHBCH3), 3.83 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3),
4.00 (dd, J = 10.2 Hz, J = 1.5 Hz, 1 H, NCHAHBCH), 4.12 (dd,
2J = 10.2 Hz, 3J = 7.5 Hz, 1 H, NCHAHBCH), 6.13 (dd, 3J = 7.5 Hz
3J = 1.5 Hz, 1 H, CH), 6.89 (s, 1 H, Ar-H), 8.23 (br s, 1 H, NH).
CH2Cl2 (50 mL). The soln was washed with H2O (2 × 50 mL), dried
2
3
(Na2SO4), and concentrated. The crude product was crystallized
from hexane at –15 °C to give a yellowish solid; yield: 5.34 g
(75%); mp 104–106 °C.
13C NMR (75 MHz, CD3CN): δ = 14.2, 14.4, 49.8, 64.2, 88.7, 99.2,
IR (KBr): 3268 (NH), 1654 (C=O) cm–1.
157.9, 161.8, 166.8.
HRMS (ESI): m/z [M+] calcd for C9H13ClN3OS: 246.0462; found:
246.0472.
1H NMR (300 MHz, CDCl3): δ = 1.28 (t, J = 6.9 Hz, 6 H, 2 × CH3),
2.56 (s, 3 H, SCH3), 3.61 (dq, 2J = 9.3 Hz, 3J = 6.9 Hz, 2 H,
2 × CHAHBCH3), 3.72–3.84 (m, 4 H, NCH2 and 2 × CHAHBCH3),
4.67 (t, J = 5.4 Hz, 1 H, OCH), 9.42 (br s, 1 H, NH), 10.27 (s, 1 H,
CHO).
13C NMR (75 MHz, CDCl3): δ = 14.7, 15.6, 43.6, 63.1, 100.5,
105.0, 160.4, 164.6, 177.0, 190.5.
3-Ethoxy-7-methoxy-5-(methylsulfanyl)-2,3-dihydroimid-
azo[1,2-c]pyrimidin-1-ium Tetrafluoroborate (6h)
Reaction time: 1 h. Colorless solid; yield: 73 mg (74%); mp 120 °C
(dec.).
IR (KBr): 3359 (NH) cm–1.
Anal. Calcd for C12H18ClN3O3S: C, 45.07; H, 5.67. Found: C,
45.29; H, 5.67.
1H NMR (300 MHz, CD3CN): δ = 1.26 (t, J = 6.9 Hz, 3 H, CH3),
2.76 (s, 3 H, SCH3), 3.65 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H,
CHAHBCH3), 3.80 (dq, 2J = 9.0 Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3),
Acknowledgment
2
3
4.00 (dd, J = 12.6 Hz, J = 2.4 Hz, 1 H, NCHAHBCH), 4.02 (dd,
2J = 12.6 Hz, 3J = 7.2 Hz, 1 H, NCHAHBCH), 4.11 (s, 3 H, OCH3),
6.01 (s, 1 H, Ar-H), 6.05 (dd, 3J = 7.2 Hz 3J = 2.4 Hz, 1 H, CH), 7.59
(br s, 1 H, NH).
This study was partly supported by the European Social Fund Agen-
cy as part of the project ‘High-Tech Materials Development Re-
search and Application’ No. VP1-3.1-ŠMM-08-K-01-014.
13C NMR (75 MHz, CD3CN): δ = 14.0, 14.5, 49.5, 56.5, 63.7, 79.9,
87.8, 159.0, 164.8, 170.5.
HRMS (ESI): m/z [M+] calcd for C10H16N3O2S: 242.0958; found:
242.0967.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
7-(Dimethylamino)-3-ethoxy-5-(methylsulfanyl)-2,3-dihydro-
imidazo[1,2-c]pyrimidin-1-ium Tetrafluoroborate (6i)
Reaction time: 2 h; colorless solid; yield: 97 mg (95%); mp 135 °C
(dec.).
IR (KBr): 3363 (NH) cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 1.17 (t, J = 6.9 Hz, 3 H, CH3),
References
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2.66 (s, 3 H, SCH3), 3.08 (s, 3 H, NCH3), 3.29 (s, 3 H, NCH3), 3.53
2
3
2
(dq, J = 9.0 Hz, J = 6.9 Hz, 1 H, CHAHBCH3), 3.68 (dq, J = 9.0
Hz, 3J = 6.9 Hz, 1 H, CHAHBCH3), 3.80 (dd, 2J = 12.0 Hz, 3J = 1.8
Hz, 1 H, NCHAHBCH), 3.91 (dd, J = 12.0 Hz, J = 6.9 Hz, 1 H,
NCHAHBCH), 5.55 (s, 1 H, Ar-H), 6.00 (dd, 3J = 6.9 Hz 3J = 1.8 Hz,
1 H, CH), 9.06 (br s, 1 H, NH).
2
3
13C NMR (75 MHz, CD3CN): δ = 14.2, 15.5, 38.4, 38.8, 49.1, 62.8,
73.0, 87.1, 156.4, 160.4, 160.8.
HRMS (ESI): m/z [M+] calcd for C11H19N4OS: 255.1274; found:
255.1286.
4-Chloro-6-methoxy-2-(methylsulfanyl)-5-nitropyrimidine (9)
Na2CO3 (0.49 g, 4.62 mmol) was added to a soln of pyrimidine 717
(1.0 g, 4.16 mmol) in MeOH (30 mL), and the mixture was stirred
at r.t. for 6 h. H2O (150 mL) was added and the resulting precipitate
was collected by filtration, dried, and crystallized (hexane) to give
a colorless solid; yield: 0.63 g (64%); mp 78–79 °C (Lit.19 77.5–
79.5 °C).
1H NMR (300 MHz, CDCl3): δ = 2.60 (s, 3 H, SCH3), 4.13 (s, 3 H,
OCH3).
(10) Chhabria, M. T.; Jani, M. H. Eur. J. Med. Chem. 2009, 44,
3837.
13C NMR (75 MHz, CDCl3): δ = 14.8, 56.2, 128.8, 151.4, 160.9,
173.8.
(11) (a) Nagamatsu, T.; Tsurubayashi, S.; Sasaki, K.; Hirota, T.
Synthesis 1991, 303. (b) Hirabayashi, A.; Mukaiyama, H.;
Kobayashi, H.; Shiohara, H.; Nakayama, S.; Ozawa, M.;
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Anal. Calcd for C6H6ClN3O3S: C, 30.58; H, 2.57. Found: C, 30.75;
H, 2.54.
4-Chloro-6-[(2,2-diethoxyethyl)amino]-2-(methylsulfanyl)py-
rimidine-5-carbaldehyde (10)
2,2-Diethoxyethylamine (3.6 mL, 24.7 mmol) was added to a sus-
pension
of
4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-
carbaldehyde16 (5.0 g, 22.4 mmol) in i-PrOH (100 mL), and the
mixture was stirred until all the crystals had dissolved. Et3N (3.4 mL
24.3 mmol) was then added. After 10 min, the solvent was evapo-
rated under reduced pressure, and the product was extracted with
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2438–2446

2446
R. Juskenas et al.
PAPER
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(15) Masevicius, V.; Juskenas, R.; Tumkevicius, S.
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Synthesis 2013, 45, 2438–2446
© Georg Thieme Verlag Stuttgart · New York