Two-Step Regioselective Synthesis of 3-(Sulfonylamino)imidazo[1,2-a]pyrimidines from 2-Aminopyrimidines and N-(2,2-Dichloro-2-phenylethylidene)arensulfonamides

Article abstract of DOI:10.1002/ejoc.201402695

The reaction of 2-aminopyrimidines with N-(2,2-dichloro-2-phenylethylidene)arenesulfonamides affords the corresponding products of nucleophilic addition to the azomethine group, N-[2,2-dichloro-2-phenyl-1-(heterylamino)ethyl]sulfonamides, in good yields.

Full text of DOI:10.1002/ejoc.201402695

Job/Unit: O42695
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Date: 27-08-14 17:56:12
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FULL PAPER
DOI: 10.1002/ejoc.201402695
Two-Step Regioselective Synthesis of 3-(Sulfonylamino)imidazo-
[1,2-a]pyrimidines from 2-Aminopyrimidines and N-(2,2-Dichloro-2-
phenylethylidene)arensulfonamides
Igor B. Rozentsveig,*[a] Valery Yu. Serykh,[a] Gulnur N. Chernysheva,[a]
Evgeniy V. Kondrashov,[a] Alena I. Fedotova,[a] Igor A. Ushakov,[a] Evgeny V. Tretyakov,[b]
and Galina V. Romanenko[b]
Keywords: Nitrogen heterocycles / Sulfonamides / Nucleophilic addition / Rearrangement / Regioselectivity
The reaction of 2-aminopyrimidines with N-(2,2-dichloro-2-
give imidazo[1,2-a]pyrimidin-3-ylsulfonamides in the pres-
phenylethylidene)arenesulfonamides affords the correspond- ence of NaOH, whereas the expected isomeric imidazo[1,2-a]-
ing products of nucleophilic addition to the azomethine
group, N-[2,2-dichloro-2-phenyl-1-(heterylamino)ethyl]sulf-
onamides, in good yields. The latter are easily cyclized to
pyrimidin-2-ylsulfonamides are not formed. A tentative
mechanism for the formation of annulated heterocyclic deriv-
atives through Dimroth rearrangement has been proposed.
Introduction
N-Functionalized polyhaloaldimines and polyhaloketim-
ines are significant representatives of azomethine systems.[1]
Due to the presence of the electron-withdrawing substitu-
ents, imines of such type are exceedingly active in reactions
with O-, N-, and S-nucleophiles, aromatics and heteroarom-
atics, providing effective approaches for the preparation of
diverse amide derivatives.[1,2] Polyhaloaldimine or polyhalo-
ketimine molecules contain two electrophilic reactive sites,
namely the carbon atom of electron-deficient azomethine
group and the carbon atom of the polyhalomethyl group.
Thus, haloimines are promising dielectrophiles that can be
used as key reagents in the preparation of biologically active
amino acids, amidines, and heterocycles.[1–3]
Scheme 1. Synthesis of phenyldichloroacetaldimines 1a–c and their
reaction with 2-aminopyrimidines 2a–f.
We have worked out new approaches for the synthesis
of sulfonylamino-substituted heterocyclic derivatives[3d,3e,4]
based on phenyldichloroacetaldimines 1. Highly electro-
philic imines 1 are available through synthetic methods
based on free-radical reaction of N,N-dichlorosulfonamides
with phenylacetylene[5] (Scheme 1).
idines or (sulfonylamino)imidazo[2,1-b]thiazoles. In a con-
tinuation of our previous studies, in the present work we
explored the possibility of obtaining (sulfonylamino)imid-
azo[1,2-a]pyrimidines from imines 1 and 2-aminopyrimid-
ines 2.
It should be noted that amino-substituted imidazo[1,2-a]-
pyrimidines are valuable reagents[6a,6b] and biologically
active compounds,[6b–6e] having antimicrobial activity,[6c] ex-
hibiting the property of potassium channel modulators,[6d]
and they are promising drugs for prophylaxis and treatment
of proliferative diseases.[6e] The development of new syn-
thetic methodologies for the preparation of such derivatives
andthesynthesisofnew representativesoftheimidazo[1,2-a]-
pyrimidine series are thus urgent tasks.
It was shown[4] that reaction of imines 1 with 2-amino-
pyridines or 2-aminothiazole allows the selective one-pot,
two-step synthesis of (sulfonylamino)imidazo[1,2-a]pyr-
[a] A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch
of the Russian Academy of Sciences,
Favorsky Str., 1, Irkutsk 664033, Russia
E-mail: i_roz@irioch.irk.ru
http://www.irkinstchem.ru/index.php/ru/
http://www.isc.irk.ru/Eng/irich_e.htm
[b] International Tomography Center, Siberian Branch of the
Russian Academy of Sciences,
Results and Discussion
It is known that reactions of imines or imine analogues
produced in situ, with aminopyrimidines lead to the forma-
Institutskaya Str., 3a, Novosibirsk 630090, Russia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402695.
Eur. J. Org. Chem. 0000, 0–0
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I. B. Rozentsveig et al.
Table 1. Screening of conditions for the reaction of imines 1a–c with aminopyrimidines 2a–h and yields of adducts 3–8.
FULL PAPER
Entry Imine 1 (Ar)
2
R1
R2
R3
T [°C]
Time [h] Solvent
Adduct 3–8
Yield [%]
1
2
3
4
5
6
7
8
1a (4-ClC6H4)
1a (4-ClC6H4)
1a (4-ClC6H4)
1a (4-ClC6H4)
1a (4-ClC6H4)
1b (Ph)
1c (4-MeC6H4)
1a (4-ClC6H4)
1b (Ph)
1c (4-MeC6H4)
1a (4-ClC6H4)
1b (Ph)
1c (4-MeC6H4)
1a (4-ClC6H4)
1b (Ph)
1c (4-MeC6H4)
1a (4-ClC6H4)
1a (4-ClC6H4)
1b (Ph)
1c (4-MeC6H4)
1a (4-ClC6H4)
1a (4-ClC6H4)
1b (Ph)
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
2e
2e
2e
2e
2f
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
Br
Br
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
100
room temp.
room temp.
room temp.
100
room temp.
room temp.
room temp.
100
10
10
10
6
6
6
6
6
6
6
6
6
6
6
6
6
10
10
10
10
10
10
10
10
20
20
CCl4
toluene
CH3CN
DMF
3a
3a
3a
3a
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7a
7b
7c
8a
8a
8b
8c
9
0
0
0
78
86
63
62
71
91
60
87
65
66
90
81
82
36
80
70
90
0
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DMF
DMF
DMF
1,4-dioxane
DMF
DMF
DMF
DMF
DMF
9
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
Cl
CF3
H
H
H
H
H
H
Cl
2f
25
39
44
0
2f
2f
2g
2h
1c (4-MeC6H4)
1a (4-ClC6H4)
1a (4-ClC6H4)
thien-2-yl
100
10
0
tion of pyrimidine-substituted aminal derivatives,[7a–7f] a doublet in weak field at δ = 8.0–8.5 ppm from the SO2NH
which are good reagents[7e,7f] and biologically active com- proton, doublet of doublets at δ = 6.1–6.4 ppm from the
pounds.[7g] We found that 2-aminopyrimidines 2 react with CH group (3JNH–CH = 9.2–9.8 Hz), and a doublet or broad
imines 1 in the same manner to give the products of nucleo- singlet at δ = 6.0–7.0 ppm from the Het-NH fragment. For
philic addition 3–8 (see Scheme 1). The process proceeds dimethylpyrimidine derivatives 5a–c, the protons of methyl
selectively with the participation of azomethine groups of groups are equivalent and appear as double-intensity sing-
1
imines 1a–c and exocyclic amino groups of aminopyrimid- lets. These features of the H NMR spectra as well as the
ines 2. The nature of the solvents had a significant impact 13C NMR spectroscopic data and the results of 2D NMR
on the product yield. The reaction was realized in high po- experiments unambiguously established the structure of the
larity solvents such as 1,4-dioxane or N,N-dimethylform- compounds synthesized. The values of 15N chemical shifts
amide (DMF) (Table 1).
of adducts 3–8 were determined based on 2D 1H-15N
Adducts 3–8 were formed in good yield under mild con- HMBC spectra.
ditions with 2-aminopyrimidine (2a) and methyl-substituted
It is interesting to note that compounds 6a–c in [D6]di-
aminopyrimidines 2b–d when 1,4-dioxane was used as the methyl sulfoxide (DMSO) exhibit two groups of signals in
1
most appropriate solvent (see Table 1). In the case of 5- the H and 13C NMR spectra, probably due to different
bromo- or 5-chloro-substituted derivatives 2e or 2f, DMF associations or conformers stabilized by hydrogen bonds.
was used as solvent, because the yields of the corresponding
It was shown previously[4] that heterocyclization of ad-
adducts 7 and 8 in dioxane were lower. Aminodichloropyr- ducts obtained from imines 1 and 2-aminopyridines pro-
imidine 2g and trifluoromethyl-substituted aminopyrimid- ceeds smoothly in dioxane in the presence of NaOH. We
ine 2h did not form adducts under the conditions we applied the same conditions for heterocyclization and found
studied. Clearly, electron-withdrawing substituents deacti- that 3–8 were transformed easily into 3-arylsulfonylamino-
vate the nucleophilicity of amino pyrimidines and the for- 2-phenylimidazo[1,2-a]pyrimidine
mation of the expected products 9 and 10 was hindered or (Scheme 2, Table 2). The formation of isomeric 2-arylsulf-
completely blocked. onylamino-3-phenylimidazo[1,2-a]pyrimidines 11Ј–16Ј was
derivatives
11–16
The structures of adducts 3–8 were defined by IR and not detected. In the absence of NaOH, even under heating
NMR spectroscopic analysis and supported by elemental or in the presence of potassium or sodium carbonates,
analysis. The IR spectra of compounds 3–8 contain charac- heterocyclic derivatives were not obtained.
teristic absorption bands attributed to SO2 and NH groups.
Synthesis of 11–14 could be realized as a one-pot, two-
1
In the H NMR spectra, typical signals of protons of step procedure without isolation of the intermediate ad-
aromatic and pyrimidine rings with corresponding multi- ducts 3–6 (Scheme 2, Table 2). Adducts 7 and 8 were
plicity and intensity were observed. Moreover, typical sig- formed with the highest yields in DMF but attempts to per-
nals of the NH-CH-NH fragment were presented, namely form their subsequent one-pot heterocyclization led to
2
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Synthesis of 3-(Sulfonylamino)imidazo[1,2-a]pyrimidines
Scheme 2. Synthesis of imidazo[1,2-a]pyrimidines 11–16.
Table 2. One-pot synthesis of imidazo-pyrimidines 11–14 and heterocyclization of adducts 7 and 8 into imidazo-pyrimidines 15 and 16.
Entry Ar
R1
R2
R3
T [°C]
Time [h] Solvent
Imidazo-pyrimidine
Yield [%][a]
1
2
3
4
5
6
7
8
4-ClC6H4
4-ClC6H4
Ph
4-MeC6H4
4-ClC6H4
Ph
4-MeC6H4
4-ClC6H4
Ph
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
50
100
40
room temp.
100
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
5
5
5
5
5
5
5
5
5
5
5
5
5
10
10
10
10
10
5
1,4-dioxane
THF
11a
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
14b
14c
15a
15a
15a
15a
15a
15a
15b
15c
16a
16b
16c
76
70
89
65
51
65
53
60
77
64
79
73
74
0
0
0
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
CCl4
toluene
CH3CN
DMF
DMF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-MeC6H4
4-ClC6H4
Ph
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
H
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
0
0
H
H
H
H
H
H
59, 76[b]
38, 54[b]
33, 51[b]
47, 88[b]
36, 91[b]
48, 84[b]
5
5
5
5
4-MeC6H4
4-ClC6H4
Ph
H
H
4-MeC6H4
5
[a] Yield based on starting imines 1a–c. [b] Yield based on adducts 7 and 8, respectively.
strong resinification. We succeeded in preparing the corre-
sponding imidazo-pyrimidines 15 and 16 in satisfactory ferent nucleophilicity of endocyclic nitrogen atoms caused
yields only in dioxane. by nonsymmetrical arrangement of the substituents in the
The heterocyclization of adducts 4a–c and 6a–c resulted starting aminopyrimidines.
This selectivity can probably be explained by the dif-
in the selective formation of imidazo-pyrimidines 12a–c and
NMR and IR spectroscopic analysis of the reaction
14a–c, whereas isomeric derivatives with substituents at products 11–16 showed that all of them belong to the same
other positions on the pyrimidine moiety were not formed structural type; we therefore carried out X-ray single-crystal
(Scheme 2, Table 2).
analysis for 11c as a typical derivative (Figure 1).
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I. B. Rozentsveig et al.
FULL PAPER
The 13C NMR chemical shifts from carbon atoms of a
pyrimidine moiety move downfield by 8–14 ppm when they
are associated with methyl substituents. This allowed the
arrangement of the methyl groups in the pyrimidine ring of
imidazo-pyrimidines 12, 13, 14 to be established. For exam-
ple, the chemical shifts from C-5 and C-7 atoms in the 13C
NMR spectrum of 11a are found at δ = 132.6 and
152.0 ppm, respectively (these NMR spectroscopic data are
in agreement with the spectra of unsubstituted imidazo[1,2-
a]pyrimidine[8]). For 5,7-dimethylimidazo-pyrimidine 13a,
chemical shifts from the C-5 and C-7 carbon atoms move
to δ = 145.5 and 160.8 ppm, respectively (Table 3, entries 1
and 3). For monomethyl-substituted imidazo-pyrimidine
12a, atom C-5 resonates at the same field as C-5 for com-
pound 11a (131.7 ppm), but the chemical shift from carbon
C-7 (δ = 161.4 ppm) is in the same field as the C-7 reso-
nance of 13a (δ = 160.8 ppm) (entries 1–3). This downfield
displacement of the signal from C-7 allows one to make a
conclusion about the presence of the methyl substituent at
the C-7 carbon atom. For compounds 13a and 14a, the
chemical shifts from the C-5 carbon atoms are identical (δ
= 145.5 ppm), whereas the C-7 carbon atoms resonate at
different frequencies (entries 3 and 4). This is consistent
with the assumption that the same substituents (methyl
groups) are associated with C-5 carbon atoms and different
substituents (methyl group and chlorine atom) are bonded
with C-7 carbon atoms.
Figure 1. X-ray structure of the dimer {11c·MeOH}2.
The X-ray diffraction studies revealed that, in the solid
state, two molecules of 11c and two molecules of methanol
are connected through hydrogen bonds (N11–H···O1w and
O1w–H···N19Ј) forming the centrosymmetrical dimer
{11c·MeOH}2. Notably, in every molecule of 11c, the pla-
nes of the two phenyl rings are almost parallel (the angle
between the planes is equal to 4.8°) and lie at a distance of
approximately 3.3 Å, which corresponds to typical π-stack-
ing.
The structures of the compounds obtained were unam-
1
Table 3. The chemical shifts from C-5 and C-7 carbon atoms in the
biguously deduced from their H, 13C and 15N NMR spec-
13C NMR spectra of compounds 11a, 12a, 13a, and 14a.
troscopic data using 1H-13C HSQC, 1H-13C HMBC, 1H-15N
HMBC, and NOESY 2D NMR experiments. To establish
the imidazo-pyrimidine structures HMBC 1H–13C tech-
niques were used (Scheme 3), which were optimized for
13C–1H coupling constants of 10 Hz, which are typical for
carbon and proton atoms separated by three bonds.
Entry Imidazo-pyrimidine R1
Ar = 4-ClC6H4
C-5
δ [ppm]
R3
C-7
δ [ppm]
1
2
3
4
11a
12a
13a
14a
H
H
Me
Me
132.6
131.7
145.5
145.5
H
152.0
161.4
160.8
151.6
Me
Me
Cl
A possible reaction pathway leading to the formation of
compounds 11–16 is under discussion. The reaction can
proceed through heterocyclization of adducts 3–8 into inter-
mediate imidazo-pyrimidines 11Ј–16Ј, which undergo fur-
ther isomerization into the final heterocycles 11–16 accord-
ing to the Dimroth rearrangement (Scheme 4). It should be
noted that based on reported data,[9] this type of isomeriza-
tion runs in the reverse direction: in the presence of a base,
3-aminoimidazo[1,2-a]pyrimidines undergo isomerization
1
Scheme 3. Main H-13C HMBC correlations for imidazo-pyrimid-
ine 11c.
The values of 15N chemical shifts in the 1D 15N spectrum into 2-aminoimidazo[1,2-a]pyrimidines. This reaction is one
for 11c are in agreement with the proposed structure. The of the methods for the preparation of 2-aminoimidazo[1,2-
determination of 15N chemical shifts from the 1D 15N a]pyrimidine derivatives.[9] We found that under the condi-
NMR spectra was difficult due to the low solubility of imid- tions described in the method[9] (alkali in water/methanol
azo-pyrimidines 11–16 and because of the long time re- solution), the transformation of compounds 11–16 into iso-
quired to complete the NMR experiments. Thus, the values meric imidazo-pyrimidine derivatives 11Ј–16Ј does not take
of 15N chemical shifts of other imidazo-pyrimidines were place.
obtained only for N-4 and N-8 nitrogen atoms using 2D
To explain the contradiction discussed above, we carried
1H-15N HMBC spectra. This technique also allows the ar- out quantum-chemical calculations [MP2 6-311+G(d,p);
rangement of R1 and R3 substituents on the pyrimidine Firefly QC package,[10a] which is partially based on the
fragment to be determined from their correlations with N- GAMESS (US)[10b] source code] of formation energy for 3-
8 (ca. –100 ppm) and N-4 (ca. – 190 ppm) atoms.
amino-2-phenylimidazo[1,2-a]pyrimidines 11a–c, model
4
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Synthesis of 3-(Sulfonylamino)imidazo[1,2-a]pyrimidines
Scheme 4. Possible reaction pathway for the formation of imidazo-pyrimidine derivatives 11–16.
compounds 17a–e, and isomeric 2-amino-3-phenylimid- tion conditions (alkali medium), compounds 11–16 exist as
azo[1,2-a]pyrimidines 11Јa–c and 17Јa–e. The calculations sulfonamidic anions of the type A or AЈ. For these anions,
show that the total energy of 2-aminoimidazo-pyrimidines the calculations show that sulfonamidic derivatives A are
17Јa–e is lower by 2.2–4.1 kcal/mol in comparison with iso- more stable by 7.5–13.5 kcal/mol in comparison with iso-
meric 3-aminoimidazo-pyrimidines 17a–e (Table 4, en- meric anions AЈ (Table 5). Calculations using the PCM sol-
tries 1–5). This difference in energies allows the direction of vation method (see Table S3 in the Supporting Information)
isomerization described in the paper to be explained.[9] The do not reveal a significant difference between the relative
difference of formation energy between 17Ј and 17 is re- energies of anions A and AЈ. This energy difference can
duced to 2.9 and 2.2 kcal/mol in the case of compounds serve as a driving force for the unusual direction of Dimroth
with electron-withdrawing methylsulfonyl and trifluoro- rearrangement and isomerization of 2-(sulfonylamino)imid-
methylsulfonyl groups, respectively (entries 4 and 5). Never- azo-pyrimidines 11Ј–16Ј into 3-sulfonylamino-substituted
theless, even for compounds with the CF3SO2 group, the 2- derivatives 11–16 according to the Scheme 4.
amino substituted derivative is preferable.
Table 5. Relative energies of anions A and AЈ in the gas phase at
fully optimized geometries by MP2/6-311+G(d,p) (units in kcal/
mol).
Table 4. Relative energies of neutral molecules in the gas phase at
fully optimized geometries by MP2/6-311+G(d,p) for compounds
17a–e, 17Јa–e, 11a–c, and 11Јa–c (units in kcal/mol).
Thus, the results of the calculations are consistent with
the pathway shown in Scheme 4, with the experimental data
presented herein, and with the results described by Carb-
allares et al.[9] For 2-amino- and 3-amino-substituted imid-
azo[1,2-a]pyrimidine derivatives, isomerization through the
Dimroth rearrangement is directed towards the formation
of 2-aminoimidazo-pyrimidines when alkylamino groups
are in the structure (compounds mentioned in previous
studies[9]). However, the reaction is directed toward 3-
amino-substituted isomers when strong N–H acidic sulfonyl
amino groups are presented.
In contrast to compounds 17 and 17Ј, 3-arylsulfonyl-
aminosubstituted isomers 11a–c are surprisingly more
stable then 2-(arylsulfonylamino)imidazo-pyrimidines 11Јa–
c by 2.4–3.3 kcal/mol (Table 4, entries 6–8). This stability
can probably be explained by the more effective intramolec-
ular π-stacking coordination between the aromatic ring of
the arylsulfonic group and the benzene ring at C-2 position.
A possibility of intramolecular π-stacking is revealed by the
XRD study (see Figure 1). It should be noted that examples
of intramolecular π-stacking for some arylsulfonamide de-
rivatives, annulated imidazole and pyrimidine derivatives
have been reported.[11]
Conclusions
Moreover, because sulfonamide derivatives are strong N–
The reaction of 2-aminopyrimidines with N-(sulfonyl)-
H acids, it should be taken into account that under the reac- phenyldichloroacetaldimines leads to the formation of the
Eur. J. Org. Chem. 0000, 0–0
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I. B. Rozentsveig et al.
FULL PAPER
off, washed with cold CCl4 (3ϫ 1 mL), and dried in vacuo with
P2O5.
corresponding adducts, which can be transformed into 3-
(sulfonylamino)imidazo[1,2-a]pyrimidine derivatives in
good yields. On the basis of this reaction, an effective syn-
N-(2-Phenyl-2,2-dichloroethylidene)-4-chlorobenzenesulfonamide
thetic method for the preparation of 3-(sulfonylamino)imid- (1a): Yield 10.12 g (93 %); colorless solid; m.p. 104–105 °C. IR
(KBr): ν = 1170, 1310 (SO ), 1630 (C=N) cm–1 1H NMR
.
˜
azo[1,2-a]pyrimidines has been worked out. The advantages
of this method are available starting reagents, mild condi-
tions, and high selectivity. The known multistage meth-
ods,[6c,12] based on nitration or nitrosation of imidazo-pyr-
imidine substrate followed by reduction of nitro or nitroso
groups, are much more laborious. The method based on
1,2-bis(benzotriazolyl)-1,2-diaminoethanes[13] is suitable for
morpholine derivatives only. Other promising methods
based on three-component reactions of isocyanides with
aminopyrimidines and aldehydes[6a,14] require longer time
(up to 48 h), expensive catalysts in some cases, and they are
never used for the preparation of sulfonylamino-substituted
derivatives containing the synthetically useful and pharma-
cophoric sulfonamide groups. It can be argued that the
method proposed herein complements known literary pro-
tocols and expands the range of functionalized imidazo-
pyrimidine derivatives, which are now available for further
investigation of biological activity and other properties.
2
(400.13 MHz, CDCl3): δ = 7.35, 7.90 (m, 9 H, Ph, C6H4), 8.60 (s,
1 H, N=CH) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 85.70
(CCl2), 127.08 (CoЈ), 129.01 (Co), 129.84 (CmЈ), 129.87 (Cm), 130.57
(CpЈ), 135.16 (Ci), 136.26 (CiЈ), 141.33 (Cp), 168.59 (N=CH) ppm.
N-(2-Phenyl-2,2-dichloroethylidene)benzenesulfonamide (1b): Yield
8.86 g (90%); colorless solid; m.p. 101–102 °C. IR (KBr): ν = 1160,
˜
1
1310 (SO2), 1620 (C=N) cm–1. H NMR (400.13 MHz, CDCl3): δ
= 7.33, 7.93 (m, 10 H, 2 Ph), 8.51 (s, 1 H, N=CH) ppm. 13C NMR
(100.61 MHz, CDCl3): δ = 85.73 (CCl2), 127.03 (CoЈ), 128.36 (Co),
128.95 (CmЈ), 129.47 (Cm), 130.48 (CpЈ), 134.45 (Cp), 136.39 (Ci),
136.57 (CiЈ), 168.22 (N=CH) ppm.
N-(2-Phenyl-2,2-dichloroethylidene)-4-methylbenzenesulfonamide
(1c): Yield 9.03 g (88 %); colorless solid; m.p. 105–106 °C. IR
(KBr): ν = 1150, 1310 (SO ), 1630 (C=N) cm–1 1H NMR
.
˜
2
(400.13 MHz, CDCl3): δ = 2.43 (s, 3 H, CH3), 7.30, 7.82 (m, 9 H,
Ph, C6H4), 8.56 (s, 1 H, N=CH) ppm. 13C NMR (100.61 MHz,
CDCl3): δ = 21.69 (CH3), 85.71 (CCl2), 126.92 (CoЈ), 128.34 (Co),
128.86 (CmЈ), 130.07 (Cm), 130.39 (CpЈ), 133.24 (Ci), 136.32 (CiЈ),
145.67 (Cp), 167.61 (N=CH) ppm.
General Procedure for Synthesis of Adducts 3–6: 2-Aminopyrimid-
ine 2a–d (2.8 mmol) was added to a solution of imine 1 (2.8 mmol)
in 1,4-dioxane (10 mL) and the solution was stirred on a magnetic
stirrer for 6 h at room temp. The reaction mixture was diluted with
water (100 mL) and the precipitate was filtered off, dried, and
recrystallized from ethanol.
Experimental Section
General Remarks: All reagents were of reagent grade. Solvents were
dried by standard procedures and distilled prior to use. NMR spec-
tra were recorded with a Bruker DPX 400 spectrometer (1H,
400.13 MHz; 13C, 100.61 MHz; 15N, 40.53 MHz) at 25 °C with
HMDS as an internal standard. Chemical shifts are reported in
ppm (δ) and coupling constants (J) in Hz. IR spectra were recorded
with a Bruker IFS-25 spectrophotometer in KBr. Melting points
were measured with a Kofler micro hot-stage apparatus. Elemental
analyses for C, H, N, and S were obtained with a Thermo Finnigan
Flash series1112 EA analyzer. Cl was determined by titration of
the combustion products with mercuric nitrate in the presence of
diphenylcarbazone. The GC/MS analyses were performed with a
Shimadzu GC–MS-QP5050A instrument (EI, 70 eV).
4-Chloro-N-[2,2-dichloro-2-phenyl-1-(pyrimidin-2-ylamino)ethyl]-
benzenesulfonamide (3a): Yield 1.10 g (86%); colorless solid; m.p.
1
196–198 °C. IR (KBr): ν = 1164, 1340 (SO ), 3331 (NH) cm–1. H
˜
2
NMR (400.13 MHz, [D6]DMSO): δ = 6.30 (dd, 3J = 9.4, 3J =
9.8 Hz, 1 H, CH), 6.55 (d, 3J = 9.8 Hz, 1 H, NH), 6.58 (t, 3J =
4.7 Hz, 1 H, 5-H), 7.25, 7.61 (AAЈBBЈ, 4 H, 4-ClC6H4), 7.33–7.40
3
(m, 3 H, 3,4,5-H C6H5), 7.70 (m, 2 H, 2,6-H C6H5), 8.09 (d, J =
4.7 Hz, 2 H, 4,6-H), 8.43 (d, J = 9.4 Hz, 1 H, NHSO2) ppm. 13C
3
NMR (100.61 MHz, [D6]DMSO): δ = 69.90 (CH), 95.62 (CCl2),
112.54 (C-5), 127.88, 128.50, 129.91, 139.08 (C6H5), 128.95, 129.19,
137.77, 139.96 (4-ClC6H4), 157.94 (C-4,6), 160.55 (C-2) ppm.
C18H15Cl3N4O2S (457.76): calcd. C 47.23, H 3.30, Cl 23.23, N
12.24, S 7.00; found C 47.31, H 3.28, Cl 23.37, N 12.11, S 6.92.
The intensity data for the single crystal of 11c·MeOH were col-
lected with a SMART APEX DUO automated diffractometer
(Bruker AXS) by using the standard procedure. It should be noted
that 11c·MeOH crystals were very small (0.02ϫ 0.02ϫ 0.02 mm)
and their reflectance was quite poor. The structures were solved by
direct methods and refined by the full-matrix least-squares pro-
cedure anisotropically for non-hydrogen atoms. The H atoms were
calculated geometrically and included in the refinement as riding
groups. All calculations were fulfilled with the SHELXTL 6.14 pro-
gram package.
N-[2,2-Dichloro-2-phenyl-1-(pyrimidin-2-ylamino)ethyl]benzenesulf-
onamide (3b): Yield 0.75 g (63%); colorless solid; m.p. 184–185 °C.
IR (KBr): ν = 1167, 1351 (SO ), 3371 (NH) cm–1 1H NMR
.
˜
2
3
3
(400.13 MHz, [D6]DMSO): δ = 6.37 (dd, J = 9.0, J = 9.5 Hz, 1
H, CH), 6.50 (d, J = 9.5 Hz, 1 H, NH), 6.55 (m, 1 H, 5-H), 7.22
3
(m, 2 H, 2,6-H C6H5SO2), 7.33–7.38 (m, 4 H, 3,4,5-H C6H5, 4-H
C6H5SO2), 7.62 (m, 2 H, 3,5-H C6H5SO2), 7.71 (m, 2 H, 2,6-H
C6 H5 ), 8.08 (m, 2 H, 4,6-H), 8.25 (d, 3 J = 9.0 Hz, 1 H,
NHSO2) ppm. 13C NMR (100.61 MHz, [D6]DMSO): δ = 69.93
(CH), 95.90 (CCl2), 112.57 (C-5), 127.19, 127.98, 129.89, 139.14
(C6H5), 128.48, 128.84, 132.75, 141.14 (C6H5SO2), 158.11 (C-4,6),
160.64 (C-2) ppm. C18H16Cl2N4O2S (423.32): calcd. C 51.07, H
3.81, Cl 16.75, N 13.24, S 7.57; found C 51.21, H 3.75, Cl 16.59,
N 13.35, S 7.48.
CCDC-1003709 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
General Procedure for Synthesis of Imines 1a–c:[5] N,N-Dichloro-
arenesulfonamide (30 mmol) was added portionwise to a solution
of phenylacetylene (4.10 g, 40 mmol) in CCl4 (20 mL) under argon
with stirring to avoid overheating to more than 40 °C. Once the
self-heating interaction had been stopped, the reaction mixture was
stirred for 3 h at 60 °C, then allowed to stand at –5 °C until a
precipitate of imines 1–3 was formed. The precipitate was filtered
N-[2,2-Dichloro-2-phenyl-1-(pyrimidin-2-ylamino)ethyl]-4-methyl-
benzenesulfonamide (3c): Yield 0.76 g (62%); colorless solid; m.p.
1
194–196 °C. IR (KBr): ν = 1157, 1332 (SO ), 3344 (NH) cm–1. H
˜
2
NMR (400.13 MHz, [D6]DMSO): δ = 2.16 (s, 3 H, CH3), 6.28 (dd,
6
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Date: 27-08-14 17:56:12
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Synthesis of 3-(Sulfonylamino)imidazo[1,2-a]pyrimidines
3
3
3J = 9.1, J = 9.5 Hz, 1 H, CH), 6.40 (d, J = 9.5 Hz, 1 H, NH),
6.56 (t, 3J = 4.28 Hz, 1 H, 5-H), 6.97, 7.48 (AAЈBBЈ, 4 H, 4-
CH3C6H4), 7.36–7.38 (m, 3 H, 3,4,5-H C6H5), 7.70 (m, 2 H, 2,6-H
C6H5), 8.07–8.11 (m, 3 H, 4,6-H, NHSO2) ppm. 13C NMR
(100.61 MHz, [D6]DMSO): δ = 69.85 (CH), 95.85 (CCl2), 112.32
(C-5), 127.27, 127.93, 129.80, 139.06 (C6H5), 128.40, 129.22,
137.98, 142.93 (4-CH3C6H4), 157.80 (C-4,6), 160.54 (C-2) ppm.
21.89, N 11.53, S 6.60; found C 49.33, H 3.89, Cl 21.75, N 11.49,
S 6.76.
N-{2,2-Dichloro-1-[(4,6-dimethylpyrimidin-2-yl)amino]-2-phenyl-
ethyl}benzenesulfonamide (5b): Yield 0.82 g (65%); light-brown so-
lid; m.p. 172–174 °C. IR (KBr): ν = 1170, 1340 (SO ), 3408
˜
2
(NH) cm–1. H NMR (400.13 MHz, [D6]DMSO): δ = 2.06 (s, 6 H,
1
3
CH3), 6.14 (d, J = 9.6 Hz, 1 H, NH), 6.27 (s, 1 H, 5-H), 6.36 (dd,
C
19H18Cl2N4O2S (437.34): calcd. C 52.18, H 4.15, Cl 16.21, N
12.81, S 7.33; found C 52.05, H 4.08, Cl 16.36, N 12.62, S 7.24.
3J = 9.1, J = 9.6 Hz, 1 H, CH), 7.20 (m, 2 H, 3.5-H C6H5), 7.28–
3
7.36 (m, 4 H, 3,4,5-H C6H5, 4-H C6H5SO2), 7.64 (m, 2 H, 2.6-
H C6H5), 7.70 (m, 2 H, 2,6-H C6H5), 8.28 (d, 3J = 9.1 Hz, 1 H,
NHSO2) ppm. 13C NMR (100.61 MHz, [D6]DMSO): δ = 23.16
(CH3), 69.30 (CH), 95.58 (CCl2), 110.74 (C-5), 126.65, 127.45,
129.30, 138.71 (C6H5), 127.85, 128.13, 132.03, 140.63 (C6H5SO2),
159.76 (C-2), 166.50 (C-4,6) ppm. C20H20Cl2N4O2S (451.37): calcd.
C 53.22, H 4.47, Cl 15.71, N 12.41, S 7.10; found C 53.11, H 4.41,
Cl 15.87, N 12.37, S 7.17.
4-Chloro-N-{2,2-dichloro-1-[(4-methylpyrimidin-2-yl)amino]-2-phen-
ylethyl}benzenesulfonamide (4a): Yield 0.94 g (71%); colorless solid;
m.p. 179–181 °C. IR (KBr): ν = 1163, 1338 (SO ), 3327 (NH) cm–1.
˜
2
1H NMR (400.13 MHz, [D6]DMSO): δ = 2.14 (s, 3 H, CH3), 6.27–
6.31 (m, 2 H, CH, NH), 6.46 (br.s, 1 H, 5-H), 7.25, 7.61 (AAЈBBЈ,
4 H, 4-ClC6H4), 7.36–7.40 (m, 3 H, 3,4,5-H C6H5), 7.70 (m, 2 H,
2,6-H C6H5), 7.92 (br. s, 1 H, 6-H), 8.37 (d, 3J = 6.4 Hz, 1 H,
NHSO2) ppm. 13C NMR (100.61 MHz, [D6]DMSO): δ = 23.83
(CH3), 69.79 (CH), 95.54 (CCl2), 111.95 (C-5), 127.85, 128.42,
129.84, 139.04 (C6H5), 128.85, 129.15, 137.68, 139.64 (4-ClC6H4),
157.31 (C-6), 160.31 (C-2), 167.73 (C-4) ppm. C19H17Cl3N4O2S
(471.79): calcd. C 48.37, H 3.63, Cl 22.54, N 11.88, S 6.80; found
C 48.24, H 3.65, Cl 22.41, N 11.97, S 6.88.
N-{2,2-Dichloro-1-[(4,6-dimethylpyrimidin-2-yl)amino]-2-phenyl-
ethyl}-4-methylbenzenesulfonamide (5c): Yield 0.86 g (66%); color-
less solid; m.p. 188–190 °C. IR (KBr): ν = 1163, 1338 (SO ), 3393
˜
2
(NH) cm–1. H NMR (400.13 MHz, [D6]DMSO): δ = 2.07 (s, 6 H,
1
3
CH3-Pyr), 2.15 (s, 3 H, CH3), 6.04 (d, J = 9.5 Hz, 1 H, NH), 6.25
3
3
(dd, J = 9.3, J = 9.5 Hz, 1 H, CH), 6.29 (s, 1 H, 5-H), 6.96, 7.50
(AAЈBBЈ,4 H, 4-CH3C6H4), 7.31–7.39 (m, 3 H, 3,4,5-H C6H5), 7.70
(m, 2 H, 2,6-H C6H5), 8.06 (d, 3J = 9.3 Hz, 1 H, NHSO2) ppm.
13C NMR (100.61 MHz, [D6]DMSO): δ = 21.26 (CH3), 23.71
(CH3-Pyr), 69.83 (CH), 95.87 (CCl2), 111.03 (C-5), 128.03, 128.35,
129.79, 139.16 (C6H5), 127.35, 129.09, 137.99, 142.85 (4-
CH3C6H4), 160.27 (C-2), 166.53 (C-4,6) ppm. C21H22Cl2N4O2S
(465.40): calcd. C 54.20, H 4.76, Cl 15.24, N 12.04, S 6.89; found
C 54.29, H 4.74, Cl 15.11, N 12.09, S 6.95.
N-{2,2-Dichloro-1-[(4-methylpyrimidin-2-yl)amino]-2-phenylethyl}-
benzenesulfonamide (4b): Yield 1.11 g (91%); colorless solid; m.p.
180–182 °C. IR (KBr): ν = 1166, 1329 (SO ), 3329 (NH) cm–1. H
1
˜
2
NMR (400.13 MHz, [D6]DMSO): δ = 2.11 (s, 3 H, CH3), 6.34–6.39
(m, 2 H, CH, NH), 6.41 (br. s, 1 H, 5-H), 7.20 (m, 2 H, 3,5-H
C6H5), 7.30–7.37 (m, 4 H, 3,4,5-H C6H5, 4-H C6H5SO2), 7.62 (m,
2 H, 2.6-H C6H5), 7.69 (m, 2 H, 2,6-H C6H5), 7.91 (br. s, 1 H, 6-
H), 8.28 (d, 3 J = 5.9 Hz, 1 H, NHSO2 ) ppm. 1 3 C NMR
(100.61 MHz, [D6]DMSO): δ = 23.80 (CH3), 69.75 (CH), 95.79
(CCl2), 111.91 (C-5), 127.06, 127.85, 129.75, 139.08 (C6H5), 128.32,
128.65, 132.54, 141.01 (C6H5SO2), 157.16 (C-6), 160.32 (C-2),
167.70 (C-4) ppm. C19H18Cl2N4O2S (437.34): calcd. C 52.18, H
4.15, Cl 16.21, N 12.81, S 7.33; found C 52.03, H 4.11, Cl 16.29,
N 12.70, S 7.29.
4-Chloro-N-{2,2-dichloro-1-[(4-chloro-6-methylpyrimidin-2-yl)-
amino]-2-phenylethyl}benzenesulfonamide (6a): Yield 1.28 g (90%);
colorless solid; m.p. 159–161 °C. IR (KBr): ν = 1169, 1343 (SO ),
˜
2
3218, 3351 (NH) cm–1. 1H NMR (400.13 MHz, [D6]DMSO): δ =
2.15 and 2.21 (s and s, 3 H, CH3), 6.26 and 6.08 (br. s and br. s, 1
H, CH), 6.54 and 6.58 (s and s, 1 H, 5-H), 6.98 (br. s, 1 H, NH),
7.30, 7.65 (AAЈBBЈ, 4 H, 4-ClC6H4), 7.35–7.37 (m, 3 H, 3,4,5-H
C6H5), 7.69 (m, 2 H, 2,6-H C6H5), 8.41 (d, 3J = 9.5 Hz, 1 H,
NHSO2) ppm. 13C NMR (100.61 MHz, [D6]DMSO): δ = 22.98 and
23.23 (CH3), 69.43 (CH), 94.44 (CCl2), 108.09 and 110.28 (C-5),
127.37, 127.89, 129.41, 138.25 (C6H5), 128.36, 128.72, 137.37,
138.95 (4-ClC6H4), 159.78 (C-2), 169.13 (C-4), 169.76 (C-6) ppm.
C19H16Cl4N4O2S (506.23): calcd. C 45.08, H 3.19, Cl 28.01, N
11.07, S 6.33; found C 45.21, H 3.22, Cl 28.15, N 11.19, S 6.29.
N-{2,2-Dichloro-1-[(4-methylpyrimidin-2-yl)amino]-2-phenylethyl}-
4-methylbenzenesulfonamide (4c): Yield 0.76 g (60%); orange solid;
m.p. 166–168 °C. IR (KBr): ν = 1160, 1329 (SO ), 3328 (NH) cm–1.
˜
2
1H NMR (400.13 MHz, [D6]DMSO): δ = 2.12 (s, 3 H, CH3-Pyr),
2.22 (s, 3 H, CH3), 6.24–6.29 (m, 2 H, CH, NH), 6.44 (br. s, 1 H,
5-H), 6.97, 7.49 (AAЈBBЈ, 4 H, 4-CH3C6H4), 7.34–7.39 (m, 3 H,
3,4,5-H C6H5), 7.70 (m, 2 H, 2,6-H C6H5), 7.90 (br. s, 1 H, 6-H),
8.07 (d, J = 6.9 Hz, 1 H, NHSO2) ppm. 13C NMR (100.61 MHz,
3
[D6]DMSO): δ = 21.31 (CH3), 23.91 (CH3-Pyr), 69.88 (CH), 95.90
(CCl2), 111.81 (C-5), 128.00, 128.41, 129.83, 139.16 (C6H5), 127.34,
129.21, 138.01, 142.93 (4-CH3C6H4), 157.43 (C-6), 160.41 (C-2),
167.50 (C-4) ppm. C20H20Cl2N4O2S (451.37): calcd. C 53.22, H
4.47, Cl 15.71, N 12.41, S 7.01; found C 53.14, H 4.42, Cl 15.62,
N 12.35, S 7.08.
N-{2,2-Dichloro-1-[(4-chloro-6-methylpyrimidin-2-yl)amino]-2-phen-
ylethyl}benzenesulfonamide (6b): Yield 1.07 g (81%); colorless solid;
m.p. 143–145 °C. IR (KBr): ν = 1165, 1334 (SO ), 3372 (NH) cm–1.
˜
2
1H NMR (400.13 MHz, [D6]DMSO): δ = 2.07 and 2.12 (s and s, 3
H, CH3), 6.11 and 6.27 (br. s and br. s, 1 H, CH), 6.51 (s, 1 H, 5-
H), 6.96 (br. s, 1 H, NH), 7.26 (m, 2 H, 3,5-H C6H5SO2), 7.33–7.37
(m, 4 H, 3,4,5-H C6H5, 4-H C6H5SO2), 7.65–7.70 (m, 4 H, 2,6-H
4-Chloro-N-{2,2-dichloro-1-[(4,6-dimethylpyrimidin-2-yl)amino]-2-
phenylethyl}benzenesulfonamide (5a): Yield 1.18 g (87%); colorless
3
C6H5, 2,6-H C6H5SO2), 8.31 (d, J = 9.3 Hz, 1 H, NHSO2) ppm.
13C NMR (100.61 MHz, [D6]DMSO): δ = 22.96 and 23.26 (CH3),
69.44 (CH), 94.74 (CCl2), 110.18 and 110.39 (C-5), 126.75, 127.44,
129.40, 138.36 (C6H5), 127.88, 128.21, 132.20, 140.36 (C6H5SO2),
159.44 and 159.84 (C-2), 169.07 (C-4), 169.75 (C-6) ppm.
C19H17Cl3N4O2S (471.79): calcd. C 48.37, H 3.63, Cl 22.54, N
11.88, S 6.80; found C 48.49, H 3.59, Cl 22.45, N 11.81, S 6.75.
solid; m.p. 184–186 °C. IR (KBr): ν = 1170, 1344 (SO ), 3398
˜
2
(NH) cm–1. H NMR (400.13 MHz, [D6]DMSO): δ = 2.09 (s, 6 H,
1
CH3), 6.12 (d, 3J = 9.4 Hz, 1 H, NH), 6.28 (dd, 3J = 8.4, 3J =
9.4 Hz, 1 H, CH), 6.32 (s, 1 H, 5-H), 7.24, 7.62 (AAЈBBЈ, 4 H, 4-
ClC6H4), 7.36–7.38 (m, 3 H, 3,4,5-H C6H5), 7.70 (m, 2 H, 2,6-H
C6H5), 8.34 (d, 3J = 8.4 Hz, 1 H, NHSO2) ppm. 13C NMR
(100.61 MHz, [D6]DMSO): δ = 23.58 (CH3), 69.69 (CH), 95.45 N-{2,2-Dichloro-1-[(4-chloro-6-methylpyrimidin-2-yl)amino]-2-phen-
(CCl2), 111.15 (C-5), 127.81, 128.29, 129.74, 138.98 (C6H5), 128.68, ylethyl}-4-methylbenzenesulfonamide (6c): Yield 1.12 g (82%); col-
129.07, 137.58, 139.53 (4-ClC6H4), 160.11 (C-2), 166.72 (C-
orless solid; m.p. 184–186 °C. IR (KBr): ν = 1170, 1341 (SO ), 3409
˜
2
1
4,6) ppm. C20H19Cl3N4O2S (485.81): calcd. C 49.45, H 3.94, Cl (NH) cm–1. H NMR (400.13 MHz, [D6]DMSO): δ = 2.14 (s, 3 H,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
Date: 27-08-14 17:56:12
Pages: 12
I. B. Rozentsveig et al.
ClC6H4), 7.37–7.38 (m, 3 H, 3,4,5-H C6H5), 7.69 (m, 2 H, 2,6-H
FULL PAPER
CH3), 2.18 (s, 3 H, CH3), 6.03 and 6.19 (br. s and br. s, 1 H, CH),
6.57 (s, 1 H, 5-H), 6.83 (br. s, 1 H, NH), 7.02, 7.52 (AAЈBBЈ, 4 H, C6H5), 8.16 (s, 2 H, 4,6-H), 8.50 (br. s, 1 H, NHSO2) ppm. 13C
4-CH3C6H4), 7.36–7.38 (m, 3 H, 3,4,5-H C6H5), 7.68 (m, 2 H, 2,6- NMR (100.61 MHz, [D6]DMSO): δ = 70.27 (CH), 95.15 (CCl2),
H C6H5), 8.09 (d, 3J = 9.5 Hz, 1 H, NHSO2) ppm. 13C NMR
(100.61 MHz, [D6]DMSO): δ = 20.75 (CH3), 22.91 and 23.23
(CH3), 69.46 (CH), 94.70 (CCl2), 110.05 (C-5), 126.92, 127.47,
119.98 (C-5), 127.77, 128.47, 129.90, 138.82 (C6H5), 128.94, 129.22,
137.86, 139.59 (4-ClC6H4), 156.03 (C-4,6), 158.96 (C-2) ppm.
C18H14Cl4N4O2S (492.21): calcd. C 43.92, H 2.87, Cl 28.81, N
129.38, 138.31 (C6H5), 127.86, 128.65, 137.17, 142.62 (4- 11.38, S 6.51; found C 43.83, H 2.84, Cl 28.75, N 11.25, S 6.47.
CH3C6H4), 159.43 and 159.80 (C-2), 169.01 (C-4), 169.69 (C-
6) ppm. C20H19Cl3N4O2S (485.81): calcd. C 49.45, H 3.94, Cl
21.89, N 11.53, S 6.60; found C 49.57, H 3.90, Cl 21.99, N 11.60,
S 6.51.
N-{2,2-Dichloro-1-[(5-chloropyrimidin-2-yl)amino]-2-phenylethyl}-
benzenesulfonamide (8b): Yield 0.50 g (39%); colorless solid; m.p.
181–183 °C. IR (KBr): ν = 1162, 1339 (SO ), 1627 (C=N), 3417
˜
2
(NH) cm–1. H NMR (400.13 MHz, [D6]DMSO): δ = 6.25 (dd, J
= 9.5, 3J = 9.8 Hz, 1 H, CH), 6.96 (d, 3J = 9.8 Hz, 1 H, NH),
7.24 (m, 2 H, 3.5-H C6H5), 7.36–7.39 (m, 4 H, 3,4,5-H C6H5, 4-H
C6H5SO2), 7.63 (m, 2 H, 2.6-H C6H5), 7.69 (m, 2 H, 2,6-H C6H5),
1
3
General Procedure for the Synthesis of Adducts 7 and 8: 2-Amino-
pyrimidine 2e,f (2.8 mmol) was added to a solution of imine 1
(2.8 mmol) in DMF (10 mL) and the solution was stirred on mag-
netic stirrer for 5 h at room temp. The reaction mixture was shaken
with acetone (30 mL), diluted with water (100 mL) and allowed to
stand for 5 h. The precipitate was filtered off, dried, and recrys-
tallized from ethanol.
8.15 (s, 2 H, 4,6-H), 8.34 (d, J = 9.5 Hz, 1 H, NHSO2) ppm. 13C
3
NMR (100.61 MHz, [D6]DMSO): δ = 70.37 (CH), 95.46 (CCl2),
119.84 (C-5), 127.23, 127.90, 129.95, 138.99 (C6H5), 128.52, 128.91,
132.71, 141.07 (C6H5SO2), 156.18 (C-4,6), 159.09 (C-2) ppm.
C18H15Cl3N4O2S (457.76): calcd. C 47.23, H 3.30, Cl 23.23, N
12.24, S 7.00; found C 47.32, H 3.38, Cl 23.15, N 12.38, S 7.16.
N-{1-[(5-Bromopyrimidin-2-yl)amino]-2,2-dichloro-2-phenylethyl}-4-
chlorobenzenesulfonamide (7a): Yield 1.20 g (80%); colorless solid;
m.p. 184–186 °C. IR (KBr): ν = 1166, 1352 (SO ), 3228, 3350
N-{2,2-Dichloro-1-[(5-chloropyrimidin-2-yl)amino]-2-phenylethyl}-4-
methylbenzenesulfonamide (8c): Yield 0.58 g (44%); colorless solid;
˜
2
(NH) cm–1. H NMR (400.13 MHz, [D6]DMSO): δ = 6.16 (dd, J
= 9.1, 3J = 9.7 Hz, 1 H, CH), 6.99 (d, 3J = 9.7 Hz, 1 H, NH), 7.29,
7.62 (AAЈBBЈ, 4 H, 4-ClC6H4), 7.36–7.40 (m, 3 H, 3,4,5-H C6H5),
7.69 (m, 2 H, 2,6-H C6H5), 8.21 (s, 2 H, 4,6-H), 8.48 (d, 3J =
1
3
m.p. 172–174 °C. IR (KBr): ν = 1156, 1334 (SO ), 3330, 3425
˜
2
(NH) cm–1. H NMR (400.13 MHz, [D6]DMSO): δ = 2.19 (s, 3 H,
1
CH3), 6.13 (dd, 3J = 9.1, 3J = 9.5 Hz, 1 H, CH), 6.81 (d, 3J =
9.1 Hz, 1 H, NHSO2) ppm. 13C NMR (100.61 MHz, [D6]DMSO): 9.5 Hz, 1 H, NH), 7.01, 7.48 (AAЈBBЈ, 4 H, 4-CH3C6H4), 7.37–
δ = 70.27 (CH), 95.19 (CCl2), 108.02 (C-5), 127.85, 128.57, 129.99, 7.39 (m, 3 H, 3,4,5-H C6H5), 7.69 (m, 2 H, 2,6-H C6H5), 8.14 (s, 2
138.90 (C6H5), 129.02, 129.31, 137.98, 139.64 (4-ClC6H4), 157.89 H, 4,6-H), 8.16 (d, 3J = 9.1 Hz, 1 H, NHSO2) ppm. 13C NMR
(C-4,6), 159.17 (C-2) ppm. C18H14BrCl3N4O2S (536.66): calcd. C (100.61 MHz, [D6]DMSO): δ = 20.84 (CH3), 69.88 (CH), 94.99
40.29, H 2.63, N 10.44, S 5.97; found C 40.17, H 2.60, N 10.30, S
5.93.
(CCl2), 119.38 (C-5), 126.96, 127.48, 129.46, 138.45 (C6H5), 128.04,
128.85, 137.47, 142.71 (4-CH3C6H4), 155.45 (C-4,6), 158.63 (C-
2) ppm. C19H17Cl3N4O2S (471.79): calcd. C 48.37, H 3.63, Cl
22.54, N 11.88, S 6.80; found C 48.15, H 3.55, Cl 22.42, N 11.79,
S 6.75.
N-{1-[(5-Bromopyrimidin-2-yl)amino]-2,2-dichloro-2-phenylethyl}-
benzenesulfonamide (7b): Yield 0.98 g (70%); colorless solid; m.p.
166–168 °C. IR (KBr): ν = 1160, 1341 (SO ), 3292, 3395
˜
2
(NH) cm–1. H NMR (400.13 MHz, [D6]DMSO): δ = 6.24 (dd, J
General Procedure for Synthesis of Imidazo-pyrimidines 11–14: 2-
Aminopyrimidine 2a–d (2.8 mmol) was added to a solution of im-
1
3
= 9.5, 3J = 9.6 Hz, 1 H, CH), 6.95 (d, 3J = 9.6 Hz, 1 H, NH),
7.24 (m, 2 H, 3.5-H C6H5), 7.36–7.40 (m, 4 H, 3,4,5-H C6H5, 4-H ine 1 (2.8 mmol) in 1,4-dioxane (10 mL) and the solution was
C6H5SO2), 7.63 (m, 2 H, 2.6-H C6H5), 7.69 (m, 2 H, 2,6-H C6H5), stirred on a magnetic stirrer for 5 h at room temp. NaOH (0.50 g,
3
8.19 (s, 2 H, 4,6-H), 8.33 (d, J = 9.5 Hz, 1 H, NHSO2) ppm. 13C
NMR (100.61 MHz, [D6]DMSO): δ = 70.29 (CH), 95.42 (CCl2),
107.85 (C-5), 127.23, 127.90, 129.96, 138.98 (C6H5), 128.53, 128.92,
11.2 mmol) and 1,4-dioxane (20 mL) were then added to the reac-
tion mixture and stirring was continued for 5 h at room temp. The
reaction mixture was diluted with water (100 mL), then 10% HCl
132.71, 141.07 (C6H5SO2), 158.09 (C-4,6), 159.21 (C-2) ppm. was added to pH 6, the precipitate was filtered off, dried, and
C18H15BrCl2N4O2S (502.21): calcd. C 43.05, H 3.01, N 11.16, S
6.38; found C 43.15, H 3.05, N 11.32, S 6.24.
recrystallized from ethanol.
N-(2-Phenylimidazo[1,2-a]pyrimidine-3-yl)-4-chlorobenzenesulfon-
amide (11a): Yield 0.81 g (76%); colorless solid; m.p. 265–267 °C.
N-{1-[(5-Bromopyrimidin-2-yl)amino]-2,2-dichloro-2-phenylethyl}-4-
methylbenzenesulfonamide (7c): Yield 1.30 g (90%); colorless solid;
IR (KBr): ν = 1164, 1331 (SO ), 1615 (C=N) cm–1 1H NMR
.
˜
2
m.p. 181–183 °C. IR (KBr): ν = 1155, 1333 (SO ), 3329 (NH) cm–1. (400.13 MHz, [D6]DMSO): δ = 7.13 (dd, J = 4.1, J = 6.8 Hz, 1
3
3
˜
2
1H NMR (400.13 MHz, [D6]DMSO): δ = 2.22 (s, 3 H, CH3), 6.10 H, 6-H), 7.15–7.20 (m, 3 H, 3,4,5-H C6H5), 7.22, 7.40 (AAЈBBЈ, 4
(dd, 3J = 9.5, 3J = 9.5 Hz, 1 H, CH), 6.77 (d, 3J = 9.5 Hz, 1 H,
H, 4-ClC6H4), 7.57 (m, 2 H, 2,6-H C6H5), 8.63 (dd, J = 4.1, J =
3
4
3
4
NH), 7.01, 7.48 (AAЈBBЈ, 4 H, 4-CH3C6H4), 7.37–7.39 (m, 3 H, 2.0 Hz, 1 H, 7-H), 8.77 (dd, J = 6.8, J = 2.0 Hz, 1 H, 5-H) ppm.
3
3,4,5-H C6H5), 7.69 (m, 2 H, 2,6-H C6H5), 8.14 (d, J = 9.5 Hz, 1
H, NHSO2), 8.18 (s, 2 H, 4,6-H) ppm. 13C NMR (100.61 MHz,
[D6]DMSO): δ = 20.93 (CH3), 69.79 (CH), 94.95 (CCl2), 107.37 (C-
13C NMR (100.61 MHz, [D6]DMSO): δ = 109.56 (C-6), 111.75 (C-
3), 128.60, 129.24, 137.96, 138.44 (4-ClC6H4), 128.14, 127.27,
127.99, 131.88 (C6H5), 132.63 (C-5), 141.20 (C-2), 145.64 (C-8a),
5), 126.98, 127.48, 129.47, 138.44 (C6H5), 128.05, 128.85, 137.42, 151.99 (C-7) ppm. C18H13ClN4O2S (384.84): calcd. C 56.18, H
142.74 (4-CH3C6H4), 157.53 (C-4,6), 158.74 (C-2) ppm.
C19H17BrCl2N4O2S (516.24): calcd. C 44.20, H 3.32, N 10.85, S
6.21; found C 44.05, H 3.29, N 10.79, S 6.18.
3.40, Cl 9.21, N 14.56, S 8.33; found C 56.38, H 3.46, Cl 9.34, N
14.45, S 8.38.
N-(2-Phenylimidazo[1,2-a]pyrimidine-3-yl)benzenesulfonamide
(11b): Yield 0.96 g (89 %); colorless solid; m.p. 273–275 °C. IR
4-Chloro-N-{2,2-dichloro-1-[(5-chloropyrimidin-2-yl)amino]-2-phen-
ylethyl}benzenesulfonamide (8a): Yield 0.35 g (25%); colorless solid;
(KBr): ν = 1168, 1331 (SO ), 1615 (C=N) cm–1 1H NMR
.
˜
2
m.p. 181–183 °C. IR (KBr): ν = 1162, 1334 (SO ), 3383 (NH) cm–1. (400.13 MHz, [D6]DMSO): δ = 7.12 (dd, J = 4.5, J = 6.6 Hz, 1
3
3
˜
2
1H NMR (400.13 MHz, [D6]DMSO): δ = 6.17 (br. s, 1 H, CH),
H, 6-H), 7.16–7.18 (m, 3 H, 3,4,5-H C6H5), 7.29 (m, 2 H, 3,5-H
C6H5SO2), 7.42 (m, 1 H, 4-H C6H5SO2), 7.53 (m, 2 H, 2,6-H
7.01 (d, 3J = 9.1 Hz, 1 H, NH), 7.30, 7.62 (AAЈBBЈ, 4 H, 4-
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42695
/KAP1
Date: 27-08-14 17:56:12
Pages: 12
Synthesis of 3-(Sulfonylamino)imidazo[1,2-a]pyrimidines
C6H5SO2), 7.69 (m, 2 H, 2,6-H C6H5), 8.61 (dd, 3J = 4.5, 4J =
2.0 Hz, 1 H, 7-H), 8.63 (dd, 4J = 2.0, 3J = 6.6 Hz, 1 H, 5-H), 10.84
(br. s, 1 H, NH) ppm. 13C NMR (100.61 MHz, [D6]DMSO): δ =
109.68 (C-6), 112.32 (C-3), 127.60, 127.55, 128.54, 132.52 (C6H5),
128.50, 129.59, 133.71, 140.18 (C6H5SO2), 132.79 (C-5), 141.34 (C-
4-Chloro-N-(5,7-dimethyl-2-phenylimidazo[1,2-a]pyrimidin-3-yl)-
benzenesulfonamide (13a): Yield 0.69 g (60%); colorless solid; m.p.
244–246 °C. IR (KBr): ν = 1165, 1343 (SO ), 1615 (C=N) cm–1. 1H
˜
2
NMR (400.13 MHz, [D6]DMSO): δ = 2.50 (s, 3 H, CH3), 2.96 (s,
3 H, CH3), 6.88 (s, 1 H, 6-H), 7.14, 7.29 (AAЈBBЈ, 4 H, 4-ClC6H4),
2), 145.94 (C-8a), 152.10 (C-7) ppm. C18H14N4O2S (350.39): calcd. 7.06–7.15 (m, 3 H, 3,4,5-H C6H5), 7.48 (m, 2 H, 2,6-H C6H5), 10.80
C 61.70, H 4.03, N 15.99, S 9.15; found C 61.86, H 3.98, N 15.82,
S 9.21.
(br. s, 1 H, NH) ppm. 13C NMR (100.61 MHz, [D6]DMSO): δ =
18.86 (CH3), 24.04 (CH3), 111.49 (C-6), 111.78 (C-3), 127.32,
127.32, 127.79, 132.33 (C6H5), 128.37, 128.80, 138.08, 138.71 (4-
ClC6H4), 142.25 (C-2), 145.52 (C-5), 146.62 (C-8a), 160.75 (C-
7) ppm. MS (EI): m/z (%) = 236 (100) [M – ArSO2H]+, 209 (49),
183 (23), 133 (28), 106 (40). C20H17ClN4O2S (412.89): calcd. C
58.18, H 4.15, Cl 8.59, N 13.57, S 7.77; found C 58.05, H 4.05, Cl
8.41, N 13.38, S 7.63.
N-(2-Phenylimidazo[1,2-a]pyrimidine-3-yl)-4-methylbenzenesulfon-
amide (11c): Yield 0.66 g (65%); colorless solid; m.p. 253–255 °C.
IR (KBr): ν = 1169, 1330 (SO ), 1615 (C=N) cm–1 1H NMR
.
˜
2
(400.13 MHz, [D6]DMSO): δ = 2.19 (s, 3 H, CH3), 7.02, 7.33
3
3
(AAЈBBЈ, 4 H, 4-CH3C6H4), 7.12 (dd, J = 4.1, J = 6.9 Hz, 1 H,
6-H), 7.15, 7.20 (m, 3 H, 3,4,5-H C6H5), 7.62 (m, 2 H, 2,6-H C6H5),
3
4
3
4
N-(5,7-Dimethyl-2-phenylimidazo[1,2-a]pyrimidin-3-yl)benzenesulf-
8.61 (dd, J = 4.1, J = 2.0 Hz, 1 H, 7-H), 8.66 (dd, J = 6.9, J =
2.0 Hz, 1 H, 5-H), 10.71 (br. s, 1 H, NH) ppm. 13C NMR
(100.61 MHz, [D6]DMSO): δ = 20.87 (CH3), 109.09 (C-6), 111.93
(C-3), 126.53, 129.44, 136.32, 143.52 (4-CH3C6H4), 127.84, 127.05,
127.61, 131.99 (C6H5), 132.29 (C-5), 140.88 (C-2), 145.37 (C-8a),
151.48 (C-7) ppm. MS (EI): m/z (%) = 207 (100) [M – ArSO2-
H-H]+, 181 (7), 153 (13), 129 (25), 103 (21). C19H16N4O2S (364.42):
calcd. C 62.62, H 4.43, N 15.37, S 8.80; found C 62.76, H 4.37, N
15.22, S 8.92.
onamide (13b): Yield 0.76 g (77%); light-brown solid; m.p. 237–
1
239 °C. IR (KBr): ν = 1160, 1340 (SO ), 1615 (C=N) cm–1. H
˜
2
NMR (400.13 MHz, [D6]DMSO): δ = 2.64 (s, 3 H, CH3), 3.04 (s,
3 H, CH3), 7.14–7.19 (m, 4 H, 3,4,5-H C6H5, 6-H), 7.23 (m, 1 H,
4-H C6H5SO2), 7.33 (m, 2 H, 3,5-H C6H5SO2), 7.41 (m, 2 H, 2,6-
H C6H5SO2), 7.53 (m, 2 H, 2,6-H C6H5) ppm. 13C NMR
(100.61 MHz, [D6]DMSO): δ = 18.78 (CH3), 24.17 (CH3), 113.62
(C-6), 114.91 (C-3), 126.44, 127.09, 127.68, 129.37 (C6H5), 128.31,
128.73, 133.06, 139.60 (C6H5SO2), 135.58 (C-5), 143.81 (C-2),
147.88 (C-8a), 166.09 (C-7) ppm. C18H14N4O2S (350.39): calcd. C
61.70, H 4.03, N 15.99, S 9.15; found C 61.86, H 3.95, N 15.82, S
8.97.
4-Chloro-N-(7-methyl-2-phenylimidazo[1,2-a]pyrimidin-3-yl)benz-
enesulfonamide (12a): Yield 0.57 g (51%); colorless solid; m.p. 223–
1
225 °C. IR (KBr): ν = 1165, 1322 (SO ), 1622 (C=N) cm–1. H
˜
2
NMR (400.13 MHz, [D6]DMSO): δ = 2.57 (s, 3 H, CH3), 7.06 (d,
3J = 6.9 Hz, 1 H, 6-H), 7.13–7.20 (m, 3 H, 3,4,5-H C6H5), 7.22,
7.39 (AAЈBBЈ, 4 H, 4-ClC6H4), 7.56 (m, 2 H, 2,6-H C6H5), 8.61
(d, 3J = 6.9 Hz, 1 H, 5-H) ppm. 13C NMR (100.61 MHz, [D6]-
DMSO): δ = 24.45 (CH3), 109.97 (C-6), 111.37 (C-3), 125.77,
126.85, 127.49, 131.97 (C6H5), 128.33, 128.94, 131.68, 138.01 (4-
ClC6H4), 138.01 (C-2), 131.67 (C-5), 145.34 (C-8a), 161.35 (C-
7) ppm. C19H15ClN4O2S (398.87): calcd. C 52.21, H 3.79, Cl 8.89,
N 14.05, S 8.04; found C 52.35, H 3.71, Cl 8.98, N 14.25, S 8.15.
4-Methyl-N-(5,7-dimethyl-2-phenylimidazo[1,2-a]pyrimidin-3-yl)-
benzenesulfonamide (13c): Yield 0.70 g (64 %); brown solid; m.p.
242–244 °C. IR (KBr): ν = 1161, 1327 (SO ), 1623 (C=N) cm–1. 1H
˜
2
NMR (400.13 MHz, [D6]DMSO): δ = 2.17 (s, 3 H, CH3), 2.50 (s,
3 H, CH3-C5), 2.96 (s, 3 H, CH3-C7), 6.87, 7.19 (AAЈBBЈ, 4 H, 4-
CH3C6H4), 7.05 (m, 2 H, 3,5-H C6H5), 7.12 (m, 1 H, 4-H C6H5),
7.52 (m, 2 H, 2,6-H C6H5), 10.81 (br. s, 1 H, NH) ppm. 13C NMR
(100.61 MHz, [D6]DMSO): δ = 19.34 (CH3), 21.35 (CH3), 24.54
(CH3), 111.81 (C-6), 112.63 (C-3), 127.49, 127.76, 128.12, 132.92
(C6H5), 126.94, 129.55, 137.33, 143.44 (4-CH3C6H4), 142.65 (C-
2), 146.04 (C-5), 146.99 (C-8a), 160.96 (C-7) ppm. C21H20N4O2S
(392.47): calcd. C 64.27, H 5.14, N 14.28, S 8.17; found C 64.15,
H 5.06, N 14.08, S 8.06.
N-(7-Methyl-2-phenylimidazo[1,2-a]pyrimidin-3-yl)benzenesulfon-
amide (12b): Yield 0.66 g (65%); colorless solid; m.p. 279–281 °C.
IR (KBr): ν = 1168, 1335 (SO ), 1622 (C=N) cm–1 1H NMR
.
˜
2
(400.13 MHz, [D6]DMSO): δ = 2.55 (s, 3 H, CH3), 7.00 (d, 3J =
6.8 Hz, 1 H, 6-H), 7.16 (m, 2 H, 3,5-H C6H5), 7.16 (m, 1 H, 4-H
C6H5), 7.28 (m, 2 H, 3,5-H C6H5SO2), 7.42 (m, 1 H, 4-H
C6H5SO2), 7.51 (m, 2 H, 2,6-H C6H5SO2), 7.65 (m, 2 H, 2,6-H
C6 H5 ), 8.44 (d, 3 J = 6.8 Hz, 1 H, 5-H) ppm. 1 3 C NMR
(100.61 MHz, [D6]DMSO): δ = 24.91 (CH3), 110.27 (C-6), 111.95
(C-3), 126.95, 127.27, 128.21, 132.58 (C6H5), 128.34, 129.44,
133.51, 140.19 (C6H5SO2), 131.95 (C-5), 140.19 (C-2), 145.74 (C-
8a), 161.66 (C-7) ppm. C19H16N4O2S (364.42): calcd. C 62.62, H
4.43, N 15.37, S 8.80; found C 62.54, H 4.38, N 15.18, S 8.65.
4-Chloro-N-(7-chloro-5-methyl-2-phenylimidazo[1,2-a]pyrimidin-3-
yl)benzenesulfonamide (14a): Yield 0.96 g (79%); colorless solid;
m.p. 249–251 °C. IR (KBr): ν = 1164, 1338 (SO ), 1611
˜
2
(C=N) cm–1. 1H NMR (400.13 MHz, [D6]DMSO): δ = 3.00 (s, 3
H, CH3), 7.08–7.19 (m, 6 H, 6-H, 3,4,5-H C6H5, 2,6-H 4-ClC6H4),
7.31 (d, 2 H, 3,5-H 4-ClC6H4), 7.49 (m, 2 H, 2,6-H C6H5), 10.97
(br. s, 1 H, NH) ppm. 13C NMR (100.61 MHz, [D6]DMSO): δ =
19.24 (CH3), 11.45 (C-6), 113.52 (C-3), 127.84, 128.17, 128.33,
131.91 (C6H5), 128.80, 129.28, 138.54 (4-ClC6H4), 143.48 (C-2),
145.46 (C-5), 149.45 (C-8a), 151.64 (C-7) ppm. C19H14Cl2N4O2S
(433.31): calcd. C 52.67, H 3.26, Cl 16.36, N 12.93, S 7.40; found
C 52.60, H 3.29, Cl 16.42, N 12.99, S 7.28.
4-Methyl-N-(7-methyl-2-phenylimidazo[1,2-a]pyrimidin-3-yl)benz-
enesulfonamide (12c): Yield 0.56 g (53%); colorless solid; m.p. 252–
1
254 °C. IR (KBr): ν = 1162, 1335 (SO ), 1623 (C=N) cm–1. H
˜
2
NMR (400.13 MHz, [D6]DMSO): δ = 2.20 (s, 3 H, CH3), 2.56 (s, N-(7-Chloro-5-methyl-2-phenylimidazo[1,2-a]pyrimidin-3-yl)benz-
3 H, CH3), 7.00, 7.33 (AAЈBBЈ, 4 H, 4-CH3C6H4), 7.03 (d, 3J =
enesulfonamide (14b): Yield 0.96 g (73%); colorless solid; m.p. 259–
1
6.8 Hz, 1 H, 6-H), 7.12–7.18 (m, 3 H, 3,4,5-H C6H5), 7.59 (m, 2
261 °C. IR (KBr): ν = 1165, 1340 (SO ), 1610 (C=N) cm–1. H
˜
2
3
H, 2,6-H C6H5), 8.50 (d, J = 6.8 Hz, 1 H, 5-H), 10.62 (br. s, 1 H,
NMR (400.13 MHz, [D6]DMSO): δ = 3.00 (s, 3 H, CH3), 7.22 (s,
NH) ppm. 13C NMR (100.61 MHz, [D6]DMSO): δ = 21.35 (CH3), 1 H, 6-H), 7.07–7.12 (m, 3 H, 3,4,5-H C6H5), 7.16 (m, 2 H, 3,5-H
24.97 (CH3), 110.30 (C-6), 111.91 (C-3), 127.01, 127.39, 127.90,
C6H5SO2), 7.31 (m, 1 H, 4-H C6H5SO2), 7.38 (m, 2 H, 2,6-H
132.64 (C6H5), 128.26, 129.89, 136.83, 143.96 (4-CH3C6H4), 140.64 C6H5SO2), 7.59 (m, 2 H, 2,6-H C6H5), 11.26 (br. s, 1 H, NH) ppm.
(C-2), 132.06 (C-5), 145.83 (C-8a), 161.62 (C-7) ppm. C20H18N4O2S
(378.45): calcd. C 63.47, H 4.79, N 14.80, S 8.47; found C 63.35,
H 4.86, N 14.68, S 8.56.
13C NMR (100.61 MHz, [D6]DMSO): δ = 18.92 (CH3), 111.38 (C-
6), 113.70 (C-3), 126.63, 127.59, 128.83, 131.36 (C6H5), 128.08,
128.83, 133.00, 140.25 (C6H5SO2), 144.91 (C-5), 142.61 (C-2),
Eur. J. Org. Chem. 0000, 0–0
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I. B. Rozentsveig et al.
149.41 (C-8a), 151.64 (C-7) ppm. C19H15ClN4O2S (398.87): calcd. (443.32): calcd. C 51.48, H 3.41, N 12.64, S 7.23; found C 51.55,
FULL PAPER
C 57.21, H 3.79, Cl 8.89, N 14.05, S 8.04; found C 57.35, H 3.82,
Cl 8.93, N 14.15, S 8.09.
H 3.44, N 12.59, S 7.30.
4-Chloro-N-(6-chloro-2-phenylimidazo[1,2-a]pyrimidin-3-yl)benzene-
sulfonamide (16a): Yield 0.55 g (47%); colorless solid; m.p. 292–
4-Methyl-N-(7-chloro-5-methyl-2-phenylimidazo[1,2-a]pyrimidin-3-
yl)benzenesulfonamide (14c): Yield 0.86 g (74%); colorless solid;
1
294 °C. IR (KBr): ν = 1164, 1343 (SO ), 1612 (C=N) cm–1. H
˜
2
NMR (400.13 MHz, [D6]DMSO): δ = 7.18–7.25 (m, 3 H, 3,4,5-H
C6H5), 7.26 (AAЈBBЈ, 2 H, 2,6-H 4-ClC6H4), 7.43 (AAЈBBЈ, 2 H,
3,5-H 4-ClC6H4), 7.65 (m, 2 H, 2,6-H C6H5), 8.68 (d, J = 2.4 Hz,
m.p. 256–258 °C. IR (KBr): ν = 1175, 1334 (SO ), 1612
˜
2
(C=N) cm–1. 1H NMR (400.13 MHz, [D6]DMSO): δ = 2.16 (s, 3
H, CH3), 3.00 (s, 3 H, CH3), 6.88, 7.19 (AAЈBBЈ, 4 H, 4-CH3C6H4),
7.06 (m, 2 H, 3,5-H C6H5), 7.13–7.16 (m, 2 H, 6-H, 4-H C6H5),
7.50 (m, 2 H, 2,6-H C6H5), 10.77 (br. s, 1 H, NH) ppm. 13C NMR
(100.61 MHz, [D6]DMSO): δ = 18.86 (CH3), 20.86 (CH3), 110.90
(C-6), 113.50 (C-3), 127.40, 127.53, 127.81, 131.65 (C6H5), 126.52,
129.18, 136.57, 143.25 (4-CH3C6H4), 143.14 (C-2),145.00 (C-5),
149.09 (C-8a), 151.06 (C-7) ppm. C20H17ClN4O2S (412.89): calcd.
C 58.18, H 4.15, Cl 8.59, N 13.57, S 7.77; found C 58.29, H 4.21,
Cl 8.64, N 13.51, S 7.62.
4
1 H, 5-H), 8.84 (d, 4J = 2.4 Hz, 1 H, 7-H), 11.00 (br. s, 1 H,
NH) ppm. 13C NMR (100.61 MHz, [D6]DMSO): δ = 104.56 (C-6),
112.36 (C-3), 127.46, 128.30, 128.37, 131.81 (C6H5), 128.79, 129.46,
138.07, 138.71 (4-ClC6H4), 132.12 (C-5), 142.28 (C-2), 144.00 (C-
8a), 152.05 (C-7) ppm. C18H12Cl2N4O2S (419.28): calcd. C 51.56,
H 2.88, Cl 16.91, N 13.36, S 7.65; found C 51.64, H 2.86, Cl 16.84,
N 13.28, S 7.71.
N-(6-Chloro-2-phenylimidazo[1,2-a]pyrimidin-3-yl)benzenesulfon-
amide (16b): Yield 0.39 g (36%); colorless solid; m.p. 290–292 °C.
General Procedure for the Synthesis of Imidazo-pyrimidines 15 and
16: 2-Aminopyrimidine 2e,f (2.8 mmol) was added to a solution of
imine 1 (2.8 mmol) in DMF (10 mL) and the solution was stirred
on a magnetic stirrer for 5 h. The reaction mixture was shaken with
acetone (30 mL), diluted with water (100 mL), and allowed to stand
for 5 h. The precipitate was filtered off and dried, then dissolved
in 1,4-dioxane (30 mL) and NaOH (0.50 g, 11.2 mmol) was added.
The reaction mixture was stirred for 5 h, mixed with water
(100 mL), and 10% HCl was added to pH 6. The precipitate of the
final imidazo-pyrimidine 15, 16 was filtered off, dried, and recrys-
tallized from ethanol.
IR (KBr): ν = 1164, 1334 (SO ), 1611 (C=N) cm–1 1H NMR
.
˜
2
(400.13 MHz, [D6]DMSO): δ = 7.18–7.22 (m, 3 H, 3,4,5-H C6H5),
7.31 (m, 2 H, 3,5-H C6H5SO2), 7.44 (m, 1 H, 4-H C6H5SO2), 7.54
4
(m, 2 H, 2,6-H C6H5SO2), 7.73 (m, 2 H, 2,6-H C6H5), 8.61 (d, J
4
= 2.4 Hz, 1 H, 5-H), 8.63 (d, J = 2.4 Hz, 1 H, 7-H), 10.91 (br. s,
1 H, NH) ppm. 13C NMR (100.61 MHz, [D6]DMSO): δ = 112.90
(C-6), 117.51 (C-3), 127.04, 127.52, 128.72, 130.09 (C6H5), 128.47,
129.55, 133.75, 139.94 (C6H5SO2), 132.05 (C-5), 142.50 (C-2),
144.04 (C-8a), 150.52 (C-7) ppm. C18H13ClN4O2S (384.84): calcd.
C 56.18, H 3.40, Cl 9.21, N 14.56, S 8.33; found C 56.25, H 3.44,
Cl 9.28, N 14.45, S 8.39.
N-(6-Bromo-2-phenylimidazo[1,2-a]pyrimidin-3-yl)-4-chlorobenzene-
4-Methyl-N-(6-chloro-2-phenylimidazo[1,2-a]pyrimidin-3-yl)benz-
enesulfonamide (16c): Yield 0.57 g (48%); colorless solid; m.p. 288–
sulfonamide (15a): Yield 0.77 g (59%); colorless solid; m.p. 276–
1
278 °C. IR (KBr): ν = 1165, 1346 (SO ), 1613 (C=N) cm–1. H
˜
2
290 °C. IR (KBr): ν = 1163, 1336 (SO ), 1613 (C=N) cm–1. 1H
˜
2
NMR (400.13 MHz, [D6]DMSO): δ = 7.19–7.23 (m, 3 H, 3,4,5-H
C6H5), 7.25, 7.41 (AAЈBBЈ, 4 H, 4-ClC6H4), 7.63 (m, 2 H, 2,6-H
NMR (400.13 MHz, [D6]DMSO): δ = 2.22 (s, 3 H, CH3), 7.05, 7.35
(AAЈBBЈ, 4 H, 4-CH3C6H4), 7.18–7.24 (m, 3 H, 3,4,5-H C6H5),
4
4
C6H5), 8.66 (d, J = 2.4 Hz, 1 H, 5-H), 8.86 (d, J = 2.4 Hz, 1 H,
6-H), 11.02 (br. s, 1 H, NH) ppm. 13C NMR (100.61 MHz, [D6]-
DMSO): δ = 112.55 (C-6), 117.58 (C-3), 127.44, 128.29, 128.34,
131.81 (C6H5), 128.79, 129.42, 138.02, 138.66 (4-ClC6H4), 130.21
(C-5), 142.56 (C-2), 144.05 (C-8a), 150.55 (C-7) ppm.
4
7.70 (m, 2 H, 2,6-H C6H5), 8.55 (d, J = 2.4 Hz, 1 H, 5-H), 8.63
4
(d, J = 2.4 Hz, 1 H, 7-H), 10.76 (br. s, 1 H, NH) ppm. 13C NMR
(100.61 MHz, [D6]DMSO): δ = 20.84 (CH3), 112.58 (C-6), 117.02
(C-3), 126.56, 129.55, 136.24, 143.80 (4-CH3C6H4), 127.12, 127.80,
127.91, 132.22 (C6H5), 131.62 (C-5), 142.18 (C-2), 143.53 (C-8a),
149.95 (C-7) ppm. C19H15ClN4O2S (398.87): calcd. C 57.21, H
3.79, Cl 8.89, N 14.05, S 8.04; found C 57.33, H 3.84, Cl 8.93, N
14.13, S 8.11.
C
18H12BrClN4O2S (463.74): calcd. C 46.62, H 2.61, N 12.08, S
6.91; found C 46.73, H 2.63, N 12.18, S 6.94.
N-(6-Bromo-2-phenylimidazo[1,2-a]pyrimidin-3-yl)benzenesulfon-
amide(15b): Yield 0.77 g (38%); colorless solid; m.p. 302–304 °C.
IR (KBr): ν = 1163, 1332 (SO ), 1608 (C=N) cm–1 1H NMR
.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra of all compounds, qantum chemical
data, crystal data, and details of X-ray experiments.
˜
2
(400.13 MHz, [D6]DMSO): δ = 7.21–7.22 (m, 3 H, 3,4,5-H C6H5),
7.32, 7.44 (m, 3 H, 3,4,5-H C6H5SO2), 7.75 (m, 2 H, 2,6-H C6H5),
8.64 (d, 4J = 2.2 Hz, 1 H, 7-H), 8.57 (d, 4J = 2.2 Hz, 1 H, 5-H) ppm.
13C NMR (100.61 MHz, [D6]DMSO): δ = 104.76 (C-6), 112.69 (C-
3), 127.06, 127.58, 128.83, 132.06 (C6H5), 128.56, 129.66, 133.89,
139.98 (C6H5SO2), 132.06 (C-5), 142.29 (C-2), 144.49 (C-8a),
152.12 (C-7) ppm. C18H13BrN4O2S (429.29): calcd. C 50.36, H
3.05, N 13.05, S 7.47; found C 50.26, H 3.08, N 13.00, S 7.57.
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289 °C. IR (KBr): ν = 1161, 1332 (SO ), 1598 (C=N) cm–1. H
˜
2
NMR (400.13 MHz, [D6]DMSO): δ = 2.24 (s, 3 H, CH3), 7.08, 7.37
(AAЈBBЈ, 4 H, 4-CH3C6H4), 7.22 (m, 1 H, 4-H C6H5), 7.24 (m, 2
4
H, 3,5-H C6H5), 7.75 (m, 2 H, 2,6-H C6H5), 8.64 (d, J = 2.4 Hz,
1 H, 7-H), 8.49 (d, 4J = 2.4 Hz, 1 H, 5-H), 10.74 (br. s, 1 H,
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104.22 (C-6), 112.50 (C-3), 126.58, 129.65, 136.40, 143.89 (4-
CH3C6H4), 127.17, 127.98, 128.03, 131.69 (C6H5), 131.52 (C-5),
141.86 (C-2), 143.49 (C-8a), 151.46 (C-7) ppm. C19H15BrN4O2S
10
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Synthesis of 3-(Sulfonylamino)imidazo[1,2-a]pyrimidines
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Received: June 5, 2014
Published Online: ᭿
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11

Job/Unit: O42695
/KAP1
Date: 27-08-14 17:56:12
Pages: 12
I. B. Rozentsveig et al.
FULL PAPER
Heterocyclic Chemistry
I. B. Rozentsveig,* V. Y. Serykh,
G. N. Chernysheva, E. V. Kondrashov,
A. I. Fedotova, I. A. Ushakov,
E. V. Tretyakov,
G. V. Romanenko ............................ 1–12
Two-Step Regioselective Synthesis of 3-
(Sulfonylamino)imidazo[1,2-a]pyrimidines
from 2-Aminopyrimidines and N-(2,2-
Dichloro-2-phenylethylidene)arensulfon-
amides
2-Aminopyrimidines react easily with elec-
trophilic N-(arylsulfonyl)phenyldichloro-
acetaldimines to give the corresponding ad-
dition products of the amine moiety to the
azomethine group. The obtained com-
pounds were successfully utilized to synthe-
size
imidazo[1,2-a]pyrimidin-3-ylsulfon-
amides regioselectively.
Keywords: Nitrogen heterocycles / Sulfon-
amides
/ Nucleophilic addition / Re-
arrangement / Regioselectivity
12
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