Synthesis, structure and rearrangement of iodinated imidazo[1,2-c]pyrimidine-5(6H)-ones derived from cytosine

Article abstract of DOI:10.1016/j.tet.2014.11.049

We describe mild and selective iodination of various 8-substituted imidazo[1,2-c]pyrimidine-5(6H)-ones (ethenocytosines). Starting ethenocytosines were obtained by cyclization of 5-halogenocytosines with chloroacetaldehyde or by subsequent Suzuki-Miyaura

Full text of DOI:10.1016/j.tet.2014.11.049

Accepted Manuscript
Synthesis, structure and rearrangement of iodinated imidazo[1,2-c]pyrimidine-5(6H)-
ones derived from cytosine
Josef Jansa , Antonín Lyčka , Aleš Růžička , Martin Grepl , Jan Vaněček
PII:
S0040-4020(14)01621-4
10.1016/j.tet.2014.11.049
TET 26198
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 September 2014
Revised Date: 4 November 2014
Accepted Date: 17 November 2014
Please cite this article as: Jansa J, Lyčka A, Růžička A, Grepl M, Vaněček J, Synthesis, structure and
rearrangement of iodinated imidazo[1,2-c]pyrimidine-5(6H)-ones derived from cytosine, Tetrahedron
(2014), doi: 10.1016/j.tet.2014.11.049.
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ACCEPTED MANUSCRIPT
Graphical abstract
I
I
I
I
Na CO3
NIS
DMF
2
NIS
DMF
N
R
N
R
N
N
O
N
O
N
O
N
O
N
MeOH
HN
HN
HN
HN
4a-i
rt
reflux
rt
R
R
1
a-i
2a-i
3a-i
R = F, Cl, Br, I, phenyl, biphenyl-4-yl, 4-methoxyphenyl, 4-formylphenyl, 4-cyanophenyl
1

ACCEPTED MANUSCRIPT
Synthesis,
structure
and
rearrangement
of
iodinated
imidazo[1,2-c]pyrimidine-5(6H)-ones derived from cytosine
a,b,*
a
c
d
a
Josef Jansa , Antonín Lyčka , Aleš Růžička , Martin Grepl , Jan Vaněček
a
Research Institute for Organic Syntheses (VUOS), Rybitví 296, CZ-533 54 Pardubice-Rybitví, Czech
Republic
b
Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu 1192/12, CZ-
771 46 Olomouc, Czech Republic
c
Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of
Pardubice, Studentská 573, CZ-532 10 Pardubice, Czech Republic
d
Farmak a.s., Na Vlčinci 16/3, CZ-771 17 Olomouc, Czech Republic
Keywords: imidazopyrimidines, iodination, Dimroth-type rearrangement, N-iodosuccinimide, cytosine,
NMR spectroscopy
*
Corresponding author. Tel.: +420466822371; fax: +420466823900.
E-mail address: josef.jansa@vuos.com (J. Jansa)
ABSTRACT
We describe mild and selective iodination of various 8-substituted imidazo[1,2-c]pyrimidine-5(6H)-
ones (ethenocytosines). Starting ethenocytosines were obtained by cyclization of 5-halogenocytosines
with chloroacetaldehyde or by subsequent Suzuki-Miyaura cross-coupling between
8-iodoimidazo[1,2-c]pyrimidine-5(6H)-one 1d and corresponding arylboronic acids. When
imidazo[1,2-c]pyrimidine-5(6H)-one or 8-iodoimidazo[1,2-c]pyrimidine-5(6H)-one 1d was iodinated
by N-iodosuccinimide (NIS) in DMF, pure 3,8-diiododerivative 2d was obtained. Under basic or acidic
conditions, this molecule is subject to rearrangement into 2,8-diododerivative 3d, which can be
subsequently iodinated to 2,3,8-triododerivative 4d. Since the positions of iodine atoms on the
imidazole ring could not be determined convincingly from NMR spectra only, X-ray analysis of 2d was
carried out with the aim of confirming the structure undoubtedly. The same sequence of reactions was
applied to another eight ethenocytosines, providing excellent regioselectivity, easy rearrangement, and
1
13
15
high yields of iodinated products. All ethenocytosines were properly characterized by H, C and N
NMR spectroscopy.
2

1. Introduction
ACCEPTED MANUSCRIPT
Halogenated compounds are considerable intermediates for a variety of organic and organometallic
reactions. In principle, an advantage of iododerivatives consists of their high reactivity. Nowadays, the
1
-3
4,5
halogen-metal exchange and cross-coupling reactions are an essential part of synthetic chemistry.
For these reasons the methods for effective iodination are of interest and N-iodosuccinimide (NIS) is
6
7
one of the most powerful reagents for iodination of both activated and deactivated aromatics.
Halogens, especially fluorine and chlorine, are widely used as substituents in medicinal chemistry.
Iodine containing drugs are less common, but we have found 3773 hits through the pharmaceutical
8
database. Out of them, there are 453 candidates in the preclinical stage, 71 in the clinical phases and 32
drugs were launched on the market. They have miscellaneous applications but their major therapeutic
groups are cancer therapy, diagnostic agents, antiinfective therapy and neurological drugs. The
9
examples of heterocyclic iodinated launched drugs are an antiviral Idoxuridine, diagnostic agent
1
0
11
12
Iomazenil, anticancer drug Trametinib, antifungal and antiprotozoal drug Clioquinol.
1
3
In recent times, organohalogens attracted attention related to halogen bonding phenomenon. Since
the iodocompounds generally form the strongest halogen bonds, they are studied more and more in the
1
4
15
16
field of medicinal, material and supramolecular chemistry.
Imidazo[1,2-c]pyrimidines and their 5-oxo derivatives (ethenocytosines) may be obtained by the
1
7-19
cyclization of 4-aminopyrimidines or cytosines respectively with α-halogenocarbonyl compounds.
2
0-23
Ethenocytosines were studied for their biological activity,
fluorescence and base-pairing
1
8
properties.
In view of halogenation of compounds similar to imidazo[1,2-c]pyrimidines, it is well established
24
that imidazo[1,2-a]pyridines undergo electrophilic attack at the 3-position. Iodination of these
2
5
26
compounds was well studied and it may be achieved using I in pyridine or chloroform, ICl in
2
2
7
28
chloroform, but preferentially with NIS in acetonitrile. In contrast to imidazo[1,2-a]pyridines, there
are relatively low reports on halogenation of 2,3-unsubstituted imidazo[1,2-c]pyrimidine scaffold.
2
9
These reactions seem to be less selective and lower yielding, apparently due to the deactivation by an
additional pyridine-type nitrogen.
Halogenation of 2,3-unsubstituted imidazo[1,2-c]pyrimidine-5(6H)-ones (ethenocytosines) was
reported very briefly in patent literature. It refers to the 3,8-dichlorination or 3,8-dibromination of 7-
3
0
(
2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine-5(6H)-one in low yields (26 and 12% respectively) and
3
1
3
-chlorination of 7-methyl-6-phenylimidazo[1,2-c]pyrimidine-5(6H)-one in 23% yield. To our best
knowledge To the best of our knowledge, only one iodination of this scaffold was reported. It refers to
the iodination of 6-benzylimidazo[1,2-c]pyrimidine-5(6H)-one by I /NaOAc in MeOH and the authors
2
3
2
describe iodination to position 3 in 46% yield.
3

3
3
This work is referring to our previous paper
which describes the synthesis of
ACCEPTED MANUSCRIPT
8-iodoimidazo[1,2-c]pyrimidin-5(6H)-one 1d and its Suzuki-Miyaura cross-coupling leading to the
derivatives 1e-i. As was described, some of these molecules, especially 1i, showed promising anticancer
activity in vitro. Hence, more modifications of these derivatives are of interest.
2
2
. Results and Discussion
.1. Chemistry
The synthesis starts from 5-halogenated cytosines. 5-Fluorocytosine, a known antimycotic drug
3
4
(
Flucytosine), was commercially available. 5-Chloro-, bromo- and iodocytosines were obtained in
large scale by direct halogenation of cytosine by known methods (see Experimental section).
-Halogenated imidazo[1,2-c]pyrimidines 1a-d were prepared in 66-86% yield by cyclization of
-halocytosines with chloroacetaldehyde in the presence of sodium acetate in water (Scheme 1). 8-Aryl
substituted imidazo[1,2-c]pyrimidines 1e-i were obtained by Suzuki-Miyaura cross-coupling between
8
5
3
3
1d and corresponding boronic acid (Scheme 1).
(
HO) B
R
2
ClCH CHO
NaOAc
2
N
N
O
N
NH2
X
O
N
O
N
Pd(dppf)Cl (3 mol%)
2
HN
HN
HN
H O, 2-4 h
X
Na CO (4 equiv)
2
2
3
70-80 °C
EtOH-H O 2:1
reflux/24 h
1a-d
2
1e-i
R
1a) X = F (66%)
1b) X = Cl (76%)
1c) X = Br (86%)
1d) X = I (86%)
1e) R = H (88%)
1f) R = Ph (81%)
1g) R = OMe (90%)
1h) R = CHO (83%)
1i) R = CN (84%)
Scheme 1. Synthesis of 8-substituted imidazo[1,2-c]pyrimidin-5(6H)-ones, yields in parentheses.
First attempts to iodinate the ethenocytosine scaffold were made on imidazo[1,2-c]pyrimidin-5(6H)-
3
5
one (prepared by similar procedure as compounds 1a-d in 68% yield) and its 8-iododerivative 1d
Scheme 2). When we started to iodinate these compounds, we supposed that iodination should proceed
(
to position 3 and/or 8 (see Introduction). It was surprising when different products were obtained by
iodination with 1.2 equivalents of NIS in refluxing CH CN and in DMF at room temperature. We
3
wanted to distinguish the position of this substitution by NMR spectroscopy but the structures could not
4

be ascertained convincingly from NMR spectra only. The main reason was that we were not able to
ACCEPTED MANUSCRIPT
distinguish quaternary carbons 5 and 8a (see chapter 2.2). For this reason, X-ray analysis of 2d was
carried out with the aim to confirm the regioselectivity of iodination undoubtedly (see chapter 2.2). It is
worthwhile to note the iodination by NIS in AcOH was not selective and iodination by I /KOH in water
2
resulted in complex reaction mixture.
3
5
When iodinating imidazo[1,2-c]pyrimidin-5(6H)-one by 1.2 equivalents of NIS in refluxing
CH CN the reaction was not clean but 2,8-diiodoethenocytosine 3d was the main product (Scheme 2).
3
In DMF at room temperature, the reaction was much more faster and a 1:1 mixture of 8-iodo- (1d) and
3,8-diodoethenocytosine 2d was isolated without impurities (Scheme 2). This result indicates a higher
reactivity of position 8 at the expense of position 3. When 2.2 equivalents of NIS was used, pure 2d was
obtained in 95% yield. The same yield of 2d was obtained by iodination of 1d with 1.1 equivalents of
NIS (Scheme 2).
I
NIS (1.2 equiv)
N
I
CH CN
O
N
3
main product
reflux
HN
3d
24 h
I
NIS (1.2 equiv)
DMF
N
N
N
I
O
N
O
N
O
N
+
1:1 mixture
HN
HN
HN
rt
I
2d
1d
24 h
I
NIS (2.2 equiv)
DMF
NIS (1.1 equiv)
DMF
N
I
N
I
O
N
O
N
rt
HN
yield 95 %
rt
HN
overnight
overnight
2d
1d
Scheme 2. Attempts to iodinate imidazo[1,2-c]pyrimidin-5(6H)-one and
-iodoimidazo[1,2-c]pyrimidin-5(6H)-one 1d.
8
Encouraged by these results we started to search for the reason of this reactivity. Solvent effect or
thermodynamic control seems to be less probable than rearrangement via a ring opening-ring closing
reaction. Such reactions This type of reaction was were reported by several papers as Dimroth-type
36
rearrangement and were reviewed by El Ashry et al. These reactions Rearrangements, rendering the
3
7
structural motif of ethenocytosine, were reported by Ivancsics and Zbiral, who described an
equilibrium ratio between original and rearranged product being ca 1:1. Further, the quantitative syn to
anti isomerizations of 1,3,4,6-tetraazapentalenes with condensed pyrimidinone rings were reported by
5

3
8-40
Bhat and Leonard.
Similar irreversible rearrangements of imidazo[1,2-c]quinazoline-5(6H)-one
ACCEPTED MANUSCRIPT
4
1
were reported by Arnold et al.
For better understanding, the rearrangement of 2d to 3d was tested in a number of ways. While
refluxing of 2d in MeOH resulted in no reaction, when even the weak base was added (NaHCO3,
NaOAc, KF), complete conversion to 3d was observed. Rearrangements of compounds 2a-i were
carried out with 1 equivalent of Na CO but it was proved that the catalytic conditions (0.1 equivalent)
2
3
is working equally. On the other hand, acid-assisted rearrangement also proceeded with 0.1 equivalent
of HCl. The facility of this rearrangement is demonstrated by the fluoroderivative 2a which is prone to
4
1
spontaneous rearrangement to 3a. This is in accordance with the findings of Arnold et al, who
described the positive effect of electron withdrawing substituents on the rate of rearrangement. These
findings should give evidence for rearrangement proceeding via ring opening-ring closing reaction
3
8,41
toward thermodynamically preferred 2-iodoethenocytosines. A plausible reaction mechanism
is
depicted in Scheme 3. The reaction starts by nucleophilic attack on the carbonyl group which may be
3
base or acid catalysed in the usual way. The sp hybridized intermediate fragments and the pyrimidine
ring opens to produce an imidazole-carbamate intermediate. Consequently, the imidazole ring may
rotate about the single bond, followed by reclosure from the less hindered side of the imidazole ring.
I
I
I
I
ROH
base or
acid
I
HO
RO
N
NH
N
R
N
R
HN
N
R
N
O
N
N
rotation
- ROH
N
O
RO
NH
NH OR
O
HN
catalysis
HN
NH
a-i
R
R
O
3
2
a-i
Scheme 3. Plausible reaction mechanism for the rearrangement of 3-substituted ethenocytosines of type
to 2-substituted ethenocytosines of type 3.
2
Based on these results the sequence of reactions depicted in Scheme 4 was proposed. Nine
ethenocytosines 1a-i were used as starting materials. These compounds were iodinated by 1.1
equivalents of NIS in DMF overnight. As was seen by TLC, the iodination of 1d was complete after 1 h
of stirring with NIS at room temperature, the isolated yield of 2d after 2 h was the same as for overnight
conditions (95%).
6

I
AC
I
CEPTED MANUSCRIPT I
I
Na CO
MeOH
NIS
DMF
2
3
NIS
DMF
N
R
N
N
N
O
N
O
N
O
N
O
N
HN
HN
2a-i
HN
HN
4a-i
rt
reflux
overnight
rt
R
R
R
overnight
overnight
1
a-i
3a-i
R = F, Cl, Br, I, phenyl, biphenyl-4-yl, 4-methoxyphenyl, 4-formylphenyl, 4-cyanophenyl
Scheme 4. Sequence of reactions for the synthesis of target iodinated compounds.
The reaction is highly selective for position 3. Even when an activating donor methoxy group was
present at the para position of benzene ring (compounds 1g and 3g), the iodination was selective if NIS
was slowly added. On the other hand, cyano and aldehyde groups were fully tolerated. Since the 3-iodo-
8-fluoroethenocytosine 2a is prone to rearrangement either during the iodination and workup, reaction
conditions were modified. To obtain pure 2a DMF was changed to THF and lower temperature was
applied, especially during the workup (see chapter 4.4.1). Pure 2a was obtained after recrystallization.
Rearrangement of 3-iodoethenocytosines 2a-i was carried out by means of 1 equivalent of Na CO in
2
3
refluxing MeOH. This reaction was selective, resulting in 83-97% yields of compounds 3a-i.
The synthetic utility of this rearrangement consists in the occasion of second iodination, leading to
2,3-diodoethenocytosines 4a-i, which are unable to be obtained by direct methods. Compounds 4a-i
were obtained in 84-96% yields by the same reaction conditions, as were for the first iodination.
2.2. Structure determinations
Products were identified and characterized by IR, MS and NMR spectroscopy. As we described
3
3
earlier for 5-iodocytosine, also 5-chloro- and 5-bromocytosine showed three broad NH protons which
mean that it exists as imino-tautomers (in DMSO-d ). For all new compounds 1a-c, 2a-i, 3a-i, 4a-i (1d-i
6
3
3
1
13
15
were described in our previous work ), the one- (1D) and two-dimensional (2D) H, C and N NMR
1
9
spectra were measured and analysed. The F NMR spectra were measured for four fluorine containing
compounds. The results are collected in Table 1 and Table 2 and numbering of atoms is depicted in
Scheme 5.
I
2
N 1
8a
I
2
N 1
8a
I
2
N 1
8a
I
2
N 1
8a
I
I
3
2
I
I
3
3
2
3
2
3
3
3
4
N 1
8a
4
N 1
8a
4
N 1
8a
4
4
4
4
O
N
O
N
O
N
O
N
O
N
O
N
O
N
5
5
5
5
5
5
5
HN
6
HN
6
HN
6
1`
HN
6
HN
6
1`
HN
6
HN
6
1`
8
X
8
X
8
8
X
8
8
8
X
7
7
7
7
7
7
7
4`
4`
4`
1a-c
2a-d
2e-i
2`
R
3a-d
3e-i
2`
R
4a-d
4e-i
2`
R
3`
3`
3`
Scheme 5. Numbering of atoms in compounds 1a-c, 2a-i, 3a-i and 4a-i for NMR purposes.
7

Table 1
ACCEPTED MANUSCRIPT
1
13
15
H, C and N chemical shifts [ppm] for the atoms numbered 1-8a in the compounds 1a-c, 2a-i, 3a-i
and 4a-i
1
15
1
Compd. X(R) δ(ppm)
1
-
2
3
4
-
5
-
6 / J( N, H)
7
8
-
8a
1
δ( H)
7.44
132.4
7.85
11.50
7.54
-
1
a
F
1
3
a
a
a
114.3
2.3
139.5b
139.0
29.3
δ( C)
-
134.5
114.1 -188.6
145.1
-261.6 / n.o.
b
b
3
230.6
1
δ( H)
-
7.45
132.3
7.45
7.88
114.0 -189.2
7.91
114.1 -190.3
-
-
11.91
7.60
127.3
7.66
-
-
1
b
Cl
Br
1
3
a
a
a
a
a
δ( C)
-
129.7
145.5
-249.6 / n.o.
103.6 142.8
1
δ( H)
-
127.2
-
-
-
145.7
-
11.94
-
90.0
-
-
1
2
c
1
3
a
δ( C)
-
132.2
7.47
-248.0 / n.o.
129.5
7.54
143.4
1
δ( H)
-
-
11.43
-
a
F
1
3
a
a
a
114.9
1.8
138.7b
141.6
28.9
δ( C)
-
130.6
-
140.9
64.2
-192.7
145.0
-261.2 / 93.6
b
b
3
230.9
1
δ( H)
7.45
140.8
7.47
140.7
7.43
140.5
7.44
140.8
7.53
140.8
7.43
140.8
7.49
140.7
7.51
140.7
-
-
63.6
-
-
-
11.82
a
7.56
128.0
7.61
-
-
2
b
Cl
Br
1
3
a
a
a
a
a
a
a
a
δ( C)
-
126.2.
-
-194.3
146.0
248.2 / 91.3
103.0 145.3
1
δ( H)
-
-
11.84
-
89.5
-
-
2
c
1
3
a
a
δ( C)
n.o.
63.5
-
-194.1
146.2
-246.9 / n.o.
130.2
7.56
145.8
1
δ( H)
-
-
-
11.73
-
147.3
-
2
d
I
1
3
a
a
δ( C)
-
-
-
-
-
-
118.9
62.9
-
-195.8
146.4
-243.0 / 93.3
134.8
7.50
59.5
-
1
δ( H)
-
-
-
11.81
2
e
H
1
3
a
a
a
a
a
a
δ( C)
128.1
61.7
-
-194.0
146.3
-247.7 / 93.2
127.3
7.56
110.7 147.3
1
δ( H)
-
-
-
11.87
-
-
2
f
Ph
1
3
a
δ( C)
125.7
61.8
-
-193.9
146.3
-247.7 / 93.4
127.3
7.36
110.2 147.2
1
δ( H)
-
-
-
11.73
-
-
2
g
OMe
CHO
CN
1
3
a
δ( C)
126.6
61.6
-
-194.0
146.3
-248.5 / 93.0
126.2
7.65
110.5 147.5
1
δ( H)
-
-
-
11.97
-
-
2
h
1
3
a
δ( C)
126.1
62.0
-
-193.9
146.2
-246.4 / 93.4
129.1
7.72
109.3 146.7
1
δ( H)
-
126.4
-
-
-193.9
-
-
146.6
-
12.03
-
-
2
i
1
3
a
δ( C)
62.2
8.05
-246.3 / 92.9
129.3
109.7 146.2
1
δ( H)
11.65
7.60
-
-
3
a
F
1
3
a
a
a
115.2
1.8
138.2b
140.7
29.1
δ( C)
-
122.4
90.3
118.0 -183.7
143.6
-260.1 / 93.5
b
b
3
230.8
1
δ( H)
-
-
90.2
-
8.05
119.3 -185.4
8.10
119.3 -185.0
8.11
119.2 -194.0
8.08
118.1 -184.3
8.11
-
-
12.00
7.61
128.2
7.68
-
-
3
b
Cl
Br
I
1
3
a
a
a
a
a
a
a
a
a
a
a
δ( C)
-
-
-
-
-
118.6
144.6
-249.0 / n.o.
102.3 144.0
1
δ( H)
-
-
-
145.1
-
12.06
-
88.6
-
-
3
c
1
3
a
δ( C)
115.7
-
90.1
-
-246.2 / 93.0
130.4
7.62
144.2
1
δ( H)
-
11.95
-
144.5
-
3
d
1
3
a
δ( C)
110.9
-
89.9
-
146.9
-
-242.2 / 91.8
135.0
7.56
58.2
-
1
δ( H)
-
12.06
3
e
H
1
3
a
δ( C)
117.8
-
90.3
-
146.4
-
-247.9 / 93.3
127.6
7.66
109.7 144.3
1
δ( H)
-
12.10
-
-
3
f
Ph
1
3
a
δ( C)
118.5
90.3
118.1 -184.1
146.3
-247.9 / 93.1
127.6
109.2 144.3
8

1
δ( H)
-
A
-
CCEP8.
T
06ED M
-
ANUSC
-
RIPT 11.98
7.45
126.5
7.72
-
3
g
OMe
CHO
CN
1
3
a
a
a
a
a
a
a
δ( C)
-
-
-
118.1
90.2
118.0 -184.1
8.04
118.2 -184.6
8.03
118.2 -184.4
146.5
-247.8 / 93.1
109.6 144.3
1
δ( H)
-
-
90.1
-
-
-
12.20
-
-
3
h
1
3
a
δ( C)
118.6
145.8
-246.6 / 92.4
129.3
7.74
108.3 144.2
1
δ( H)
-
118.7
-
-
-
145.7
-
12.22
-
-
3
i
1
3
a
δ( C)
90.1
-
-243.3 / n.o.
129.5
7.54
109.8 144.2
1
δ( H)
-
-
-187.8
-
11.52
-
-
4
a
F
1
3
a
a
a
115.7
137.9b
143.3
29.0
δ( C)
-
119.3
107.5
76.9
144.1
-260.3 / 93.6
b
b
3
1.4
231.0
1
δ( H)
-
-
-
76.5
-
-
11.92
7.58
128.8
7.60
-
-
4
b
Cl
Br
1
3
a
a
a
δ( C)
n.o.
107.5
n.o.
146.9
-249.1 / n.o.
102.1 144.5
1
δ( H)
-
-
-
-
11.92
-
88.5
-
-
4
c
1
3
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
δ( C)
-
-
-
-
-
-
-
113.7
107.4
76.3
-
-186.7
147.4
-245.8 / n.o.
131.0
7.59
144.7
1
δ( H)
-
-
-
-
11.79
-
145.0
-
4
d
I
1
3
a
δ( C)
125.2
107.3
75.9
-
-193.0
148.9
-242.7 / 93.3
135.8
7.43
58.3
-
1
δ( H)
-
-
-
-
11.93
4
e
H
1
3
a
δ( C)
115.1
107.7
74.7
-
-188.7
148.8
-247.9 / 93.0
128.1
7.55
110.1 144.8
1
δ( H)
-
-
107.7
-
-
-188.9
-
-
148.8
-
11.98
-
-
4
f
Ph
1
3
a
δ( C)
115.1
-
74.8
-
-247.9 / 92.8
128.1
7.37
109.5 144.8
1
δ( H)
11.86
-
-
4
g
OMe
CHO
1
3
a
δ( C)
115.0
-
107.7
-
74.6
-
-189.2
-
149.0
-
-248.5 / 93.1
127.1
7.58
109.8 144.8
1
δ( H)
12.04
-
-
4
h
1
3
a
δ( C)
115.5
-
107.6
-
75.0
-
-188.6
-
148.2
-
-246.3 / 93.0
129.7
7.69
108.6 144.6
1
δ( H)
12.20
-
-
4
i
CN
1
3
a
δ( C)
116.0
108.1
75.2
-188.7
148.2
-246.3 / 93.0
130.0
109.8 144.7
a
15
b 1 19
1
δ( N), J( F, H)
Table 2 was not included in the revised pdf.
9

Table 2
ACCEPTED MANUSCRIPT
1
13
15
19
H, C, N and F chemical shifts [ppm] for the substituents connected to the carbon C(8) (benzene
rings or fluorine atom)
Compd.
X(R)
δ(ppm)
1`
2`
3`
4`
R
X
1
9
1
2
a
a
F
F
δ( F)
-
-
-
-
-
-
-
-167.3
1
9
δ( F)
-
-
-
-
-167.1
1
δ( H)
-
7.81
127.8
8.04
128.2
7.82
129.0
8.17
127.9
8.21
128.1
-
7.45
128.3
7.76
126.5
6.99
113.7
7.93
129.5
7.90
132.2
-
7.39
-
-
-
-
-
-
-
-
-
2
e
H
1
3
δ( C)
1
1
1
1
1
33.0
127.6
-
1
a
δ( H)
-
-
2
f
Ph
1
3
a
δ( C)
32.1
139.2
1
δ( H)
-
-
3.84
55.2
10.03
192.6
-
2
g
OMe
CHO
1
3
δ( C)
25.3
158.8
1
δ( H)
-
-
2
h
1
3
δ( C)
39.1
134.9
1
δ( H)
-
-
108.7
-
2
i
CN
F
1
3
b
δ( C)
37.9
119.0
-
-123.3
1
9
3
a
e
δ( F)
-
-167.6
1
δ( H)
-
7.92
127.8
8.06
128.2
7.85
129.0
8.18
127.8
8.18
127.9
7.47
128.5
7.80
126.6
7.03
113.9
7.95
129.6
7.90
132.3
7.40
127.7
-
-
-
-
-
-
-
-
-
-
-
3
H
1
3
δ( C)
1
1
1
1
1
32.8
-
-
1
c
δ( H)
3
f
Ph
1
3
c
δ( C)
31.9
-
139.30
-
1
δ( H)
3.83
55.3
10.03
192.5
-
3
g
OMe
CHO
1
3
δ( C)
25.0
-
158.9
-
1
δ( H)
3
h
1
3
δ( C)
38.8
-
135.0
-
1
δ( H)
3
i
CN
F
1
3
b
δ( C)
37.6
107.7
119.0
-123.2
1
9
4
a
e
δ( F)
-
-
-
-
-
-
-
-167.4
-
1
δ( H)
7.81
7.45
7.39
4
H
1
3
δ( C)
132.7
-
127.9
7.96
128.4
7.79
127.7
-
-
-
1
c
δ( H)
-
-
-
-
-
-
-
4
f
Ph
1
3
c
δ( C)
131.8
128.3
126.6
139.3
1
δ( H)
-
7.75
129.1
8.04
7.02
113.8
7.91
-
3.83
55.3
10.01
192.4
-
4
g
OMe
CHO
CN
1
3
δ( C)
1
1
1
24.9
-
158.9
-
1
δ( H)
4
h
1
3
δ( C)
38.7
-
127.9
8.10
129.5
7.91
134.9
-
1
δ( H)
4
i
1
3
b
δ( C)
37.6
128.2
132.3
107.6
119.0
-123.2
a
b
c
1
13
δ ( H/ C) = -/139.8, 7.74/126.6, 7.51/129.0, 7.41/127.6
15
δ( N) of -C≡N group
1
13
δ ( H/ C) = -/139.7, 7.78/126.7, 7.53/129.1, 7.42/127.6
1
0

ACCEPTED MANUSCRIPT
The compounds measured can exist in three tautomeric forms A, B, C as depicted in Scheme 6.
2
2
2
1
1
1
R
N
R
R
N
R
R
R
NH
O
N
O
N
HO
N
HN
3
N
3
N
3
R
R
R
A
B
C
Scheme 6. Tautomerism of studied imidazo[1,2-c]pyrimidin-5(6H)-ones.
1
15
1
1
15
Since we observed J( N, H) in 1D gs H, N-HMQC spectra being 92 ± 2 Hz in all cases, we can
1
1
clearly exclude the structure C containing an OH group. Moreover, we observed J((N) H, H) being 5.3
±
0.3 Hz in 2,3-disubstituted derivatives and the same couplings were detectable in the H,H-COSY
3
15
1
1
spectra of other derivatives. This coupling must be due to J( N(6) H,C(7) H). The protons in positions
2
or 3 exist as singlets in 2- or 3-monosubstituted derivatives (in compounds having protons both in
3
1
1
position 2 and 3, two doublets exist with J(C(2) H, C(3) H) = 1.5 ± 0.2 Hz and no coupling with NH
proton was found). The conclusion is that the existence of the structure A was undoubtedly proved.
1
3
Proton bearing carbons were assigned by gs-HMQC. gs-HMBC and proton-coupled C NMR spectra
were measured with the aim to assign quaternary carbons. The doublet of doublet for C(5) due to
3
1
3
1
3
1
J(C(5),C(3) H) and J(C(5),C(7) H) coupling constants and doublet for C(8a) due to J(C(8a),C(7) H)
3
1
were observed in 2- monosubstituted derivatives while the doublet for C(5) due to J(C(5),C(7) H) and
3
1
3
1
doublet of doublet for C(8a) due to due to J(C(8a),C(2) H) and J(C(8a),C(7) H) coupling constants
1
3
existed in 3-monosubstituted derivatives. The higher C chemical shifts were tentatively assigned to
1
9
C(5) and the slightly lower ones to C(8a) in 2,3-disubstituted derivatives. The F chemical shifts in
compounds 1a, 2a, 3a and 4a are very similar and resonate in the narrow range -167.1 to -167.6 ppm.
1
5
1
15
N chemical shifts were read from 2D gs H, N-HMBC spectra. The assignment is based on the fact
1
15
that a residual doublet of N-H is observed in the H, N-HMBC spectra and N-H proton correlated with
1
5
nitrogen N(4). Typical ranges of N chemical shifts are as follows: -110.9 to -134.5 (N(1)), -183.7 to
195.8 (N(4)), -242.2 to -249.6 (N(6)-H) and -260.1 to -261.6 (N(6)-H) for fluorine-containing
compounds.
-
-1
The IR spectra revealed the aromatic and acidic proton bands in the range 2800-3500 cm . The
carbonyl group (band Amide I) of the ethenocytosine ring absorbed strongly in the range from 1702 to
-1
1
748 cm and additional stronger bands typical for secondary amides and heteroaromatic double bonds
were usually well observed in intervals 1600-1670, 1500-1580 (band Amide II and aromatic bands) and
-1
1
200-1300 cm (band Amide III). The signal of other functional groups like cyano (band 2224-2230
1
1

-
1
-1
-1
cm ), methoxy (bands 2834, 1340, 1180, 1033 cm ), aldehyde (band 1692-1710 cm ), mono (bands
ACCEPTED MANUSCRIPT
-1
-1
7
00 and 750 cm ) and para-substituted benzene ring (band 840 cm ) were clearly observed. Although
-1
the position of the carbonyl band (Amide I) changes in the range from 1702 to 1748 cm , we did not
observe any unambiguous shift for 2- or 3-substituted or 2,3-disubstituted ethenocytosines, respectively.
This shift of the carbonyl band (Amide I) is probably caused by intermolecular bonding.
The structure of 2d caused difficulties in terms of NMR spectra assignments and interpretation was
evaluated by X-ray diffraction methods on the single crystalline material. Although a lot of structures of
many pyrimidine-1,3-dione derivatives has been reported, including a couple of halogenated (iodinated)
compounds like for example 5-iodouracil and other biologically interesting compounds, only a limited
number of structures is known for the system of particular interest: imidazo[1,2-c]pyrimidine-5(6H)-
4
2-51
one.
The only example of halogenated compound slightly similar to the species under investigation
5
2
is the structure of 4-fluoro-2-methyl-3-phenylpyrimido[1,6-a]benzimidazol-1(2H)-one.
Fig. 1. The molecular structure (ORTEP 50% probability level) of 2d. Selected interatomic distances
[
Å] and angles [°]: C1 N1 1.397(4), N1 C2 1.393(5), C2 C3 1.430(5), C3 C4 1.350(5), C4 N2 1.362(5),
N2 C1 1.355(4), N1 C5 1.393(4), C5 C6 1.352(5), C6 N3 1.385(5), N3 C2 1.313(5), I1 C3 2.067(4), I2
C5 2.058(4), C1 O1 1.222(5); C1 N1 C2 124.2(3), C2 N1 C5 105.6(3), C1 N2 C4 125.7(3), C2 N3 C6
1
05.0(3).
1
2

ACCEPTED MANUSCRIPT
Fig. 2. The supramolecular architecture of 2d, N-H...C(=O) and I...I bonds are depicted with dotted
lines, C-H...N contacts and π-π stacking in not shown.
The perfectly planar structure of 2d (Fig. 1) reveals rather localized character of π-electron density
and thus the double bond type between C3-C4, C2-N3 and C5-C6 atoms which is clearly recognized
5
3,54
from a shortening of respective interatomic distances in comparison to reported single bonds
or even
5
3,55
the sum of the covalent radii for C-C or C-N, respectively.
The progressive shortening of the C-I
bond in comparison to the same measures by 0.1Å is also detected which is a reflection of the short
intermolecular I-I (3.785(3)Å, C-I...I-C torsion 169.85(11)°) halogen non-covalent contact in
5
6,57
heterocyclic compounds (Fig. 2).
Moreover molecules of 2d are interconnected to the planar 2D sheets by the H-bond from N-H to
C(=O) groups (N...O distance of 2.803(3)Å), C-H...N (C...N distance of 3.285(4)Å) contacts and π-π
stacking (interplanar distance of 3.007(3)Å) between heterocyclic rings.
3. Conclusion
In summary, we have developed a useful strategy for the synthesis of 3-iodo, 2-iodo and
,3-diodoethenocytosines, which possess high variability at position 8. The iodination of ethenocytosine
2
core by NIS in DMF proceeds smoothly at room temperature running selectively to position 3, when
position 8 is engaged. This reactivity was undoubtedly confirmed by X-ray crystallography of
compound 2d. 3-Iodoethenocytosines 2a-i rearrange readily to the 2-iododerivatives 3a-i under acidic
or basic conditions through the ring opening-ring closing reaction. These rearranged compounds 3a-i
1
3

were suitable substrates for a second iodination leading to the 2,3-diiodoethenocytosines 4a-i. All
ACCEPTED MANUSCRIPT
1
13
15
ethenocytosines were properly characterized by H, C and N NMR spectroscopy.
4
4
. Experimental section
.1. General Methods
1
The NMR spectra were measured on a Bruker Avance II 400 at 400.13 MHz ( H), 100.62 MHz
1
3
15
19
1
(
C), 40.54 MHz ( N) and 376.50 MHz ( F) or Bruker Avance 500 at 500.13 MHz ( H) and
1
3
1
13
1
25.67 MHz ( C) in DMSO-d at ambient temperature. The H and C chemical shifts were referenced
6
1
13
15
19
to the residual signal of the solvent (δ = 2.55 ( H) and 39.6 ( C)). The N and F chemical shifts were
referred to external nitromethane in a coaxial capillary and internal CFCl ), respectively, both having
3
(
δ = 0.0). For all chemical shifts and their assignment to the particular atoms see the Tables 1-2.
The X-ray data for colourless crystals of 2d (obtained by slow evaporation of THF solution) were
obtained at 150K using Oxford Cryostream low-temperature device on a Nonius KappaCCD
diffractometer with Mo K radiation (λ = 0.71073Å), a graphite monochromator, and the φ and χ scan
α
5
8
mode. Data reductions were performed with DENZO-SMN. The absorption was corrected by
5
9
60
integration methods. Structures were solved by direct methods (Sir92) and refined by full matrix
2
61
least-square based on F (SHELXL97). Hydrogen atoms were mostly localized on a difference Fourier
map, however to ensure uniformity of treatment of crystal, all hydrogen were recalculated into idealized
positions (riding model) and assigned temperature factors H (H) = 1.2 U (pivot atom). H atoms in
iso
eq
aromatic rings were placed with C-H distances of 0.93Å, and 0.86 for N-H bonds.
2
2
2
o
2
o
2 2
½
R = ∑ F - F
 /∑F , GOF = [∑(w(F - F ) )/(N
- Nparams)] for all data, R(F) = ∑  F  -
int
o
o,mean
c
diffrs
o
2
2
o
2 2
2 2 ½

F   /∑ F  for observed data, wR(F ) = [∑(w(F - F ) )/(∑w(F ) )] for all data.
c
o
c
o
Crystallographic data for structural analysis have been deposited with the Cambridge Crystallographic
Data Centre, CCDC no. 1019008. Copies of this information may be obtained free of charge from the
Director, CCDC, 12 Union Road, Cambridge CB2 1EY, UK (fax: +44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk).
Crystallographic data for 2d: C H I N O, M = 386.91, triclinic, P -1, a = 4.5380(2), b = 10.2510(4),
6
3 2
3
3
c = 10.4351(6) Å, α = 64.692(4), β = 86.388(4), γ = 82.033(4)°, Z = 2, V = 434.60(4) Å , D = 2.957
c
-3
-1
g.cm , µ = 7.189 mm , T /T = 0.350/0.669; -5 ≤ h ≤ 5, -13 ≤ k ≤ 13, -13 ≤ l ≤ 13; 7486 reflections
min max
measured (θmax = 27.5°), 1975 independent (R = 0.0306), 1785 with I > 2
σ
(I), 109 parameters, S =
int
1
1
.111, R1(obs. data) = 0.0254, wR2(all data) = 0.0617; max., min. residual electron density = 0.938, -
-3
.254 eǺ .
1
4

HRMS analyses were measured with Thermo Exactive instrument by the same method described
ACCEPTED MANUSCRIPT
3
3
earlier. The identification of the respective structures was performed with less than 0.7 ppm difference
between experimental and theoretically calculated value.
-1
IR spectra were recorded on a Nicolet 6700 FT-IR over the range of 400-4000 cm by KBr pellet
method. Melting points were determined on a Stuart SMP3 apparatus. The majority of iodinated
derivatives were unstable at temperatures above 200 °C. This phenomenon manifested by darkening of
crystals and release of iodine vapours. Reaction progress was monitored by thin-layer chromatography
(dichloromethane/methanol 5:1 or EtOAc/hexane 1:1 as mobile phase), which was performed on
SiO 60 F plates with UV detection at 254 nm. All starting materials were commercially available or
2
254
their preparation is cited in the text.
4.2. Synthesis of halocytosines
6
2
4.2.1. 5-Chlorocytosine
Cytosine (10 g, 90 mmol) was dissolved in glacial acetic (150 ml) acid at 70 °C. N-Chlorosuccinimide
13.2 g, 99 mmol) was added in the course of 10 min. The reaction mixture was stirred at 73-77 °C for
h and the product precipitated from reaction mixture. Acetic acid was evaporated under reduced
(
4
pressure. The residue was suspended in water (300 ml) and the pH was adjusted to 8-9 by solid sodium
carbonate (24 g, 0.23 mol). This mixture was stirred for 1 h, the product was filtered, washed with water
6
2
1
(
200 ml) and dried. Yield 12.4 g (95%), white crystals, mp 276-279 °C dec. (lit. >288 °C dec.), H
NMR (400 MHz, DMSO-d ): δ 7.09 (br s, 1H, NH), 7.67 (br s, 1H, NH), 7.72 (s, 1H, CH), 10.81 (br s,
6
1
3
1
H, NH); C NMR (100.6 MHz, DMSO-d ): δ 98.1, 141.3, 155.6, 162.4.
6
6
3
4.2.2. 5-Bromocytosine
Cytosine (50 g, 0.45 mol) was suspended in water (750 ml). Bromine (23.1 ml, 0.45 mol) was added in
the course of 70 min, whereas the temperature did not exceed 33 °C. The mixture was stirred at ambient
temperature for 4 h and then refrigerated overnight. White crystals were collected by filtration and dried
6
3
to obtain 5-bromocytosine hydrobromide. Yield 95.9 g (79 %), mp 250-255 °C dec. (lit. 255-256 °C
1
13
dec.), H NMR (400 MHz, DMSO-d ): δ 8.13 (s, 1H, CH); C NMR (100.6 MHz, DMSO-d ): δ 85.3,
6
6
146.4, 151.6, 160.4.
The obtained hydrobromide was suspended in water (1000 ml) and sodium carbonate (20.6 g,
0.194 mol) was slowly added. Thereafter the suspension was stirred overnight. The product was filtered
6
4
1
and dried at 50-60 °C. Yield 62 g (73%), white solid, mp 243-247 °C dec. (lit. 245-255 °C dec.), H
NMR (400 MHz, DMSO-d ): δ 6.88 (br s, 1H, NH), 7.69 (br s, 1H, NH) 7.78 (s, 1H, CH), 10.83 (br s,
6
1
3
1
H, NH); C NMR (100.6 MHz, DMSO-d ): δ 85.3, 144.1, 155.6, 162.8.
6
1
5

ACCEPTED MANUSCRIPT
4.2.3. 5-Iodocytosine
3
3
It was synthesized by the method described earlier.
4.3. Synthesis of haloethenocytosines
4.3.1. 8-Fluoroimidazo[1,2-c]pyrimidin-5(6H)-one (1a)
To the mixture of 5-fluorocytosine (25 g, 0.194 mol) and sodium acetate (39.7 g, 0.484 mol) in water
250 ml), chloroacetaldehyde (57% solution in water, 43.9 ml, 0.387 mol) was added. The mixture was
(
stirred for 3 h at 75-80 °C. Then the mixture was cooled to room temperature and stirred overnight.
Precipitated product was filtered, washed with water (250 ml) and dried. Yield 19.6 g (66%), brown
powder. Analytical sample was recrystallized from acetone and dried at 50-60 °C/30 mbar to obtain
white crystals, mp 258-260 °C, IR (KBr): 3435, 3182, 3115, 3083, 2806, 1733, 1720, 1659, 1578, 1500,
1
4
417, 1368, 1329, 1290, 1267, 1240, 1136, 1108, 1092, 930, 855, 789, 738, 716, 655, 642, 554,
-1
+
74 cm . HRMS m/z [M + H] calcd. for C H FN O: 154.04112, found 154.04110.
6
5
3
4.3.2. 8-Chloroimidazo[1,2-c]pyrimidin-5(6H)-one (1b)
To the mixture of 5-chlorocytosine (20 g, 0.137 mol) and sodium acetate (28.2 g, 0.344 mol) in water
200 ml), chloroacetaldehyde (57% solution in water, 31.1 ml, 0.275 mol) was added. The mixture was
(
stirred for 130 min at 70 °C. Then the mixture was cooled to room temperature and stirred overnight.
Product was filtered, washed with water (250 ml) and dried. Yield 17.7 g (76%), beige powder.
Analytical sample was recrystallized from acetone and dried at 50-60 °C/30 mbar to obtain white
crystals, mp 275-278 °C, IR (KBr): 3431, 3167, 3066, 2805, 1732, 1723, 1717, 1615, 1556, 1416, 1283,
-1
+
1
248, 1191, 1140, 1113, 925, 875, 759, 744, 715, 635, 592, 554 cm . HRMS m/z [M + H] calcd. for
C H ClN O: 170.01157, found 170.01156.
6
5
3
4
.3.3. 8-Bromoimidazo[1,2-c]pyrimidin-5(6H)-one (1c)
To the mixture of 5-bromocytosine (20 g, 0.105 mol) and sodium acetate (21.6 g, 0.263 mol) in water
200 ml), chloroacetaldehyde (57% solution in water, 23.8 ml, 0.21 mol) was added. The mixture was
(
stirred for 3 h at 80 °C. Then the mixture was cooled to room temperature and stirred overnight. Product
was filtered, washed with water (250 ml) and dried. Yield 19.3 g (86%), light brown powder. Analytical
sample was recrystallized from acetone and dried at 50-60 °C/30 mbar to obtain yellowish crystals, mp
2
1
2
31-232 °C, IR (KBr): 3435, 3138, 3115, 3074, 2820, 1736, 1714, 1613, 1551, 1487, 1284, 1250, 1172,
-1
+
135, 1111, 918, 868, 782, 751, 715, 638, 573, 557 cm . HRMS m/z [M + H] calcd. for C H BrN O:
6
5
3
13.96105, found 213.96113.
1
6

4
.3.4. 8-Iodoimidazo[1,2-c]pyrimidin-5(6H)-one (1d)
ACCEPTED MANUSCRIPT
3
3
It was synthesized by the method described earlier.
4.4. General procedure for the synthesis of 3-iodoethenocytosines
To the mixture of 8-substituted imidazo[1,2-c]pyrimidin-5(6H)-one 1a-i (1-15 g) in DMF
(10-20 ml/g), NIS (1.1 equivalents) was added in the course of 10 min. This mixture was stirred at room
temperature overnight. Thereafter, DMF was evaporated under reduced pressure at 50 °C and the
residue was suspended under stirring in 0.1 M sodium thiosulfate (40 ml/1 g of starting ethenocytosine)
overnight. Product was filtered, washed with water (50 ml/1 g of starting ethenocytosine) and dried to
obtain pure products (NMR). Analytical samples of all products were recrystallized from an appropriate
solvent (see in parenthesis beyond mp) and dried at 50-60 °C/30 mbar.
Different procedures were applied in case of 2a and 2g (see below).
4.4.1. 8-Fluoro-3-iodoimidazo[1,2-c]pyrimidin-5(6H)-one (2a)
According to the general procedure the mixture of 2a and 3a was obtained in 87% yield. This
product was directly used for the next step. For the synthesis of pure 2a, the procedure was as follows.
To a suspension of 1a (1 g, 6.53 mmol) in THF (20 ml), NIS (1.62 g, 7.2 mmol) was added in the
course of 10 min. The reaction mixture was stirred at 20 °C for 21 h. Then the solvent was evaporated
under reduced pressure without external heating. The residue was stirred in 0.1 M sodium thiosulfate
(40 ml) for 3 h. Product was filtered, washed with water (50 ml) and dried in vacuo to obtain 1.32 g
(73%) of product. Pure product was obtained by recrystallization from acetone-hexane-dichlormethane
(3:1:1). Yield 0.63 g (35%), light brown solid, mp 232-235 °C dec., IR (KBr): 3426, 3223, 3095, 2921,
1719, 1665, 1569, 1497, 1471, 1342, 1329, 1255, 1238, 1141, 1114, 1069, 955, 946, 840, 798, 741, 659,
-1
+
6
11, 577, 476 cm . HRMS m/z [M + H] calcd. for C H FIN O: 279.93776, found 279.93767.
6
4
3
4.4.2. 8-Chloro-3-iodoimidazo[1,2-c]pyrimidin-5(6H)-one (2b)
Yield 23 g (88%), white crystals, mp 245-248 °C dec. (acetone/water 10:1), IR (KBr): 3428, 3111,
3
1
2
050, 2854, 2796, 2730, 2689, 1718, 1621, 1546, 1515, 1389, 1329, 1310, 1263, 1238, 1188, 1145,
-1
+
102, 926, 865, 853, 764, 750, 644, 613, 601, 578 cm . HRMS m/z [M + H] calcd. for C H ClIN O:
6
4
3
95.90821, found 295.90823.
4.4.3. 8-Bromo-3-iodoimidazo[1,2-c]pyrimidin-5(6H)-one (2c)
Yield 21.7 g (91%), yellow solid, mp 230-235 °C dec. (acetone/water 10:2), IR (KBr): 3437, 3128,
3
6
068, 2908, 2854, 2801, 1730, 1616, 1542, 1328, 1310, 1257, 1169, 1145, 1096, 913, 858, 744, 639,
-1
+
09, 569, 505 cm . HRMS m/z [M + H] calcd. for C H BrIN O: 339.85769, found 339.85749.
6
4
3
1
7

ACCEPTED MANUSCRIPT
4.4.4. 3,8-Diiodoimidazo[1,2-c]pyrimidin-5(6H)-one (2d)
Yield 2.8 g (95%), white solid, mp 238-244 °C dec. (methanol), IR (KBr): 3427, 3087, 2908, 1719,
-1
1
607, 1536, 1337, 1313, 1248, 1162, 1146, 1097, 1027, 903, 847, 745, 634, 559 cm . HRMS m/z
+
[
M + H] calcd. for C H I N O: 387.84382, found 387.84408.
6
4 2
3
4.4.5. 3-Iodo-8-phenylimidazo[1,2-c]pyrimidin-5(6H)-one (2e)
Yield 1.56 g (98%), yellowish crystals, mp 196-198 °C (acetonitrile), IR (KBr): 3435, 3123, 3066,
2
1
913, 2819, 2634, 1725, 1618, 1540, 1496, 1443, 1385, 1339, 1325, 1294, 1261, 1156, 1139, 1093,
-1
+
032, 986, 920, 873, 767, 701, 670, 652, 608, 582, 564, 481 cm . HRMS m/z [M + H] calcd. for
C H IN O: 337.97848, found 337.97826.
12
9
3
4.4.6. 8-(Biphenyl-4-yl)-3-iodoimidazo[1,2-c]pyrimidin-5(6H)-one (2f)
Yield 1.79 g (96%), gold crystals, mp 276-285 °C dec. (acetonitrile), IR (KBr): 3442, 3246, 3129, 2943,
1
6
728, 1622, 1541, 1518, 1481, 1405, 1385, 1324, 1257, 1135, 1091, 919, 845, 826, 766, 729, 697, 650,
-1
+
10, 579, 570, 494 cm . HRMS m/z [M + H] calcd. for C H IN O: 414.00978, found 414.00958.
1
8
13
3
4.4.7. 3-Iodo-8-(4-methoxyphenyl)imidazo[1,2-c]pyrimidin-5(6H)-one (2g)
According to the general procedure the iodination exhibited approximately 80% selectivity for position
, as detected by NMR. For the synthesis of pure 2g, the procedure was as follows.
To the solution of 1g (1.5 g, 6.22 mmol) in DMF (30 ml), NIS (1.47 g, 6.53 mmol) was added at 15-
0 °C in the course of 8 h. This mixture was stirred at room temperature overnight. Thereafter, DMF
3
2
was evaporated under reduced pressure at 50 °C and the residue was suspended under stirring in 0.1 M
sodium thiosulfate (40 ml) overnight. Product was filtered, washed with water (80 ml) and dried. Yield
2
5
1
5
.2 g (96%), light brown solid. Analytical sample was recrystallized from acetonitrile and dried at
0-60 °C/30 mbar to obtain off-white solid, mp 190-194 °C, IR (KBr): 3435, 3220, 3084, 2933, 2834,
709, 1622, 1609, 1543, 1512, 1461, 1344, 1299, 1249, 1182, 1148, 1093, 1033, 829, 802, 754, 548,
-1
+
13 cm . HRMS m/z [M + H] calcd. for C H IN O : 367.98905, found 367.98917.
1
3
11
3
2
4.4.8. 4-(3-Iodo-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidin-8-yl)benzaldehyde (2h)
Yield 1.48 g (97%), yellowish crystals, mp 204-206 °C (acetonitrile), IR (KBr): 3432, 3244, 3173,
2
1
3
940, 2842, 1715, 1624, 1602, 1566, 1542, 1388, 1343, 1330, 1312, 1295, 1249, 1217, 1177, 1141,
-1
+
090, 832, 764, 753, 653, 608, 571, 495, 482 cm . HRMS m/z [M + H] calcd. for C H IN O :
1
3
9
3
2
65.97340, found 365.97326.
4.4.9. 4-(3-Iodo-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidin-8-yl)benzonitrile (2i)
1
8

Yield 1.39 g (91%), white crystals, mp 223-224 °C (acetonitrile), IR (KBr): 3405, 3222, 3090, 2937,
ACCEPTED MANUSCRIPT
2
5
224, 1708, 1622, 1605, 1541, 1509, 1408, 1391, 1332, 1256, 1150, 1134, 1091, 853, 837, 749, 610,
-1
+
74, 541, 499 cm . HRMS m/z [M + H] calcd. for C H IN O: 362.97373, found 362.97353.
1
3
8
4
4.5. General procedure for the rearrangement of 3-iodoethenocytosines
The mixture of 8-substituted 3-iodoimidazo[1,2-c]pyrimidin-5(6H)-one 2a-i (1-15g), Na CO3
2
(1 equivalent) and MeOH (20 ml/g) was stirred at reflux overnight (15-24 h). Thereafter, MeOH was
evaporated under reduced pressure. Water (20 ml/g) was added to the residue and the mixture was
acidified with acetic acid (2.2 equivalents with respect to starting 3-iododerivative). Obtained
suspension was stirred overnight. Product was filtered, washed with water (50 ml/1 g of starting 3-
iododerivative) and dried to obtain pure products (NMR). Analytical samples of all products were
recrystallized from an appropriate solvent (see in parenthesis beyond mp) and dried at 50-60 °C/30
mbar.
4.5.1. 8-Fluoro-2-iodoimidazo[1,2-c]pyrimidin-5(6H)-one (3a)
Yield 13.4 g (90%), white crystals, mp 251-255 °C dec. (acetone), IR (KBr): 3444, 3229, 3153, 3138,
3
1
097, 3087, 2920, 2829, 1733, 1652, 1563, 1482, 1392, 1351, 1316, 1291, 1245, 1207, 1120, 1093,
-1
+
070, 945, 840, 799, 745, 735, 714, 687, 644, 626, 556, 480 cm . HRMS m/z [M + H] calcd. for
C H FIN O: 279.93776, found 279.93766.
6
4
3
4.5.2. 8-Chloro-2-iodoimidazo[1,2-c]pyrimidin-5(6H)-one (3b)
Yield 9.2 g (92%), white crystals, mp 265-268 °C dec. (acetone/water 10:1), IR (KBr): 3439, 3219,
3
1
151, 3089, 3054, 2911, 2827, 1735, 1715, 1685, 1611, 1538, 1497, 1487, 1384, 1352, 1313, 1273,
-1
+
205, 1182, 1127, 1078, 995, 943, 851, 776, 733, 715, 652, 623, 615, 560 cm . HRMS m/z [M + H]
calcd. for C H ClIN O: 295.90821, found 295.90820.
6
4
3
4.5.3. 8-Bromo-2-iodoimidazo[1,2-c]pyrimidin-5(6H)-one (3c)
Yield 8.6 g (86%), beige crystals, mp 247-250 °C dec. (acetone/water 10:1), IR (KBr): 3434, 3219,
3
1
151, 3085, 3053, 2913, 2827, 1730, 1715, 1614, 1601, 1530, 1480, 1382, 1351, 1314, 1267, 1204,
-1
+
168, 1126, 1078, 969, 938, 838, 733, 713, 642, 623, 598, 559, 501 cm . HRMS m/z [M + H] calcd.
for C H BrIN O: 339.85769, found 339.85750.
6
4
3
4
.5.4. 2,8-Diiodoimidazo[1,2-c]pyrimidin-5(6H)-one (3d)
Yield 8.31 g (83%), yellowish crystals, mp 247-251 °C dec. (methanol), IR (KBr): 3432, 3216, 3151,
077, 2915, 1727, 1603, 1521, 1479, 1375, 1353, 1318, 1264, 1204, 1159, 1125, 1076, 954, 932, 733,
3
1
9

-
1
+
7
13, 637, 623, 588, 559, 500 cm . HRMS m/z [M + H] calcd. for C H I N O: 387.84382, found
6 4 2 3
ACCEPTED MANUSCRIPT
387.84381.
4.5.5. 2-Iodo-8-phenylimidazo[1,2-c]pyrimidin-5(6H)-one (3e)
Yield 0.93 g (93%), yellowish crystals, mp 202-204 °C (acetonitrile), IR (KBr): 3433, 3214, 3150,
3
6
083, 2935, 1708, 1623, 1537, 1496, 1445, 1360, 1292, 1258, 1208, 1131, 1079, 1031, 932, 842, 766,
-1
+
97, 648, 580, 492 cm . HRMS m/z [M + H] calcd. for C H IN O: 337.97848, found 337.97829.
1
2
9
3
4.5.6. 8-(Biphenyl-4-yl)-2-iodoimidazo[1,2-c]pyrimidin-5(6H)-one (3f)
Yield 1.6 g (94%), white solid, mp 281-284 °C dec. (acetone), IR (KBr): 3395, 3224, 3151, 3130, 3090,
3
1
060, 3033, 2938, 1702, 1617, 1538, 1518, 1489, 1482, 1447, 1407, 1390, 1360, 1330, 1292, 1255,
-1
210, 1135, 1118, 1082, 996, 931, 830, 770, 757, 736, 706, 669, 588, 510, 405 cm . HRMS m/z
+
[
M + H] calcd. for C H IN O: 414.00978, found 414.00951.
1
8
13
3
4.5.7. 2-Iodo-8-(4-methoxyphenyl)imidazo[1,2-c]pyrimidin-5(6H)-one (3g)
Yield 1.34 g (89%), beige crystals, mp 223-225 °C (acetonitrile), IR (KBr): 3435, 3213, 3148, 3072,
2934, 2834, 1709, 1610, 1538, 1511, 1460, 1419, 1359, 1299, 1265, 1247, 1214, 1183, 1120, 1083,
-1
+
1
033, 930, 826, 803, 739, 670, 625, 560, 550, 514, 409 cm . HRMS m/z [M + H] calcd. for C H
13 11
IN O : 367.98905, found 367.98907.
3
2
4.5.8. 4-(2-Iodo-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidin-8-yl)benzaldehyde (3h)
Yield 0.95 g (95%), beige crystals, mp 242-251 °C dec. (acetonitrile), IR (KBr): 3438, 3209, 3158,
3
1
088, 2943, 2831, 1713, 1692, 1619, 1603, 1567, 1536, 1507, 1477, 1423, 1394, 1360, 1317, 1295,
-1
261, 1212, 1178, 1143, 1082, 931, 836, 776, 732, 694, 607, 566, 494, 484, 415 cm . HRMS m/z
+
[
M + H] calcd. for C H IN O : 365.97340, found 365.97331.
1
3
9
3
2
4.5.9. 4-(2-Iodo-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidin-8-yl)benzonitrile (3i)
Yield 0.92 g (97%), white solid, mp 263-267 °C dec. (acetonitrile), IR (KBr): 3437, 3214, 3082, 2952,
2
8
3
855, 2230, 1712, 1620, 1606, 1536, 1507, 1475, 1415, 1358, 1346, 1284, 1259, 1211, 1140, 1081, 932,
-1
+
40, 757, 725, 667, 626, 570, 541, 502, 410 cm . HRMS m/z [M + H] calcd. for C H IN O:
1
3
8
4
62.97373, found 362.97354.
4.6. General procedure for the synthesis of 2,3-diiodoethenocytosines
This iodination was carried out according to the general procedure (see chapter 4.4) which was
described above for 3-iododerivatives. These iodinations started from 8-substituted
2
0

2
-iodoimidazo[1,2-c]pyrimidin-5(6H)-ones 3a-i (0.5-2g). In the case of methoxy-substituted compound
ACCEPTED MANUSCRIPT
3g, more careful procedure was employed (see chapter 4.4.7) for obtaining pure 4g. Analytical samples
of all products were recrystallized from an appropriate solvent (see in parenthesis beyond mp) and dried
at 50-60 °C/30 mbar.
4.6.1. 8-Fluoro-2,3-diiodoimidazo[1,2-c]pyrimidin-5(6H)-one (4a)
Yield 2.44 g (84%), gold crystals, mp 262-266 °C dec. (acetonitrile), IR (KBr): 3426, 3309, 3121, 2925,
-1
1
738, 1704, 1663, 1567, 1430, 1327, 1256, 1184, 1115, 964, 860, 806, 740, 698, 681, 570, 425 cm .
+
HRMS m/z [M + H] calcd. for C H FI N O: 405.83440, found 405.83436.
6
3
2
3
4
.6.2. 8-Chloro-2,3-diiodoimidazo[1,2-c]pyrimidin-5(6H)-one (4b)
Yield 2.65 g (93%), white crystals, mp 285-288 °C dec. (acetonitrile), IR (KBr): 3446, 3221, 3079,
921, 1720, 1622, 1539, 1441, 1375, 1321, 1288, 1244, 1202, 1185, 1105, 949, 742, 667, 623, 580, 428
2
-1
+
cm . HRMS m/z [M + H] calcd. for C H ClI N O: 421.80485, found 421.80458.
6
3
2
3
4.6.3. 8-Bromo-2,3-diiodoimidazo[1,2-c]pyrimidin-5(6H)-one (4c)
Yield 2.56 g (93%), white crystals, mp 294-298 °C dec. (acetonitrile), IR (KBr): 3439, 3216, 3076,
2
5
917, 1717, 1614, 1534, 1441, 1377, 1322, 1288, 1241, 1201, 1173, 1105, 1011, 936, 743, 654, 607,
-1
+
79, 429 cm . HRMS m/z [M + H] calcd. for C H BrI N O: 465.75434, found 465.75419.
6
3
2
3
4.6.4. 2,3,8-Triiodoimidazo[1,2-c]pyrimidin-5(6H)-one (4d)
Yield 1.24 g (93%), white crystals, mp >280 °C dec. (acetone), IR (KBr): 3438, 3207, 3069, 2911,
-1
1
708, 1608, 1526, 1439, 1289, 1239, 1199, 1165, 1106, 1003, 744, 649, 597, 580, 427 cm . HRMS m/z
+
[
M + H] calcd. for C H I N O: 513.74047, found 513.74014.
6
3 3
3
4.6.5. 2,3-Diiodo-8-phenyl-imidazo[1,2-c]pyrimidin-5(6H)-one (4e)
Yield 0.62 g (90%), yellowish crystals, mp 245-253 °C dec. (acetonitrile), IR (KBr): 3434, 3207, 3113,
2
5
943, 1706, 1632, 1538, 1496, 1446, 1430, 1342, 1312, 1282, 1236, 1198, 1102, 781, 764, 752, 700,
-1
+
84, 493, 423 cm . HRMS m/z [M + H] calcd. for C H I N O: 463.87512, found 463.87489.
1
2
8 2
3
4.6.6. 8-(Biphenyl-4-yl)-2,3-diiodoimidazo[1,2-c]pyrimidin-5(6H)-one (4f)
Yield 0.61 g (94%), beige crystals, mp 253-256 °C dec. (acetonitrile), IR (KBr): 3435, 3212, 3085,
2952, 1706, 1622, 1537, 1484, 1444, 1432, 1321, 1278, 1233, 1198, 1102, 1008, 988, 835, 786, 770,
-1
+
7
49, 729, 703, 683, 589, 578, 514, 441 cm . HRMS m/z [M + H] calcd. for C H I N O: 539.90642,
18 12 2 3
found 539.90621.
2
1

4
.6.7. 2,3-Diiodo-8-(4-methoxyphenyl)imidazo[1,2-c]pyrimidin-5(6H)-one (4g)
ACCEPTED MANUSCRIPT
Yield 0.64 g (96%), yellow crystals, mp 197-201 °C dec. (acetonitrile), IR (KBr): 3431, 3218, 3080,
2
8
4
932, 2834, 1711, 1624, 1609, 1537, 1511, 1460, 1438, 1340, 1295, 1252, 1198, 1181, 1102, 1029, 831,
-1
+
03, 750, 578, 553, 521 cm . HRMS m/z [M + H] calcd. for C H I N O : 493.88569, found
1
3
10 2
3
2
93.88549.
4.6.8. 4-(2,3-Diiodo-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidin-8-yl)benzaldehyde (4h)
Yield 0.63 g (94%), yellowish crystals, mp 241-250 °C dec. (acetonitrile), IR (KBr): 3436, 3089, 2938,
1
7
4
731, 1709, 1621, 1603, 1566, 1534, 1506, 1436, 1389, 1318, 1276, 1220, 1198, 1175, 1099, 992, 833,
-1
+
75, 750, 697, 577, 495, 427 cm . HRMS m/z [M + H] calcd. for C H I N O : 491.87004, found
1
3
8 2
3
2
91.86983.
4.6.9. 4-(2,3-Diiodo-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidin-8-yl)benzonitrile (4i)
Yield 0.60 g (90%), off-white solid, mp 283-286 °C dec. (acetonitrile), IR (KBr): 3434, 3251, 3165,
2
6
4
940, 2224, 1724, 1624, 1607, 1534, 1505, 1431, 1409, 1338, 1313, 1275, 1233, 1198, 1100, 834, 748,
-1
+
70, 578, 541, 502, 428 cm . HRMS m/z [M + H] calcd. for C H I N O: 488.87037, found
13
7 2
4
88.87015.
Acknowledgements
This work was supported by the Ministry of Industry and Trade of the Czech Republic (projects
FR-TI1/202 and FR-TI4/177). We thank Dagmar Zvolánková for technical help.
Supplementary data
Supplementary data related to this article can be found at XXX
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Supplementary data
Synthesis, structure and rearrangement of iodinated
imidazo[1,2-c]pyrimidine-5(6H)-ones derived from
cytosine
a,b,*
a
c
d
a
Josef Jansa , Antonín Lyčka , Aleš Růžička , Martin Grepl , Jan Vaněček
a
b
c
d
Research Institute for Organic Syntheses (VUOS), Rybitví 296, CZ-533 54 Pardubice-
Rybitví, Czech Republic
Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu
1
192/12, CZ-771 46 Olomouc, Czech Republic
Department of General and Inorganic Chemistry, Faculty of Chemical Technology,
University of Pardubice, Studentská 573, CZ-532 10 Pardubice, Czech Republic
Farmak a.s., Na Vlčinci 16/3, CZ-771 17 Olomouc, Czech Republic
*
Corresponding author. Tel.: +420466822371; fax: +420466823900.
E-mail address: josef.jansa@vuos.com (J. Jansa)
Contents
1
13
H and C NMR spectra of the synthesized products………………………………..…S2-S40
S1

ACCEPTED MANUSCRIPT
5
-Chlorocytosine
O
N
NH2
Cl
HN
S2

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5
-Bromocytosine
O
N
NH2
Br
HN
S3

ACCEPTED MANUSCRIPT
5
-Iodocytosine
O
N
NH2
I
HN
S4