Synthesis and biological evaluations of new pyrrolo[2,3-b]pyrimidine as SDI analogs

Article abstract of DOI:10.3987/COM-07-11302

The synthesis of new pyrrolo[2,3-d]pyrimidines variously substituted on the N-1 and C-2 atoms are described. Access to these compounds, which have modest activity compared with the first inhibitor SDI, involves, as the key step, the formation of a pyrrolopyrimidine skeleton from the 5-amino-2-(methoxymethyl)pyrimidine.

Full text of DOI:10.3987/COM-07-11302

HETEROCYCLES, Vol. 75, No. 5, 2008
1163
HETEROCYCLES, Vol. 75, No. 5, 2008, pp. 1163 - 1189. © The Japan Institute of Heterocyclic Chemistry
Received, 14th December, 2007, Accepted, 5th February, 2008, Published online, 8th February, 2008. COM-07-11302
SYNTHESIS
AND
BIOLOGICAL
EVALUATIONS
OF
NEW
PYRROLO[2,3-b]PYRIMIDINE AS SDI ANALOGS
Jérôme Guillard and Marie-Claude Viaud-Massuard*
EA 3857 Laboratoire de Synthèse et Physicochimie, Organique et Thérapeutique,
University of Tours, 31 avenue Monge, 37200 Tours, Université François Rabelais,
Tours, France. Phone: 33 247 36 72 28; Email: guillard@univ-tours.fr
Abstract – The synthesis of new pyrrolo[2,3-d]pyrimidines variously substituted on
the N-1 and C-2 atoms are described. Access to these compounds, which have
modest activity compared with the first inhibitor SDI, involves, as the key step, the
formation of
a
pyrrolopyrimidine skeleton from the 5-amino-2-
(methoxymethyl)pyrimidine.
INTRODUCTION
Sorbitol dehydrogenase (SDH) a member of the medium-chain dehydrogenase/reductase protein family
and the second enzyme of the polyol glucose metabolism pathway converts sorbitol to fructose strictly
using NAD(+) as a coenzyme.1 SDH is expressed almost ubiquitously in all mammalian tissues. The
enzyme has attracted considerable interest2,3 due to its implication in the development of diabetic
complications and futhermore its tertiary structure may facilitate drug conception.4,5 Modelling studies
suggest that SDH is structurally homologous to mammalian alcohol dehydrogenase with respect to
conserving zinc binding motif and a hydrophobic substrate-binding pocket.6,7 Recently, the
three-dimensional (3-D) structure of a mammalian SDH was established, and it was found that while the
overall 3-D structure of SDH and alcohol dehydrogenase are similar, the zinc coordination in the active
sites of the two enzymes is different.8 The available structural and biochemical information about SDH is
currently being overviewed in a structure-based approach to develop drugs for the treatment or prevention
of the complications of diabetes.9
The first reported in vivo active sorbitol dehydrogenase inhibitor (SDI, Figure 1) is the
4-[4-(N,N-dimethylsulfanoyl)piperazino]-2-hydroxymethylpyrimidine (WAY 135706) which inhibits
SDH with an IC50 value of 1 μM.10 Searching for new potent sorbitol dehydrogenase inhibitors, based on
a model of recent modelling studies on the active site of SDH and interesting inhibition of WAY 135706

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HETEROCYCLES, Vol. 75, No. 5, 2008
we decided to synthesize SDI analogs as expected sorbitol dehydrogenase inhibitory activity.
O
N
S NMe2
O
N
N
N
HO
SDI
IC50 = 1 μM
Figure1. Structure of SDI
Herein, we report the synthesis and biological preliminary studies as sorbitol dehydrogenase inhibitor of
hydroxymethylpyrimidine derivatives 1-5, (hydroxymethyl)pyrrolo[2,3-d]pyrimidine derivatives 6 and 7,
and 6,7,8,9-tetrahydropyrazino[2’,1’:5,1]pyrrolo[2,3-d]pyrimidine derivative 7 (Figure 2).
Me
N
O
O
N
S NMe2
O
N
N S NMe2
O
N
N
n
N
N
Me
HO2C
OH
1
2-4 n = 1,2,3
N
N
HO
O
N
N
O
S
HO
N
N
N
O
N
NH
O
N S NMe2
O
6
O
5
Me
N
N
O
O
HO
N
HO
S NMe2
O
N
N
N
N
N
S NMe2
O
Me
Me
7
8
Figure 2. Structures of the target molecules derived from SDI
RESULTS AND DISCUSSION
Synthesis of 4-(4-dimethylsulfamoylpiperazin-1-yl)pyrimidine-2-carboxylic acid 1
The synthesis of aldehyde 9 was achieved under Swern conditions11 with SDI.12 Subsequent treatment of
9 by manganese dioxide in the presence of sodium cyanide and acetic acid in ethanol provided the
corresponding carboxylic acid ethyl ester 10. The desired 4-(4-dimethylsulfamoylpiperazin-
1-yl)pyrimidine-2-carboxylic acid 1 was then obtained by acidic hydrolysis using Dowex resin with a
good yield (Scheme 1).13

HETEROCYCLES, Vol. 75, No. 5, 2008
1165
O
a, b
O
N S
O
N
N S NMe2
N
N
N
NMe2
N
O
N
HO
c
OHC
SDI
9
O
N S
O
O
N S
O
d
N
N
NMe2
N
NMe2
N
N
N
H5C2O2C
HO2C
10
1
Scheme 1. Synthesis of Compound 1
Reagents and conditions: a) DMSO, (COCl)2, CH2Cl2, -60 °C. b) Et3N, -60 °C to rt, 70% within 2 steps.
c) NaCN, MnO2, AcOH, EtOH, rt, 24 h, 60%. d) DOWEX, H2O, reflux, 81%.
Synthesis of N-(2-[N”-2-(hydroxymethyl)pyrimidin-4-yl)-N”-methyl]alkylamino)-N,N’,N’-trimethyl
sulfamides 2 and 3
The required 2-methoxyacetamidine hydrochloride 11 was prepared in 2 steps from commercially
available methoxyacetonitrile with 86% yield. The first step involved a treatment at 0 °C with hydrogen
chloride in ethanol to provide the intermediate imidate. Then, addition of ammonia in methanol gave the
corresponding amidine 11 (Scheme 2).12
+
NH2
, Cl-
a, b
CN
MeO
MeO
NH2
11
Scheme 2. Synthesis of Compound 11
Reagents and conditions: a) HCl, EtOH, 0 °C. b) NH3, MeOH, rt, 86% within 2 steps.
The cyclo-condensation of 11 with ethyl formylacetate sodium salt 1214 afforded the corresponding
hydroxypyrimidine which was converted using POCl3 under reflux in 24 % yield to its chlorinated
derivative 13 (Scheme 3).
-
+
Na+
, Cl
,
N
O
O
NH2
a, b
+
MeO
MeO
OEt
N
Cl
H
NH2
13
12
11
Scheme 3. Synthesis of Compound 13
Reagents and conditions: a) H2O, rt. b) POCl3, 70 °C to reflux, 24% within 2 steps.
The target compounds 2 and 3 were prepared as outlined in Scheme 4. N,N’-alkyldiamines were
condensed on N,N-dimethylsulfamoyl chloride in the presence of potassium carbonate in ethanol at 0 °C
to afford the derivatives 14 and 15. The second step involved a nucleophilic substitution between these

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HETEROCYCLES, Vol. 75, No. 5, 2008
sulfonamide intermediates and the previously described chloropyrimidine 13, in THF at reflux, providing
respectively 16 and 17 in excellent yields. Finally, treatment by boron tribromide in dichloromethane led
to the desired compounds 2 and 3 with good yield.
O
S
H
N
H
a
Me
N
NMe2
Me
N
n
Me
N
n
H
O
n = 1,2
Me
14-15
Me
N
O
S
O
Me
N
b
Me
c
N
NMe2
N
S N
O
N
n
N
n
CH3
N
O
N
Me
Me
2-3
OH
16-17
OMe
Scheme 4. Synthesis of Compounds 2 and 3
Reagents and conditions: a) ClSO2N(CH3)2, K2CO3, EtOH, 0 °C, (14, n = 1, 66%), (15, n = 2, 41%). b) 13,
THF, reflux; (16, n = 1, 95%), (17, n = 2, quant.). c) BBr3, CH2Cl2, 0 °C, (2, n = 1, quant.), (3, n = 2,
90%).
Synthesis of N-(2-[N”-2-(hydroxymethyl)pyrimidin-4-yl)-N”-methyl]butylamino)-N,N’,N’-
trimethylsulfamide 4
The reaction of 13 with 1,4-diaminobutane in the presence of triethylamine in refluxing tetrahydrofuran
provided 18 in 81% yield. The latter was condensed on N,N-dimethylsulfamoyl chloride using potassium
carbonate to obtain 19 in moderate yield. The introduction of the methyl group was carried out under
classic conditions with methyl iodide and sodium hydride leading to the intermediate 20 which was
treated by boron tribromide to furnish the final compound 4 (Scheme 5).
N
a
N
MeO
NH2
MeO
N
N
H
N
Cl
18
7
O
S
b
c
N
H
N
MeO
NMe2
N
N
N
H
O
19
Me
N
O
S
N
MeO
HO
NMe
N
Me
O
20
CH
N
3O
N
d
CH3
S
N
N
N
CH3
CH3
O
4
Scheme 5. Synthesis of Compound 4
Reagents and conditions: a) 1,4-diaminobutane, Et3N, THF, reflux, 81%. b) ClSO2NMe2, Et3N, CH2Cl2, rt,
67%. c) NaH, MeI, DMF, rt, 62%. d) BBr3, CH2Cl2, 0 °C, 79%.

HETEROCYCLES, Vol. 75, No. 5, 2008
1167
Synthesis of 1-[4-(2-hydroxymethylpyrimidin-4-yl)piperazin-1-sulfonyl)imidazolidine-2,4-dione 5
Treatment of hydantoïn with potassium hydroxide in ethanol under reflux followed by reaction with
benzyl bromide in the presence of potassium iodide in N,N-dimethylformamide afforded the
3-benzyl-imidazolidine-2,4-dione 21.15 Exposure of 21 to sulfuryl chloride in chloroform at rt yielded to
22 in 81% yield (Scheme 6).
O
O
O
a, b
c
HN
N
HN
NH
N
N
ClSO2
O
O
O
21
22
Scheme 6. Synthesis of Compound 22
Reagents and conditions: a) KOH, EtOH, reflux. b) BnBr, KI, DMF, 80 °C, 49% within 2 steps. c)
SO2Cl2, Et3N, CHCl3, rt, 81%.
Finally, the imidazolidine target was prepared according to scheme 7. Reaction of pyrimidine 13 with
excess of piperazine in THF gave the 2-(methoxymethyl)-4-(piperazin-1-yl)-pyrimidine 23. Condensation
of 23 and 22 followed by debenzylation with aluminium chloride gave the desired imidazolidine 5.16
a
N
N
MeO
MeO
N
N
N
Cl
NH
13
23
b
N
MeO
O
N
N
O
S
N
N
N
O
O
24
N
c
HO
O
N
N
O
S
N
N
NH
O
O
5
Scheme 7. Synthesis of Compound 5
Reagents and conditions: a) piperazine, Et3N, THF, reflux, 91%. b) 22, NaH, DMF, 80 °C, 24%. c) AlCl3,
toluene, 90 °C, 41%.

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HETEROCYCLES, Vol. 75, No. 5, 2008
Synthesis of N,N,N’-trimethyl-N’-(2-[2-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl)-
sulfamide 6
The desired 2-(methoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine 29 was prepared as outlined in Scheme 8
from 4-chloro-2-(methoxymethyl)pyrimidine 13. The first step involved amination17 of 13 in a sealed
tube at 120 °C with a 30% ammonia solution and provided 25 (91% yield). This amino compound was
then treated with bromine in presence of calcium carbonate to give the corresponding bromopyrimidine
26 with moderate yield.18 In accordance with Kumar conditions,19 the latter was coupled with
trimethylsilylacetylene to form derivative 27. Finally, treatment of 27 with (Boc)2O with catalytic amount
of DMAP followed by treatment with sodium ethoxide in ethanol led to derivative 29 in a good yield
(Scheme 9).20,21
Br
a
b
N
N
N
MeO
MeO
MeO
N
NH2
N
NH2
N
Cl
25
26
13
Si(Me)3
c
Si(Me)3
d
e
N
N
N
MeO
MeO
MeO
N
N
NH2
N
N
N(Boc)2
H
7
27
28
29
Scheme 8. Synthesis of 2-(Methoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine 29
Reagents and conditions: a) NH4OH, sealed tube, 91%. b) Br2, CaCO3, H2O, 60°C, 59%. c)
trimethylsilylacetylene, Pd(PPh3)2Cl2, CuI, Et3N, THF, 40 °C, 91%. d) (Boc)2O, DMAP, THF, rt,
quantitative. e) EtONa, EtOH, reflux, 81%.
After, the required sulfamide 33 was prepared in a 4 step sequence from 29. The first step involved a
N-alkylation with 1,2-dibromoethane and sodium hydride in N,N-dimethylformamide to provide 30.
Treatment of 30 with sodium azide in N,N-dimethylformamide followed by reduction on Lindlar catalyst
in methanol provided amine 32 with 83% within 2 steps. This latter was condensed on
N,N-dimethylsulfamoyle chloride in a mixture of methylene chloride and triethylamine at rt to give 33 in
a satisfactory yield. 33 was then treated with methyl iodide in the presence of sodium hydride to lead 34
which is demethylated to yield the desired pyrrolo[2,3-d]pyrimidine 6. In the same way the derivative 35
was prepared from 33 in 85% yield (Scheme 9).

HETEROCYCLES, Vol. 75, No. 5, 2008
1169
b
N
a
N
N
MeO
MeO
MeO
N
N
N
N
N
N
H
N3
31
Br
29
30
c
d
N
N
MeO
MeO
N
N
N
N
O
NMe2
N
S
O
NH2
33
32
H
e
f
N
N
MeO
HO
N
N
N
N
O
O
N S NMe2
O
NMe2
34
N S
O
6
Me
Me
g
N
N
MeO
HO
N
N
N
N
O
O
N S NMe2
NMe2
N S
33
35
H
H
O
O
Scheme 9. Synthesis of N,N,N’-Trimethyl-N’-(2-[2-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl)
sulfamide 6
Reagents and conditions: a) dibromoethane, NaH, DMF, rt, 85%. b) NaN3, DMF, rt, 83%. c) H2, Pd-Lindlar,
EtOH, rt, quantitative. d) ClSO2NMe2, Et3N, CH2Cl2, 73%. e) MeI, NaH, DMF, 91%. f) BBr3, CH2Cl2, 0 °C,
80%. g) BBr3, CH2Cl2, 0 °C, 88%.
Synthesis of N-(1-[2-(hydroxymethyl)-7-methylpyrrolo[2,3-d]pyrimidin-6-yl]methyl)-N,N’,N’-
trimethylsulfamide 7
In order to prepare the analog substituted in position 2 by a sulfamide chain, compound 25 was used as
starting derivative. Thus, amine 25 was submitted to an iodination reaction with N-iodosuccinimide in
methanol to give 36 with a yield of 56%.22 After, the pyrrolopyrimidine 37 was obtained by reaction
between compound 36 and pyruvic acid in the presence of triethylamine under palladium catalysis.23 The
next step consisted in the esterification of compound 37 in ethanol with thionyl chloride to form
derivative 28 which was then reduced by treatment with lithium aluminium hydride.24 The azide group
was introduced via a Mitsunobu–type substitution using zinc azide/bis pyridine complex to afford 40 in a
satisfactory yield.25 Eventually and according to the same sequences as previously described in scheme 3
like reduction,26 introduction of sulfamide chain, methylation and demethylation, the expected compound
7 was obtained in good yield (Scheme 10).

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HETEROCYCLES, Vol. 75, No. 5, 2008
I
a
N
N
b
N
CO2H
MeO
MeO
MeO
N
N
NH2
N
NH2
N
H
25
36
37
N
c
e
d
g
N
N
CH2OH
CO2Et
MeO
MeO
N3
MeO
N
N
N
N
N
N
H
H
H
40
39
38
f
N
O
N
MeO
MeO
N S
NMe2
N
NH2
N
N
N
H
O
H
H
42
41
h
N
i
O
N
O
S
HO
N S NMe2
MeO
N
Me
N
NMe2
N
N
N
43
O
Me
O
Me
Me
7
Scheme 10. Synthesis of N-(1-[2-(Hydroxymethyl)-7-methylpyrrolo[2,3-d]pyrimidin-6-yl]methyl)-
N,N’,N’-trimethylsulfamide 7
Reagents and conditions: a) NIS, MeOH, 50 °C, 56%. b) CH3COCOOH, Pd(OAc)2, Et3N, DMF, 105 °C,
64%. c) SOCl2, EtOH, 0 °C to reflux 71% ; d) LiAlH4, THF, rt, 83%. e) ZnN6-2Py, DIAD, PPh3, THF, rt,
50%. f) H2, Pd, Lindlar, EtOH, rt, quant. g) ClSO2N(CH3)2, Et3N, CH2Cl2, rt, 51%. h) MeI, NaH, DMF, rt,
79%. i) BBr3, CH2Cl2, 0 °C, 85%.
Synthesis of N,N-dimethyl-2-(hydroxymethyl)-6,7,8,9-tetrahydropyrazino[2’,1’:5,1]pyrrolo[2,3-d]-
pyrimidine-7-sulfonamide 8
Following our interest in the development of SDI analogs, we decided to introduce a pyrazine ring on the
pyrrolopyrimidine skeleton. In order to achieve this, we introduced on position 1 of the azide 40
precedently synthesized, the bromoalkyl chain under Bös et al. conditions.27 Compound 44, obtained with
a yield of 65%, was submitted to reduction using Lindlar palladium as catalyst giving the cyclic
derivative 45 in 92% yield. Treatment of 42 with N,N-dimethylsulfamoyl chloride following the classic
method gave the corresponding sulfamide 46 with moderate yield. Finally compound 8 was obtained by
demethylation in the presence of boron tribromide in methylene chloride (Scheme 11).

HETEROCYCLES, Vol. 75, No. 5, 2008
1171
N
a
b
N
N
MeO
N3
N
MeO
N3
N
N
H
MeO
N
N
N
N
NH
40
Br
44
45
c
N
d
HO
O
MeO
N
O
N
N
N
N
N
NMe2
S
S NMe2
O
O
8
46
Scheme 11. Synthesis of N,N-Dimethyl-2-(hydroxymethyl)-6,7,8,9-tetrahydropyrazino[2’,1’:5,1]-
pyrrolo[2,3-d]pyrimidine-7-sulfonamide 8
Reagents and conditions: a) 1,2-dibromoethane, NaOH, Bu4NBr, H2O, rt, 65%. b) H2, Pd, Lindlar, EtOH, rt,
92%. c) ClSO2NMe2, Et3N, CH2Cl2, rt, 63%. d) BBr3, CH2Cl2, 0 °C, 82%.
The in vitro activities of compounds 1-8 were determined by their ability to inhibit sheep liver’s SDH. The
results of inhibition are presented in Table 1.
Compounds
Formula
% Inhibition for 10-5 M
1
2
C11H17N5O4S
C11H21N5O3S
C11H17N5O3S
C12H23N5O3S
C13H25N5O3S
C12H16N6O5S
C19H22N6O5S
C12H19N5O3S
C12H19N5O3S
C12H17N5O3S
C11H17N5O3S
< 10
50
60
64
53
15
49
19
23
51
19
9
3
4
5
24
6
7
8
35
As may be seen in Table 1, compounds 3 and 9 exhibited the most potent inhibitory activity (64 and 60 % of
inhibition for 10-5 M). Compounds 2, 4, 8 and 24 had almost the same and modest inhibitory effects which
are near 50 %. On the other hand, the other products were practically inactive against SDH.
To conclude, we described the synthesis of eight analogs of sorbitol dehydrogenase which possess an
original heterocyclic skeleton. Access to these compounds involves as the key step, the formation of a

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HETEROCYCLES, Vol. 75, No. 5, 2008
pyrrolopyrimidine skeleton from the 5-amino-2-(methoxymethyl)pyrimidine. Unfortunately, among all the
molecules synthesized and tested none showed significant activity. Another novel heterocycle is currently
under investigation the results of which will be reported elsewhere.
EXPERIMENTAL
Melting points are uncorrected. 1H-NMR and 13C-NMR spectra were recorded on a Bruker AM-300 WB
(300 MHz). The coupling constants are reported in Hz and the chemical shifts in ppm (δ, ppm) downfield
from TMS which was used as an internal standard. IR spectra were obtained with a Perkin-Elmer FT
Paragon 1000 PC. MS spectra were registered on a Perkin-Elmer SCIEX API 3000 spectrometer. Reaction
products were purified by flash chromatography using silica gel (Merck 230-400 mesh). Analytical TLC
was carried out on silica gel F254 plates. All anhydrous reactions were performed in over-dried glassware
under an atmosphere of argon. Anhydrous solvents were transferred via syringe.
The following compounds were prepared by literature methods: 2-methoxyacetamidine hydrochloride 11,28
4-chloro-2-(methoxymethyl)pyrimidine 13,29 3-benzylimidazolin-2,4-dione 21,30 2-(methoxymethyl)-4-
(piperazin-1-yl)pyrimidine 23.31
1.1. N,N-Dimethyl-4-(2-formylpyrimidin-4-yl)-1-piperazinesulfonamide 9
Under an inert atmosphere, DMSO (0.35 mL, 5 mmol) was added dropwise to a stirred solution of oxalyl
chloride (0.22 mL, 2.5 mmol) in dry CH2Cl2 (10 mL) at -60°C. After 5 minutes, a solution of SDI (500
mg, 1.66 mmol) in dry CH2Cl2 (5 mL) was added dropwise to the mixture. The reaction was stirred an
additional time (30 min) with continuous cooling. The triethylamine (2.31 mL, 16.6 mmol) was then
added and the mixture was stirred for 12 h, allowing the temperature to slowly reach rt. The residue was
taken up in water, basified with saturated aqueous NaHCO3 solution and extracted with CH2Cl2. The
combined extracts were dried over anhydrous MgSO4. After removal of the solvent in vacuo, the product
was purified by flash chromatography on silica gel (eluent: MeOH/EtOAc, 5/95) to afford 9 (347 mg,
1
70%) as yellow needles. Mp 135-136 °C (i-Pr). IR (KBr) ν: 1728, 1346, 1142 cm-1; H-NMR (CDCl3) δ
2.87 (s, 6H, N(CH3)2), 3.36 (t, 4H, J = 5.2 Hz, 4 x Hpiperazin), 3.84 (t, 4H, J = 5.2 Hz, 4 x Hpiperazin), 6.65 (d,
1H, J = 6.2 Hz, H5), 8.46 (d, 1H, J = 6.2 Hz, H6), 9.91 (s, 1H, CHO); 13C-NMR (CDCl3) δ 36.2
(-N(CH3)2), 41.5 (2 x Cpiperazin), 43.8 (2 x Cpiperazin), 102.9 (C5), 154.7 (C6), 156.9 (Cq), 159.4 (Cq), 190.1
(CHO); MS (IE) m/z = 300 (M+1); Anal. Calcd for C11H17N5O3S : C, 44.14 ; H, 5.72 ; N, 23.40. Found :
C, 44.23; H, 5.70; N, 23.15.
1.2. N,N-Dimethyl-4-[2-(ethoxycarbonyl)pyrimidin-4-yl]-1-piperazinesulfonamide 10
Under an inert atmosphere, NaCN (712 mg, 14.5 mmol), AcOH (0.27 mL, 4.5 mmol) and MnO2 (5 g, 58
mmol) were added to a stirred solution of 9 (870 mg, 2.9 mmol) in dry EtOH (12 mL). The mixture was

HETEROCYCLES, Vol. 75, No. 5, 2008
1173
stirred at rt under nitrogen for 24 h. After filtration on Celite and concentration of the filtrate in vacuo the
residue was taken up in CH2Cl2, washed with saturated aqueous NaHCO3 solution and dried over
anhydrous MgSO4. After removal of the solvent, the crude residue was purified over silica gel (eluent:
MeOH/EtOAc, 1/9) to afford 10 (626 mg, 63%) as white needles. Mp 81-82 °C (i-Pr). IR (KBr): ν
3000-2800, 1734, 1311, 1179 cm-1; 1H-NMR (CDCl3) δ 1.44 (t, 3H, J = 7.1 Hz, CH3-CH2-O), 2.88 (s, 6H,
N(CH3)2), 3.35 (t, 4H, J = 5.0 Hz, 4 x Hpiperazin), 3.82 (t, 4H, J = 5.0 Hz, 4 x Hpiperazin), 4.46 (q, 2H, J = 7.1
13
Hz, CH3-CH2-O), 6.63 (d, 1H, J = 6.2 Hz, H5), 8.39 (d, 1H, J = 6.2 Hz, H6); C-NMR (CDCl3) δ 14.2
(CH3-CH2-O), 38.3 (N(CH3)2), 43.5 (2 x Cpiperazin), 45.9 (2 x Cpiperazin), 62.4 (CH3-CH2-O), 104.4 (C5),
156.4 (Cq), 156.5 (C6), 161.8 (Cq), 164.1 (Cq); MS (IE) m/z = 344 (M+1); Anal. Calcd for C13H21N5O4S :
C, 45.47; H, 6.16; N, 20.39. Found: C, 45.21; H, 6.13; N, 20.20.
1.3. N,N-Dimethyl-4-(2-carboxypyrimidin-4-yl)-1-piperazinesulfonamide 1
A solution of 10 (400 mg, 1.17 mmol) and Dowex resin (150 mg, 500X8-400) in water (10 mL) was
heated under reflux for 15 h. The resin was then filtered off and the filtrate was freeze-dried to give 1
(281 mg, 77%) as a white foam. Mp 107-109 °C (i-Pr). IR (KBr): ν 3600-2600, 1636, 1355, 1150 cm-1;
1H-NMR (DMSO-d6+D2O) δ 2.79 (s, 6H, N(CH3)2), 3.26 (t, 2H, J = 4.7 Hz, 4 x Hpiperazin), 3.78 (sb, 2H, 4
x Hpiperazin), 6.99 (d, 1H, J = 6.4 Hz, H5), 8.30 (d, 1H, J = 6.4 H, H6); 13C-NMR (CDCl3) δ 38.4
(-N(CH3)2), 43.8 (2 x Cpiperazin), 46.2 (2 x Cpiperazin), 105.2 (C5), 155.6 (C6), 157.6 (Cq), 161.8 (Cq), 165.5
(Cq); MS (IE) m/z = 316 (M+1); Anal. Calcd for C11H17N5O4S: C, 41.90; H, 5.43; N, 22.21. Found: C,
42.15; H, 5.46; N, 22.15.
1.4. N-(2-Methylaminoethyl)-N,N’,N’-trimethylsulfamide 14
At rt, K2CO3 (2.6 g, 18.8 mmol) was added to a solution of N,N’-dimethylethane-1,2-diamine (4 mL, 37.6
mmol) in EtOH (50 mL). The mixture was then cooled to 0°C, and N,N-dimethylsulfamoyl chloride (1.96
mL, 18.8 mmol) was added dropwise. The reaction was stirred vigorously for an additional time (40 min)
under continuous cooling. The mixture was filtered and the filtrate was concentrated in vacuo. The crude
was purified on silica gel (eluent: MeOH/CH2Cl2, 1/9) to provide 14 (2.43 g, 66%) as a colourless oil. IR
1
(film): ν 3329, 3000-2800, 1324, 1143 cm-1; H-NMR (CDCl3) δ 2.55 (s, 3H, NH-CH3), 2.82 (s, 6H,
N(CH3)2), 2.87 (s, 3H, CH3-N-SO2), 2.91 (t, 2H, J = 6.3 Hz, NH-CH2), 3.40 (t, 2H, J = 6.3 Hz,
CH2-N-SO2), 3.55 (sb, 1H, NH); 13C-NMR (CDCl3) δ 35.7 (NH-CH3), 36.2 (CH3-N-SO2), 38.6
(N(CH3)2), 49.0 (NH-CH2-), 49.7 (CH2-N-SO2); MS (IE) m/z = 196 (M+1); Anal. Calcd for C6H17N3O2S:
C, 36.90; H, 8.77; N, 21.52. Found: C, 36.71; H, 8.53; N, 21.60.
1.5. N-(2-Methylaminopropyl)-N,N’,N’-trimethylsulfamide 15
At rt, K2CO3 (1.38 g, 10.0 mmol) was added to a solution of N,N’-dimethylpropane-1,3-diamine (2.5 mL,

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HETEROCYCLES, Vol. 75, No. 5, 2008
20.0 mmol) and EtOH (25 mL). The mixture was then cooled to 0 °C, and N,N-dimethylsulfamoyl
chloride (1.07 mL, 10.0 mmol) was added dropwise. The reaction was stirred vigorously for an additional
time (2 h) under continuous cooling. The mixture was filtered and the filtrate was concentrated in vacuo.
The crude was purified on silica gel (eluent: MeOH/CH2Cl2, 2/8) to provide 15 (858 mg, 41%) as a
1
colourless oil. IR (film): ν 3327, 3000-2800, 1322, 1143 cm-1; H-NMR (CDCl3+ D2O) δ 1.76 (m, 2H,
CH2-CH2-CH2), 2.43 (s, 3H, NH-CH3), 2.63 (t, 2H, J = 7.0 Hz, NH-CH2), 2.78 (s, 6H, N(CH3)2), 2.81 (s,
13
3H, CH3-N-SO2), 3.24 (t, 2H, J = 7.0 Hz, CH2-N-SO2); C-NMR (CDCl3) δ 27.3 (CH2-CH2-CH2), 34.5
(NH-CH3), 36.0 (CH3-N-SO2), 37.6 (N(CH3)2), 48.2 (NH-CH2-CH2-CH2), 48.3 (NH-CH2-CH2-CH2); MS
(IE) m/z = 210 (M+1); Anal. Calcd for C7H19N3O2S: C, 45.41; H, 7.30; N, 22.06. Found: C, 45.12; H,
7.51; N, 21.98.
1.6. N-(2-[N”-(2-(Methoxymethyl)pyrimidin-4-yl)-N”-methyl]ethylamino)-N,N’,N’-trimethyl-
sulfamide 16
Under an Argon atmosphere, 4-chloro-2-(methoxymethyl)pyrimidine 13 (800 mg, 5 mmol) and
triethylamine (0.773 mL, 5.5 mmol) were added to a stirred solution of 14 (1.08 g, 5.54 mmol) in dry
THF (4 mL). The mixture was heated under reflux for 15 h. After cooling, the solvent was removed and
the crude was purified on silica gel (eluent: MeOH/EtOAc, 1/9) to give 16 (1.51 g, 95%) as a colourless
1
oil. IR (film): ν 3000-2800, 1344, 1145 cm-1; H-NMR (CDCl3) δ 2.73 (s, 6H, -N(CH3)2) 2.89 (s, 3H,
CH3-N-SO2) 3.09 (s, 3H, N-CH3), 3.39 (t, 2H, J = 6.3 Hz, CH2-N-SO2), 3.51 (s, 3H, OCH3), 3.85 (t, 2H,
J = 6.3 Hz, N-CH2-), 4.46 (s, 2H, OCH2-), 6.35 (d, 1H, J = 6.1 Hz, H5), 8.23 (d, 1H, J = 6.1 Hz, H6);
13C-NMR (CDCl3) δ 35.7 (N-CH3), 36.0 (CH3-N-SO2), 38.0 (N(CH3)2), 47.0 (N-CH2-), 47.9
(CH2-N-SO2), 59.0 (OCH3), 75.1 (OCH2), 100.9 (C5), 155.8 (C6), 161.7 (Cq), 165.9 (Cq). MS (IE) m/z =
318 (M+1); Anal. Calcd for C12H23N5O3S: C, 43.49; H, 7.60; N, 21.13. Found: C, 43.01; H, 7.45; N,
21.30.
1.7. N-(2-[N”-(2-(Methoxymethyl)pyrimidin-4-yl)-N”-methyl]propylamino)-N,N’,N’-trimethyl-
sulfamide 17
Under an inert atmosphere, 4-chloro-2-(methoxymethyl)pyrimidine 13 (345 mg, 2.2 mmol) and
triethylamine (0.33 mL, 2.4 mmol) were added to a stirred solution of 15 (500 mg, 2.4 mmol) in dry THF
(4 mL). The mixture was heated under reflux for 15 h. After cooling, the solvent was removed and the
crude was purified on silica gel (eluent: MeOH/EtOAc, 1/9) to give 17 (720 mg, 95%) as a colourless oil.
1
IR (film): ν 3000-2800, 1324, 1145 cm-1; H-NMR (CDCl3) δ 1.90 (m, 2H, CH2-CH2-CH2), 2.79 (s, 6H,
N(CH3)2), 2.83 (s, 3H, CH3-N-SO2), 3.06 (s, 3H, N-CH3), 3.23 (t, 2H, J = 7.1 Hz, CH2-N-SO2), 3.52 (s,
3H, OCH3), 3.63 (t, 2H, J = 7.1 Hz, N-CH2), 4.46 (s, 2H, OCH2), 6.29 (d, 1H, J = 6.2 Hz, H5), 8.20 (d,
13
1H, J = 6.2 Hz, H6); C-NMR (CDCl3) δ 25.3 (CH2-CH2-CH2), 35.0 (N-CH3), 35.5 (CH3-N-SO2), 38.1

HETEROCYCLES, Vol. 75, No. 5, 2008
1175
(-N(CH3)2), 46.7 (N-CH2-CH2-CH2), 48.5 (NH-CH2-CH2-CH2), 59.0 (OCH3), 75.6 (OCH2), 100.9 (C5),
155.6 (C6), 161.5 (Cq), 166.0 (Cq); MS (IE) m/z = 332 (M+1); Anal. Calcd for C13H25N5O3S: C, 43.55; H,
6.98; N, 23.09. Found: C, 43.21; H, 6.81; N, 23.15.
1.8. N-(2-[N”-(2-(Hydroxymethyl)pyrimidin-4-yl)-N”-methyl]ethylamino)-N,N’,N’-trimethyl-
sulfamide 2
Under an inert atmosphere, compound 16 (1.48 g, 4.7 mmol) was dissolved in dry CH2Cl2 (7 mL). The
mixture was then cooled to 0 °C and a solution of BBr3 (1.1 mL, 11.6 mmol) in dry CH2Cl2 (3.5 mL) was
added dropwise. After 2 h at 0 °C, the reaction was hydrolysed, basified with saturated aqueous NaHCO3
solution and extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and
concentrated in vacuo. Finally, purification by flash chromatography on silica gel using 10% MeOH in
EtOAc as eluent gave 1.38 g (98%) of N-(2-[N”-(2-(hydroxymethyl)pyrimidin-4-yl)-N”-methyl]-
ethylamino)-N,N’,N’-trimethylsulfamide 2 as a colourless oil. IR (film): ν 3425, 2931, 1329, 1143 cm-1;
1H-NMR (DMSO-d6) δ 2.64 (s, 6H, N(CH3)2), 2.82 (s, 3H, CH3-N-SO2), 3.04 (s, 3H, N-CH3), 3.33 (t, 2H,
J = 6.4 Hz, CH2-N-SO2), 3.77 (sb, 2H, N-CH2), 4.36 (d, 2H, J = 5.9 Hz, CH2OH), 4.74 (t, 1H, J = 5.9 Hz,
CH2OH), 6.53 (d, 1H, J = 6.1 Hz, H5), 8.16 (d, 1H, J = 6.1 Hz, H6); 13C-NMR (DMSO-d6) δ 33.9
(N-CH3), 34.3 (CH3-N-SO2), 36.0 (N(CH3)2), 45.3 (N-CH2-), 46.0 (CH2-N-SO2), 62.2 (CH2OH), 98.9
(C5), 153.4 (C6), 159.4 (Cq), 165.2 (Cq); MS (IE) m/z = 304 (M+1). Anal. Calcd for C11H21N5O3S: C,
43.55; H, 6.98; N, 23.09. Found: C, 43.62; H, 6.71; N , 23.15.
1.9. N-(2-[N”-(2-(Hydroxymethyl)pyrimidin-4-yl)-N”-methyl]propylamino)-N,N’,N’-trimethyl-
sulfamide 3
Under an inert atmosphere, compound 17 (650 mg, 1.95 mmol) was dissolved in dry CH2Cl2 (4 mL). The
mixture was then cooled to 0 °C and a solution of BBr3 (0.55 mL, 5.8 mmol) in dry CH2Cl2 (5 mL) was
added dropwise. After 2 h at 0 °C, the reaction was hydrolysed, basified with saturated aqueous NaHCO3
solution and extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and
concentrated in vacuo. Finally, purification by flash chromatography on silica gel using 4% MeOH in
EtOAc as eluent gave 560 mg (90%) of N-(2-[N”-(2-(hydroxymethyl)pyrimidin-4-yl)-N”-methyl]-
propylamino)-N,N’,N’-trimethylsulfamide 3 as a colourless oil. IR (film): ν 3417, 3000-2800, 1343, 1143
1
cm-1; H-NMR (DMSO-d6) δ 1.78 (m, 2H, CH2-CH2-CH2), 2.70 (s, 6H, N(CH3)2), 2.76 (s, 3H,
CH3-N-SO2), 3.03 (s, 3H, N-CH3), 3.14 (t, 2H, J = 7.2 Hz, CH2-N-SO2), 3.55 (tb, 2H, N-CH2), 4.34 (d,
2H, J = 5.8 Hz, CH2OH), 4.71 (t, 2H, J = 5.8 Hz, CH2OH), 6.52 (d, 1H, J = 6.2 Hz, H5), 8.13 (d, 1H, J =
6.2 Hz, H6); 13C-NMR (CDCl3) δ 24.7 (CH2-CH2-CH2), 34.4 (N-CH3), 35.2 (CH3-N-SO2), 37.5
(N(CH3)2), 46.3 (N-CH2-CH2-CH2), 47.9 (NH-CH2-CH2-CH2), 63.5 (OCH2), 100.2 (C5), 154.5 (C6),
160.5 (Cq), 166.5 (Cq); MS (IE) m/z = 318 (M+1); Anal. Calcd for C12H23N5O3S: C, 45.41; H, 7.30; N,

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HETEROCYCLES, Vol. 75, No. 5, 2008
22.06. Found: C, 45.31; H, 7.21; N, 21.97.
1.10. N-(4-aminobutyl)-2-(methoxymethyl)pyrimidin-4-amine 18
Under an inert atmosphere, 4-chloro-2-(methoxymethyl)pyrimidine 13 (2 g, 12.6 mmol), triethylamine
(1.75 mL, 12.6 mmol) was added to a stirred solution of 1,4-diaminobutane (2.5 mL, 25.2 mmol) in dry
THF (32 mL). The mixture was heated under reflux for 15 h. After cooling, the solvent was removed and
the crude was purified on silica gel (eluent: MeOH/EtOAc, 2/8) to give 18 (2.15 g, 81%) as a colourless
1
oil. IR (film): ν 3500-3000, 3000-2800, 1605 cm-1; H-NMR (CDCl3+ D2O) δ 1.51-1.70 (m, 4H,
NH-CH2-(CH2)2-CH2-NH2), 2.75 (t, 2H, J = 6.7 Hz, CH2-NH2), 3.30 (tb, 2H, NH-CH2-), 3.50 (s, 3H,
-OCH3), 4.45 (s, 2H, OCH2), 6.21 (d, 1H, J = 5.9 Hz, H5), 8.16 (d, 1H, J = 5.9 Hz, H6); 13C-NMR
(CDCl3) δ 26.3 (NH-CH2-(CH2)2-CH2-NH2), 30.3 (NH-CH2-(CH2)2-CH2-NH2), 40.9 (CH2-NH2), 41.3
(NH-CH2), 58.7 (OCH3), 75.1 (OCH2), 101.3 (C5), 155.3 (C6), 162.3 (Cq), 166.0 (Cq); MS (IE) m/z = 211
(M+1); Anal. Calcd for C10H18N4O: C, 57.12; H, 8.63; N, 26.64. Found: C, 56.82; H, 8.41; N, 26.61.
1.11. N,N-Dimethyl-N’-(4-[N”-(2-methoxymethyl)pyrimidin-4-yl])butylaminosulfamide 19
Under an inert atmosphere, a solution of N,N-dimethylsulfamoyl chloride (2 mL, 10.4 mmol) in dry
CH2Cl2 (5 mL) was added dropwise to a solution of 18 (2 g, 9.5 mmol) and triethylamine (1.45 mL, 10.4
mmol) in dry CH2Cl2 (35 mL). The reaction was then stirred at rt. After 15h, the mixture was hydrolysed
and extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and
evaporated in vacuo. The crude was purified on silica gel (eluent: MeOH/EtOAc, 5/95) to provide 19 (2.0
g, 67%) as a yellow oil. IR (film): ν 3500-3000, 3000-2800, 1603, 1327, 1145 cm-1; 1H-NMR (CDCl3) δ
1.61-1.69 (m, 4H, NH-CH2-(CH2)2-CH2-NH2), 2.79 (s, 6H, N(CH3)2), 3.11 (m, 2H, CH2-NH-SO2-), 3.32
(m, 2H, NH-CH2-), 3.50 (s, 3H, -OCH3), 4.45 (s, 2H, OCH2), 5.23 (t, 1H, J = 3.4 Hz, NH), 5.48 (sb, 1H,
NH), 6.22 (d, 1H, J = 6.0 Hz, H5), 8.15 (d, 1H, J = 6.0 Hz, H6); 13C-NMR (CDCl3) δ 26.5
(NH-CH2-(CH2)2-CH2-NH2), 27.4 (NH-CH2-(CH2)2-CH2-NH2), 38.4 (N(CH3)2), 41.1 (CH2-NH), 43.5
(CH2-NH-SO2), 59.4 (OCH3), 75.7 (OCH2), 100.5 (C5), 155.8 (C6), 162.9 (Cq), 166.5 (Cq); MS (IE) m/z
= 318 (M+1); Anal. Calcd for C12H23N5O3S: C, 45.41; H, 7.30; N, 22.06. Found: C, 45.56; H, 7.26; N,
22.15.
1.12. N-(4-(N”-[2-(Methoxymethyl)pyrimidin-4-yl]-N”-methyl)butylamino)-N,N’,N’-trimethyl-
sulfamide 20
Under an inert atmosphere, NaH (0.34 g, 8.5 mmol) was added portionwise to a stirred solution of 19
(0.90 g, 2.8 mmol) in DMF (12 mL) at rt over 30 min. The mixture was stirred for an additional time (30
min) before MeI (0.53 mL, 8.5 mmol) was added dropwise and the mixture stirred for 3 h. Water was
then added, the product was extracted with CH2Cl2, purified by flash chromatography on silica gel

HETEROCYCLES, Vol. 75, No. 5, 2008
1177
(eluent: MeOH/CH2Cl2, 1/9) to give compound 20 (0.60 g, 62%) as a colourless oil. IR (film): ν
3000-2800, 1592, 1343, 1143 cm-1; 1H-NMR (CDCl3) δ 1.54 (m, 4H, N-CH2-(CH2)2-CH2-NH-SO2), 2.71
(s, 6H, N(CH3)2), 2.72 (s, 3H, CH3-N-SO2), 2.96 (s, 3H, N-CH3), 3.13 (t, 2H, J = 6.6 Hz, CH2-N-SO2),
3.42 (s, 3H, OCH3), 3.50 (sb, 2H, N-CH2), 4.37 (s, 2H, OCH2), 6.20 (d, 1H, J = 6.2 Hz, H5), 8.08 (d, 1H,
J = 6.0 Hz, H6); 13C-NMR (CDCl3) δ 23.9 (N-CH2-(CH2)2-CH2-N-SO2), 24.8 (N-CH2-(CH2)2-
CH2-N-SO2), 34.8 (CH3-N), 35.2 (CH3-N-SO2), 38.0 (N(CH3)2), 48.4 (N-CH2), 50.3 (CH2-N-SO2), 58.9
(OCH3), 75.5 (OCH2), 100.7 (C5), 155.3 (C6), 161.5 (Cq), 165.8 (Cq); MS (IE) m/z = 346 (M+1); Anal.
Calcd for C14H27N5O3S: C, 48.67; H, 7.88; N, 20.27. Found: C, 48.33; H, 7.60; N, 20.33.
1.13. N-(4-[N”-(2-(Hydroxymethyl)pyrimidin-4-yl)-N”-methyl]butylamino)-N,N’,N’-trimethyl-
sulfamide 4
Under an inert atmosphere, compound 20 (0.5 g, 1.4 mmol) was dissolved in dry CH2Cl2 (15 mL). The
mixture was then cooled to 0 °C and a solution of BBr3 (0.68 mL, 7.2 mmol) in dry CH2Cl2 (4 mL) was
added dropwise. After 2 h at 0 °C, the reaction was hydrolysed, basified with saturated aqueous NaHCO3
solution and extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and
concentrated in vacuo. Finally, purification by flash chromatography on silica gel using 10% MeOH in
CH2Cl2 as eluent gave 0.436 g (91%) of N-(4-[N”-(2-(hydroxymethyl)pyrimidin-4-yl)-N”-methyl]-
butylamino)-N,N’,N’-trimethylsulfamide 4 as a colourless oil. IR (film): ν 3417, 3000-2800, 1594, 1342,
1
1143 cm-1; H-NMR (CDCl3) δ 1.64 (m, 4H, N-CH2-(CH2)2-CH2-N-SO2), 2.79 (s, 9H, -N(CH3)2 and
CH3-N-SO2), 3.07 (s, 3H, N-CH3), 3.22 (t, 2H, J = 6.6 Hz, CH2-N-SO2), 3.61 (sb, 2H, N-CH2), 4.02 (sb,
1H, CH2OH), 4.58 (s, 2H, CH2OH), 6.30 (d, 1H, J = 6.2 Hz, H5), 8.15 (d, 1H, J = 6.0 Hz, H6); 13C-NMR
(CDCl3) δ 23.5 (N-CH2-(CH2)2-CH2-N-SO2), 24.5 (N-CH2-(CH2)2-CH2-N-SO2), 34.5 (CH3-N), 35.1
(CH3-N-SO2), 37.7 (N(CH3)2), 48.2 (N-CH2), 49.9 (CH2-N-SO2), 63.8 (OCH2), 100.4 (C5), 154.5 (C6),
160.8 (Cq), 166.8 (Cq); MS (IE) m/z = 332 (M+1); Anal. Calcd for C13H25N5O3S: C, 47.11; H, 7.60; N,
21.13. Found: C, 46.81; H, 7.42; N, 21.22.
1.14. 3-Benzyl-1-(chlorosulfonyl)imidazolidine-2,4-dione 22
A solution of sulfuryl chloride (3.8 mL, 47.3 mmol) in CHCl3 (13 mL) was added dropwise at 0 °C to a
solution of 21 (3 g, 15.7 mmol) and triethylamine (4.4 mL, 31.6 mmol) in CHCl3 (35 mL). The reaction
was stirred for an additional time (1 h) and the solvent was removed in vacuo. The crude was purified on
silica gel (eluent: light petroleum/EtOAc, 7/3) to provide 22 (3.96 g, 81%) as a white solid. Mp
1
130-131 °C (i-Pr). IR (KBr): ν 1740, 1723, 1411, 1174 cm-1; H-NMR (CDCl3) δ 4.42 (s, 2H, CH2-N),
4.72 (s, 2H, CH2-Ph), 7.33-7.41 (m, 5H, Harom); 13C-NMR (CDCl3) δ 43.8 (CH2-Ph), 50.3 (CH2-NH),
128.8 (2 x Carom), 129.0 (2 x Carom), 132.1 (Carom), 133.9 (Cq), 150.1 (C=O), 164.6 (C=O); MS (IE) m/z =

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HETEROCYCLES, Vol. 75, No. 5, 2008
311 (M+1 for 35Cl), m/z = 313 (M+1 for 37Cl); Calcd for C10H9ClN2O4S: C, 41.60; H, 3.14; N, 9.70.
Found: C, 41.31; H, 3.01; N, 9.41.
1.15. 3-Benzyl-1-([4-(2-(methoxymethyl)pyrimidin-4-yl)piperazin-1-yl]sulfonyl)imidazolidine-2,4-di
one 24
Under an inert atmosphere, a suspension of NaH (0.395 mg, 9.9 mmol) and compound 23 (1.15 g, 5.5
mmol) in dry DMF (35 mL) was stirred at 50 °C for 30 min. A solution of 22 (2.4 g, 8.3 mmol) in dry
DMF (18 mL) was then added dropwise. The mixture was heated at 80 °C for 15 h. After cooling, the
mixture was hydrolysed and extracted with CH2Cl2. The combined organic layers were washed with
water, dried over anhydrous MgSO4 and concentrated in vacuo. The crude was purified on silica gel
(eluent: MeOH/CH2Cl2, 4/96) to provide 24 (610 mg, 24%) as a brown solid. Mp 211-212 °C (i-Pr). IR
(KBr): ν 3000-2800, 1715, 1713, 1411, 1586, 1374, 1175 cm-1; 1H-NMR (CDCl3) δ 3.51 (m, 7H, OCH3 +
4 x Hpiperazin), 3.80 (t, 4H, J = 2.5 Hz, Hpiperazin), 4.30 (s, 2H, N-CH2-CO), 4.48 (s, 2H, OCH2), 4.64 (s, 2H,
13
CH2Ph), 6.41 (d, 1H, J = 6.2 Hz, H5), 7.28-7.38 (m, 5H, Harom), 8.29 (d, 1H, J = 6.2 Hz, H6); C-NMR
(CDCl3) δ 43.1 (CH2-Ph), 43.2 (2 x Cpiperazin), 46.1 (2 x Cpiperazin), 51.1 (N-CH2-CO), 59.2 (OCH3), 75.4
(OCH2), 101.1 (C5), 128.5 (2 x Carom), 128.8 (2 x Carom), 128.9 (Carom), 134.6 (Cq), 153.0 (Cq), 156.5 (C6),
161.4 (Cq), 166.4 (C=O), 167.0 (C=O); MS (IE) m/z = 461 (M+1); Calcd for C20H24N6O5S: C, 52.16; H,
5.25; N,18.25. Found: C, 52.23; H, 5.36; N, 18.22.
1.16. 1-([4-(2-(Methoxymethyl)pyrimidin-4-yl)piperazin-1-yl]sulfonyl)imidazolidine-2,4-dione 5
Under an inert atmosphere, AlCl3 (1.38 g, 10.4 mmol) was added to a solution of 3-benzyl-1-([4-
(2-(methoxymethyl)pyrimidin-4-yl)piperazin-1-yl]sulfonyl)imidazolidin-2,4-dione 24 (0.6 g, 1.3 mmol)
in dry toluene (30 mL). The reaction was stirred at 90 °C for 15 h. After cooling, the solvent was removed
in vacuo and the residue was taken up in EtOAc. The mixture was then basified with aqueous NaOH
solution (20%) and extracted. The combined organic layers were dried over anhydrous MgSO4 and
concentrated. The crude was purified on silica gel (eluent : MeOH/CH2Cl2, 1/9) to give 5 (190 mg, 41%)
as a white needles. Mp > 244 °C (i-Pr). IR (KBr): ν 3600-3000, 2933, 2896, 1740, 1593, 1385, 1164 cm-1;
1H-NMR (CDCl3) δ 3.39 (tb, 4H, 4 x Hpiperazin), 3.77 (bt, 4H, 4 x Hpiperazin), 4.30 (s, 2H, N-CH2-CO), 4.36
(d, 2H, J = 5.5 Hz, CH2-OH), 4.85 (t, 1H, J = 5.5 Hz, CH2-OH), 6.75 (d, 1H, J = 6.2 Hz, H5), 8.20 (d, 1H,
13
J = 6.2 Hz, H6); C-NMR (CDCl3) δ 42.8 (2 x Cpiperazin), 45.8 (2 x Cpiperazin), 52.8 (N-CH2-CO), 64.7
(CH2-OH), 101.8 (C5), 154.0 (Cq), 155.9 (C6), 161.1 (Cq), 168.3 (C=O), 169.9 (C=O); MS (IE) m/z = 357
(M+1); Calcd for C12H16N6O5S: C, 40.44; H, 4.53; N, 23.58. Found: C, 40.72; H, 4.58; N, 23.39.
1.17. 4-Amino-2-(methoxymethyl)pyrimidine 25
In a sealed tube, a solution of 4-chloro-2-(methoxymethyl)pyrimidine 13 (1 g, 6.3 mmol) in a 30 %

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aqueous (w/w) NH4OH solution (20 mL) was heated at 120 °C for 15 h. After cooling, the reaction was
extracted with CH2Cl2. The organic layers were dried over anhydrous MgSO4 and concentrated in vacuo
to give compound 25 (0.797 g, 91%) as a white solid used without further purification. Mp 112-113 °C.
IR (KBr): ν 3362, 3312 cm-1; 1H-NMR (CDCl3) δ 3.51 (s, 3H, OCH3), 4.49 (s, 2H, OCH2), 5.11 (bs, 2H,
13
NH2), 6.32 (d, 1H, J = 5.7 Hz, H5), 8.22 (d, 1H, J = 5.7 Hz, H6); C-NMR (CDCl3) δ 59.0(O-CH3),
75.3O-CH2), 103.6 (C5), 155.9 (C6), 163.2(Cq), 166.6 (Cq); MS (IE) m/z = 140 (M+1); Calcd for
C6H9N3O: C, 51.79; H, 6.52; N, 30.20. Found: C, 51.52; H, 6.44; N, 30.11.
1.18. 4-Amino-5-bromo-2-(methoxymethyl)pyrimidine 26
At 60 °C, bromine (1.08 mL, 21.2 mmol) was added dropwise to a solution of 25 (1.47 g, 10.6 mmol) and
CaCO3 (0.528 g, 5.3 mmol) in water (15 mL). The reaction was stirred vigorously for 40 min with
continuous heating. The mixture was then cooled at rt, neutralised to pH 8 using saturated aqueous
NaHCO3 solution and extracted with EtOAc. The combined extracts were dried over anhydrous MgSO4.
After removal of the solvent in vacuo, the product was purified by flash chromatography on silica gel
(eluent: EtOAc) to afford 2 (1.36 g, 59%) as a yellow solid. Mp 117-118 °C. IR (KBr): ν 3385, 3316
cm-1; 1H-NMR (CDCl3) δ 3.49 (s, 3H, OCH3), 4.45 (s, 2H, OCH2), 5.78 (sb, 2H, NH2), 8.34 (d, 1H, H6);
13C-NMR (CDCl3) δ 59.0 (O-CH3), 74.6 (O-CH2), 101.8 (Cq), 156.5 (C6), 160.1 (Cq), 165.3 (Cq); MS
79
81
(IE) m/z = 218 (M+1 for Br) m/z 220 (M+1 for Br); Calcd for C6H8BrN3O: C, 33.05; H, 3.70; N,
19.27. Found: C, 32.95; H, 3.74; N, 19.03.
1.19. 4-Amino-2-(methoxymethyl)-5-[2’-(1,1,1-trimethylsilyl)-1’-ethynyl]pyrimidine 27
Under an argon atmosphere, a mixture of 26 (1.24 g, 5.7 mmol), bis(triphenylphosphine)palladium (II)
chloride (0.398 g, 0.57 mmol), CuI (0.108 g, 0.57 mmol), trimethylsilylacetylene (1.6 mL, 11.4 mmol)
and triethylamine (33 ml) in dry THF (30 ml) was heated at 40 °C for 15 h. The reaction mixture was
evaporated in vacuo and the product was isolated by flash chromatography eluting with EtOAc-light
petroleum (1/1) affording 27 (1.22 g, 91%) as a yellow solid. Mp 92-93 °C. IR (KBr): ν 3487, 3277, 2149
cm-1; 1H-NMR (CDCl3) δ 0.28 (s, 9H, Si(CH3)3), 3.49 (s, 3H, OCH3), 4.49 (s, 2H, OCH2), 5.52 (sb, 2H,
NH2), 8.34 (s, 1H, H6); 13C-NMR (CDCl3) δ 0.0 (Si(CH3)3), 59.1 (O-CH3), 75.1 (O-CH2), 96.9 (Cq),
100.3 (Cq), 104.3 (Cq), 158.2 (C6), 163.2 (Cq), 165.5 (Cq); MS (IE) m/z = 236 (M+1); Calcd for
C17H17N3OSi: C, 56.14; H, 7.28; N, 17.85. Found: C, 55.98; H, 7.34; N, 17.78.
1.20. 4-[(N,N-Ditertiobutoxycarbonyl)amino]-2-methoxymethyl-5-[2’-(1,1,1-trimethylsilyl)-1’-
ethyn-yl]pyrimidine 28
Under an inert atmosphere, 4-amino-2-(methoxymethyl)-5-[2’-(1,1,1-trimethylsilyl)-1’-ethynyl]-

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pyrimidine 27 (1.10 g, 4.7 mmol) and 4-N,N-dimethylaminopyridine (0.057 g, 0.47 mmol) was added to a
stirred solution of tert-butyl dicarbonate (3.06 g, 14.0 mmol) in dry THF (30 mL). After 1 h stirring at
room temperature, the reaction was hydrolysed and extracted with CH2Cl2. The combined organic layers
were dried over anhydrous MgSO4 and concentrated in vacuo. Finally, purification by flash
chromatography on silica gel using 20% light petroleum in EtOAc as eluent gave 2.03 g (quant.) of
4-[(N,N-ditertiobutoxycarbonyl)amino]-2-methoxymethyl-5-[2’-(1,1,1-trimethylsilyl)-1’-ethynyl]-
1
pyramidine 28 as a colourless oil. IR (film): ν 2933, 2890, 2164, 1767, 1731 cm-1; H-NMR (CDCl3) δ
0.25 (s, 9H, Si(CH3)3), 1.41 (s, 18H, N[CO-O-C(CH3)3]2), 3.52 (s, 3H, OCH3), 4.70 (s, 2H, OCH2), 8.34
(s, 1H, H6); 13C-NMR (CDCl3) δ 0.0 (Si(CH3)3), 28.2 (N[CO-O-C(CH3)3]2), 59.4 (O-CH3), 75.1 (O-CH2),
84.0 (Cq), 95.8 (Cq), 106.2 (Cq), 116.3 (Cq), 149.5 (Cq), 161.2 (Cq), 161.5 (C6), 166.4 (Cq); MS (IE) m/z
= 436 (M+1); Calcd for C21H33N3O5Si: C, 57.90; H, 7.64; N, 9.65. Found: C, 57.98; H, 7.66; N,
9.58.
1.21. 2-(Methoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine 29
Under an inert atmosphere, a solution of 28 (1.8 g, 4.1 mmol) in dry EtOH (12 mL) was added dropwise
to a solution of sodium (0.475 g, 20.5 mmol) in dry EtOH (36 mL). The reaction was then heated at reflux
for 2.5 h. The mixture was hydrolysed and extracted with CH2Cl2. The combined organic layers were
dried over anhydrous MgSO4 and concentrated in vacuo. The crude was purified on silica gel (eluent:
MeOH/EtOAc, 1/99) to give 29 (0.546 g, 81%) as a white solid. Mp 138-139 °C. IR (KBr): ν 3128, 1598
1
cm-1; H-NMR (CDCl3) δ 3.61 (s, 3H, OCH3), 4.92 (s, 2H, OCH2), 6.60 (dd, 1H, J = 1.8, 3.5 Hz, H5),
13
7.46 (dd, 1H, J = 2.6 Hz, 3.5 Hz, H6), 9.00 (s, 1H, H4), 12.44 (sb, 1H, NH); C-NMR (CDCl3) 61.5
(O-CH3), 75.7 (O-CH2), 100.3 (C5), 118.5 (Cq), 127.9 (C6), 150.1 (C4), 152.9 (Cq), 159.5 (Cq); MS (IE)
m/z = 164 (M+1); Calcd for C8H9N3O: C, 58.89; H, 5.56; N, 25.75. Found: C, 58;74; H, 5.55; N, 25.28.
1.22. 7-(2-Bromoethyl)-2-(methoxymethyl)pyrrolo[2,3-d]pyrimidine 30
Under an inert atmosphere, sodium hydride (0.397 g, 9.9 mmol) was added portionwise to a stirred
solution of 29 (0.90 g, 5.5 mmol) in DMF (10 mL) at rt over 30 min. The mixture was stirred for an
additional time (30 min). 1,2-dibromoethane (4.75 mL, 55.1 mmol) was then added dropwise and the
mixture was stirred for 2 h at rt. After water was added, the product was extracted with CH2Cl2 and
purified by flash chromatography on silica gel (eluent: MeOH/EtOAc, 2/98) to give 30 (1.27 g, 85%) as a
yellow oil. IR (film): ν 2927, 2822, 1591 cm-1; 1H-NMR (CDCl3) δ 3.56 (s, 3H, OCH3), 3.77 (s, 2H, J =
6.3 Hz, CH2Br), 4.69 (t, 2H, J = 6.3 Hz, N-CH2), 4.76 (s, 2H, OCH2), 6.55 (d, 1H, J = 3.6 Hz, H5), 7.29
(d, 1H, J = 3.6 Hz, H6), 8.98 (s, 1H, H4); 13C-NMR (CDCl3) 30.3 (CH2-Br), 46.2 (N-CH2), 59.0 (O-CH3),
76.0 (O-CH2), 99.6 (C5), 117.7 (Cq), 129.5 (C6), 149.8 (C4), 151.0 (Cq), 159.5 (Cq); MS (IE) m/z = 270
(M+1 for 79Br), 272 (M+1 for 81Br); Calcd for C10H12BrN3O: C, 44.46; H, 4.48; N, 15.56. Found: C,

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1181
44.76; H, 4.58; N, 16.01.
1.23. 7-(2-Azidoethyl)-2-(methoxymethyl)pyrrolo[2,3-d]pyrimidine 31
Under an inert atmosphere, sodium azide (0.866 g, 13.32 mmol) was added portionwise to a stirred
solution of 30 (1.2 g, 4.44 mmol) in DMF (25 mL) at rt over 30 min. At the end of the addition, the
mixture was stirred for 15 h at rt. Water was added and the product was extracted with CH2Cl2 and
purified by flash chromatography on silica gel (eluent: MeOH/EtOAc, 3/97) to give 31 (0.852 g, 83%) as
a colourless oil. IR (film): ν 2932, 2812, 2101, 1591 cm-1; 1H-NMR (CDCl3) δ 3.56 (s, 3H, OCH3), 3.75
(s, 2H, J = 5.6 Hz, CH2N3), 4.45 (t, 2H, J = 5.6 Hz, N-CH2), 4.76 (s, 2H, OCH2), 6.57 (d, 1H, J = 3.6 Hz,
H5), 7.26 (d, 1H, J = 3.6 Hz, H6), 8.99 (s, 1H, H4); 13C-NMR (CDCl3) 43.7 (N-CH3), 50.9 (CH2-N3), 59.0
(O-CH3), 76.1 (O-CH2), 100.0 (C5), 117.7 (Cq), 129.4 (C6), 149.8 (C4), 151.1 (Cq), 159.6 (Cq); MS (IE)
m/z = 233 (M+1); Calcd for C10H12N6O: C, 51.72; H, 5.21; N, 36.19. Found: C, 50.94; H, 5.38; N, 36.15.
1.24. 2-[2-(Methoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethylamine 32
A solution of compound 31 (0.645 g, 2.8 mmol) in EtOH (7 mL) was hydrogenated under pressure (15
psi) over Lindlar palladium catalyst (97 mg) for 1 h at rt. The catalyst was then filtered over Celite and
the filtrate concentrated in vacuo to give the title compound 32 (0.573 g, quant.) as a yellow oil. IR (film):
ν 3364, 3015, 2865, 1592 cm-1; 1H-NMR (CDCl3 + D2O) δ 3.15 (t, 2H, J = 6.0 Hz, CH2NH2), 3.56 (s, 3H,
OCH3), 4.36 (t, 2H, J = 6.0 Hz, N-CH2), 4.76 (s, 2H, OCH2), 6.56 (d, 1H, J = 3.6 Hz, H5), 7.27 (d, 1H, J
13
= 3.6 Hz, H6), 8.99 (s, 1H, H4); C-NMR (CDCl3) 42.4 (CH2-NH2), 47.7 (N-CH2), 59.2 (O-CH3), 74.3
(O-CH2), 97.6 (C5), 115.8 (Cq), 127.6 (C6), 147.8 (C4), 157.5 (Cq); MS (IE) m/z = 207 (M+1); Calcd for
C10H14N4O: C, 58.24; H, 6.84; N, 27.16. Found: C, 58.33; H, 6.57; N, 27.41.
1.25. N,N-Dimethyl-N’-(2-[2-(methoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl)sulfamide 33
Under an inert atmosphere, a solution of N,N-dimethylsulfamoyl chloride (0.69 mL, 6.4 mmol) in dry
CH2Cl2 (5 mL) was added dropwise to a solution of 32 (0.665 g, 3.2 mmol) and triethylamine (0.9 mL,
6.4 mmol) in dry CH2Cl2 (12 mL). After stirring the reaction at rt for 15 h, it was hydrolysed and
extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and evaporated
in vacuo. The crude was purified on silica gel (eluent: MeOH/EtOAc, 3/97) to provide 33 (0.737 g, 73%)
1
as a white solid. Mp 144-145 °C. IR (KBr): ν 3100, 3000-2800, 1595, 1333, 1147 cm-1; H-NMR
(CDCl3) δ 2.72 (s, 6H, N(CH3)2), 3.56 (s, 3H, OCH3), 3.57 (m, 2H, CH2NH), 4.45 (m, 2H, N-CH2), 4.74
(s, 2H, OCH2), 5.65 (sb, 1H, NH), 6.56 (d, 1H, J = 3.6 Hz, H5), 7.24 (d, 1H, J = 3.6 Hz, H6), 8.99 (s, 1H,
H4); 13C-NMR (CDCl3) 38.7 (N(CH3)2), 44.4 (CH2-NH), 46.3 (N-CH2), 59.7 (O-CH3), 76.4 (O-CH2),
100.5 (C5), 118.5 (Cq), 130.9 (C6), 150.4 (C4), 151.7 (Cq), 159.9 (Cq); MS (IE) m/z = 314 (M+1); Calcd
for C12H19N5O3S: C, 45.99; H, 6.11; N, 22.35. Found: C, 46.06; H, 5.98; N, 22.32.

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1.26. N,N,N’-Trimethyl-N’-(2-[2-(methoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl)sulfamide 34
Under an inert atmosphere, sodium hydride (0.086 g, 2.15 mmol) was added portionwise to a stirred
solution of 33 (0.45 g, 1.44 mmol) in DMF (4 mL) at rt over 30 min. The mixture was stirred an
additional time (40 min), before MeI (0.134 mL, 2.15 mmol) was added dropwise and the mixture stirred
again for 2 h. Water was then added, the product was extracted with CH2Cl2, purified by flash
chromatography on silica gel (eluent: MeOH/CH2Cl2, 2/98) to give the title compound 34 (0.428 g, 91%)
as a white oil. IR (film): ν 3000-2800, 1591, 1324, 1146 cm-1; 1H-NMR (CDCl3) δ 2.63 (s, 6H, N(CH3)2),
2.66 (s, 3H, NCH3), 3.56 (s, 3H, OCH3), 3.64 (t, 2H, J = 6.0 Hz, CH2NSO2), 4.50 (t, 2H, J = 6.0 Hz,
N-CH2), 4.75 (s, 2H, OCH2), 6.56 (d, 1H, J = 3.6 Hz, H5), 7.29 (d, 1H, J = 3.6 Hz, H6), 8.97 (s, 1H, H4);
13C-NMR (CDCl3) 35.9 (N-CH3), 37.8 (N-(CH3)2), 43.0 (N-CH2), 50.4 (CH2-N-SO2) 59.0 (O-CH3), 76.1
(O-CH2), 99.8 (C5), 117.6 (Cq), 129.6 (C6), 149.7 (C4), 151.1 (Cq), 159.3 (Cq); MS (IE) m/z = 328.5
(M+1); Calcd for C13H21N5O3S: C, 47.69; H, 6.47; N, 21.39. Found: C, 47.07; H, 6.33; N, 21.66.
1.27. N,N,N’-Trimethyl-N’-[2-(2-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]sulfamide 6
Under an inert atmosphere, compound 34 (0.4 g, 1.2 mmol) was dissolved in dry CH2Cl2 (12 mL). The
mixture was then cooled to 0 °C and a solution of BBr3 (0.35 mL, 3.6 mmol) in dry CH2Cl2 (4 mL) was
added dropwise. After 2 h stirring at 0 °C, the reaction was hydrolysed, basified with saturated aqueous
NaHCO3 solution and extracted with CH2Cl2. The combined organic layers were dried over anhydrous
MgSO4 and concentrated in vacuo. Finally, purification by flash chromatography on silica gel using 2%
MeOH in CH2Cl2 as eluent gave 0.306 g (80%) of N,N,N’-trimethyl-N’-(2-[2-(hydroxymethyl)pyrrolo-
[2,3-d]pyrimidin-7-yl]ethyl)sulfamide 6 as a white solid. Mp 69-70 °C; IR (KBr): ν 3448, 3000-2800,
1
1594, 1310, 1153 cm-1; H-NMR (CDCl3) δ 2.62 (s, 6H, N(CH3)2), 2.67 (s, 3H, NCH3), 3.64 (t, 2H, J =
6.0 Hz, CH2NSO2), 3.88 (sb, 1H, CH2OH), 4.49 (t, 2H, J = 6.0 Hz, N-CH2), 4.49 (sb, 2H, CH2OH), 6.58
(d, 1H, J = 3.6 Hz, H5), 7.29 (d, 1H, J = 3.6 Hz, H6), 8.93 (s, 1H, H4); 13C-NMR (CDCl3) 35.9 (N-CH3),
37.8 (N-(CH3)2), 43.0 (CH2-NH), 50.3 (CH2-N-SO2), 64.6 (CH2-OH), 100.0 (C5), 117.6 (Cq), 149.3 (C5),
150.8 (C6), 160.9 (Cq); MS (IE) m/z = 314 (M+1); Anal. Calcd for C12H19N5O3S: C, 45.99; H, 6.11; N,
22.35; S, 10.23. Found : C, 46.25; H, 5.92; N, 22.50; S, 10.17.
1.28. N,N-Dimethyl-N’-(2-[2-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl)sulfamide 35
Under an inert atmosphere, compound 33 (0.2 g, 0.64 mmol) was dissolved in dry CH2Cl2 (7 mL). The
mixture was then cooled to 0 °C and a solution of BBr3 (0.18 mL, 1.9 mmol) in dry CH2Cl2 (2 mL) was
added dropwise. After 2 h at 0 °C, the reaction was hydrolysed, basified with saturated aqueous NaHCO3
solution and extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and
concentrated in vacuo. Finally, purification by flash chromatography on silica gel using 2% MeOH in
CH2Cl2 as eluent gave 0.162 g (85%) of N,N-dimethyl-N’-(2-[2-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-

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1183
7-yl]ethyl)sulfamide 35 as a white solid. Mp 91-92 °C; IR (KBr): ν 3442, 3171, 3000-2800, 1594, 1341,
1
1153 cm-1; H-NMR (CDCl3) δ 2.71 (s, 6H, N(CH3)2), 3.54 (m, 2H, CH2-NH), 4.13 (sb, 1H, CH2OH),
4.44 (t, 2H, J = 5.8 Hz, N-CH2), 4.84 (s, 2H, CH2OH), 5.88 (sb, 1H, NH), 5.53 (d, 1H, J = 3.5 Hz, H5),
7.28 (d, 1H, J = 3.5 Hz, H6), 8.80 (s, 1H, H4); 13C-NMR (CDCl3) 38.0 (N-(CH3)2), 43.4 (CH2-NH), 45.2
(N-CH2), 64.7 (CH2-OH), 100.0 (C5), 117.8 (Cq), 130.0 (C6), 149.3 (C4), 150.8 (Cq), 161.0 (Cq); MS (IE)
m/z = 300 (M+1); Anal. Calcd for C11H17N5O3S: C, 44.13; H, 5.72; N, 23.40; S, 10.71. Found: C, 44.30;
H, 5.74; N, 23.29; S, 10.45.
1.29. 4-Amino-5-iodo-2-(methoxymethyl)pyrimidine 36
Under an inert atmosphere, N-iodosuccinimide (14.5 g, 64.4 mmol) was added portionwise to a stirred
solution of 25 (3 g, 21.42 mmol) in dry MeOH (230 mL). The mixture was then heated at 50 °C for 60 h.
More N-iodosuccinimide (4.8 g, 21.5 mmol) was put in reaction and the solution was allowed to reflux
for 24 h. After cooling of the solution to rt, the product was extracted with CHCl3 and the combined
layers were washed with water, brine and dried over anhydrous MgSO4. Finally, purification by flash
chromatography on silica gel using 10% light petroleum in EtOAc as eluent gave 3.3 g (58%) of
4-amino-5-iodo-2-(methoxymethyl)pyrimidine 36 as a white solid. Mp 169-170 °C; IR (KBr): ν 3454,
1
300-2800, 1637 cm-1; H-NMR (DMSO-d6) δ 3.30 (s, 3H, OCH3), 4.25 (s, 2H, OCH2), 7.05 (sb, 2H,
13
NH2), 8.41 (s, 1H, H6); C-NMR (CDCl3) 58.9 (O-CH3), 75.2 (O-CH2), 76.2 (Cq), 163.1 (C6), 164.3
(Cq), 167.3 (Cq); MS (IE) m/z = 266 (M+1); Calcd for C6H8IN3O: C, 27.19; H, 3.04; N, 15.85. Found: C,
27.28; H, 3.36; N, 15.80.
1.30. (2-(Methoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)carboxylic acid 37
Under an inert atmosphere, pyruvic acid (3.9 mL, 56.6 mmol), palladium acetate (0.254 g, 1.1 mmol) and
triethylamine (7.9 mL, 56.6 mmol) were respectively added to a solution of 36 (3 g, 11.3 mmol) in dry
DMF (32 mL). The mixture was then heated at 150 °C for 15 h under nitrogen. After cooling of the
solution to rt, the solvent was removed under reduced pressure. The residue was purified on silica gel
(eluent: Et3N/MeOH/EtOAc, 1/9/90) to provide 37 (1.5 g, 64%) as a white solid. Mp 284-285 °C. IR
(KBr): ν 3440, 3195, 300-2800, 1699, 1602 cm-1; 1H-NMR (DMSO-d6) δ 3.37(s, 3H, OCH3), 4.60 (s, 2H,
OCH2), 7.20 (s, 1H, H5), 9.12 (s, 1H, H4), 12.74 (sb, 1H, NH), 13.43 (sb, 1H, CO2H); 13C-NMR
(DMSO-d6) 58.4 (O-CH3), 75.6 (O-CH2), 105.8 (C5), 116.7 (Cq), 130.7 (Cq), 152.1 (Cq), 152.5 (C4),
161.8 (Cq), 162.4 (Cq); MS (IE) m/z = 208 (M+1); Calcd for C9H9N3O3: C, 52.17; H, 4.38; N, 20.28.
Found: C, 52.72; H, 4.58; N, 20.39.
1.31. (2-(Methoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethyl carboxylate 38
Under an inert atmosphere, thionyl chloride (1.6 mL, 21.6 mmol) was added dropwise to a solution of 37

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(1.5 g, 7.2 mmol) in EtOH (21 mL) at 0 °C. The mixture was stirred for an additional 30 min, allowing it
to rise slowly to rt. The reaction was then heated under reflux for 15 h, cooled at rt and concentrated in
vacuo. The residue was purified by flash chromatography on silica gel (eluent: MeOH/CH2Cl2, 5/95) to
provide 38 (1.2 g, 71%) as a white solid. Mp 122-123 °C; IR (KBr): ν 3422, 3000-2800, 1719, 1610 cm-1;
1H-NMR (CDCl3) δ 1.41 (t, 3H, J = 7.1 Hz, OCH2-CH3), 3.56 (s, 3H, OCH3), 4.44 (q, 2H, J = 7.1 Hz,
OCH2-CH3), 4.82 (s, 2H, OCH2), 7.23 (d, 1H, J = 1.2 Hz, H5), 9.12 (s, 1H, H4), 9.91 (bs, 1H, NH);
13C-NMR (CDCl3) 14.4 (O-CH2-CH3), 59.4 (O-CH3), 62.1 (O-CH2-CH3), 75.8 (O-CH2), 106.6 (C5),
117.4 (Cq), 129.4 (Cq), 152.1 (Cq), 153.2 (C4), 161.4 (Cq), 163.1 (Cq); MS (IE) m/z = 236 (M+1); Calcd
for C11H13N3O3: C, 56.16; H, 5.57; N, 17.86. Found: C, 56.44; H, 5.69; N, 17.45.
1.32. 6-(Hydroxymethyl)-2-(methoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine 39
Under an inert atmosphere, a solution of 38 (0.6 g, 2.55 mmol) in dry THF (9 mL) was added dropwise to
a suspension of LiAlH4 (0.145 g, 3.8 mmol) in dry THF (9 mL) at rt. The reaction was then continuously
stirred for 1 h at rt. The mixture was taken up in EtOAc (20 mL) and water (5 mL) was added dropwise.
The precipitate obtained was filtered off, washed with EtOAc and the filtrate concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (eluent: MeOH/CH2Cl2, 1/9) to provide 39
(0.409 g, 83%) as a yellow solid. Mp 140-141 °C. IR (KBr): ν 3205, 3124, 3000-2800, 1586 cm-1;
1H-NMR (CDCl3) δ 3.51 (s, 3H, OCH3), 4.80 (s, 2H, CH2OH), 4.82 (s, 2H, OCH2), 6.33 (s, 1H, H5), 8.81
13
(s, 1H, H4), 11.74 (bs, 1H, NH); C-NMR (CDCl3) 58.2 (CH2OH), 59.2 (O-CH3), 75.9 (O-CH2), 98.2
(C5), 118.5 (Cq), 141.6 (Cq), 149.4 (C4), 153.2 (Cq), 158.9 (Cq); MS (IE) m/z = 178 (M+1); Calcd for
C9H11N3O: C, 61.00; H, 6.26; N, 23.73. Found: C, 60.85; H, 6.34; N, 23.39.
1.33. 6-(Azidomethyl)-2-(methoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine 40
Under an inert atmosphere, triphenylphosphine (1.06 g, 4 mmol) and zinc azide/bis pyridine complex
(0.465 g, 1.5 mmol) were successively added to a solution of alcohol 39 (0.390 g, 2 mmol) in dry THF
(20 mL). Diisopropyl azodicarboxylate (0.8 mL, 4 mmol) was then added dropwise and the reaction was
stirred for an additional time (1h) at rt. The precipitate was filtered off, washed with MeOH and the
filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent:
MeOH/CH2Cl2, 1/9) to provide 40 (0.409 g, 83%) as a yellow solid. Mp 105-112 °C. IR (KBr): ν 3111,
3000-2800, 2101, 1584 cm-1; 1H-NMR (CDCl3) δ 3.52 (s, 3H, OCH3), 4.64 (s, 2H, CH2N3), 4.90 (s, 2H,
13
OCH2), 6.56 (1, 1H, H5), 8.98 (s, 1H, H4), 11.85 (sb, 1H, NH); C-NMR (CDCl3) 48.1 (CH2-N3), 59.1
(O-CH3), 75.7 (O-CH2), 100.4 (C5), 118.2 (Cq), 135.5 (Cq), 150.0 (C4), 153.6 (Cq), 160.2 (Cq); MS (IE)
m/z = 219 (M+1); Calcd for C9H12N4O: C, 49.54; H, 4.62; N, 38.51. Found: C, 49.01; H, 4.58; N, 38.39.

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1.34. 1-[2-Methoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]methylamine 41
A solution of compound 40 (0.220 g, 1.0 mmol) in EtOH (7 mL) was hydrogenated (15 psi) over Lindlar
palladium (33 mg) for 1 h at rt. The catalyst was then filtered over Celite and the filtrate concentrated in
vacuo to give the title compound 41 (0.193 g, quant.) as a yellow oil. IR (film): ν 3500-3000, 2881, 1606
cm-1; 1H-NMR (CDCl3+D2O) 3.49 (s, 3H, OCH3), 4.05 (s, 2H, CH2NH2), 4.76 (s, 2H, OCH2), 6.30 (s, 1H,
H5), 8.84 (s, 1H, H4); 13C-NMR (CDCl3) 39.5 (CH2-NH2), 58.8 (O-CH3), 75.7 (O-CH2), 96.5 (C5), 118.0
(Cq), 132.0 (Cq), 148.5 (C4), 152.6 (Cq), 158.8 (Cq); MS (IE) m/z = 193 (M+1); Calcd for C9H12N4O: C,
56.24; H, 6.29; N, 29.15. Found: C, 55.98; H, 6.67; N, 29.39.
1.35. N,N-Dimethyl-N’-(1-[2-(methoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]methyl)sulfamide
42
Under an inert atmosphere, a solution of N,N-dimethylsulfamoyl chloride (0.21 mL, 1.98 mmol) in dry
CH2Cl2 (5 mL) was added dropwise to a solution of 41 (0.190 g, 0.99 mmol) and triethylamine (0.27 mL,
1.98 mmol) in dry CH2Cl2 (4 mL). The reaction was then stirred at rt for 15 h. The mixture was
hydrolysed and extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4
and evaporated in vacuo. The crude was purified on silica gel (eluent: MeOH/EtOAc, 5/95) to provide 42
(0.151 g, 51%) as a white solid. Mp 104-105 °C. IR (KBr): ν 3196, 3000-2720, 1345, 1145 cm-1;
1H-NMR (CDCl3) δ 2.74 (s, 6H, N(CH3)2), 3.50 (s, 3H, OCH3), 4.37 (d, 2H, J = 6.1 Hz, CH2NH), 4.74 (s,
13
2H, OCH2), 6.32 (s, 1H, H5), 6.35 (sb, 1H, CH2NH), 8.79 (s, 1H, H4), 10.68 (sb, 1H, NH); C-NMR
(CDCl3) 38.4 (N(CH3)2), 41.2 (CH2-NH), 59.3 (O-CH3), 75.9 (O-CH2), 99.3 (C5), 118.1 (Cq), 138.1 (Cq),
149.5 (C4), 154.0 (Cq), 160.5 (Cq); MS (IE) m/z = 300 (M+1); Calcd for C11H17N5O3S: C, 44.14; H, 5.72;
N, 23.39. Found: C, 44.12; H, 5.58; N, 23.57.
1.36. N-(1-[2-Methoxymethyl)-7-methylpyrrolo[2,3-d]pyrimidin-6-yl]methyl)-N,N’,N’-trimethyl-
sulfamide 43
Under an inert atmosphere, sodium hydride (57 mg, 1.41 mmol) was added portionwise to a stirred
solution of 42 (0.140 g, 0.47 mmol) in DMF (2 mL) at rt over 30 min. The mixture was stirred for an
additional time (20 min), before MeI (0.088 mL, 1.41 mmol) was added dropwise and the mixture stirred
again for 2 h. Water was then added and the product was extracted with CH2Cl2, purified by flash
chromatography on silica gel (eluent: MeOH/CH2Cl2, 2/98) to give the title compound 43 (0.140 g, 91%)
as a yellow solid. Mp 104-105 °C IR (KBr): ν 3000-2800, 1352, 1157 cm-1; 1H-NMR (CDCl3) δ 2.67 (s,
6H, CH2-N-CH3), 2.88 (s, 6H, N(CH3)2), 3.55 (s, 3H, OCH3), 3.86 (s, 3H, N-CH3), 4.50 (s, 2H,
13
CH2-N-SO2), 4.72 (s, 2H, OCH2), 6.48 (s, 1H, H5), 8.87 (s, 1H, H4); C-NMR (CDCl3) 28.6 (N-CH3),
38.3 (N(CH3)2), 34.5 (CH2-N-CH3), 47.1 (CH2-N-SO2), 59.0 (O-CH2), 76.1 (O-CH3), 100.8 (C5), 116.8
(Cq), 136.0 (Cq), 149.1 (C4), 152.6 (Cq), 159.7 (Cq); MS (IE) m/z = 328 (M+1); Calcd for C13H21N5O3S:

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HETEROCYCLES, Vol. 75, No. 5, 2008
C, 47.69; H, 6.47; N, 21.39. Found: C, 47.74; H, 6.58; N, 21.59.
1.37. N-(1-[2-(Hydroxymethyl)-7-methylpyrrolo[2,3-d]pyrimidin-6-yl]methyl)-N,N’,N’-trimethyl-
sulfamide 7
Under an inert atmosphere, compound 43 (0.115 g, 0.35 mmol) was dissolved in dry CH2Cl2 (4 mL). The
mixture was cooled to 0°C and a solution of BBr3 (0.17 mL, 1.75 mmol) in dry CH2Cl2 (2 mL) was added
dropwise. After 2 h stirring at 0 °C, the reaction was hydrolysed, basified with saturated aqueous
NaHCO3 solution and extracted with CH2Cl2. The combined organic layers were dried over anhydrous
MgSO4 and concentrated in vacuo. Finally, purification by flash chromatography on silica gel using 3%
MeOH in CH2Cl2 as eluent gave 0.093 g (85%) of N-(1-[2-(hydroxymethyl)-7-methylpyrrolo[2,3-d]-
pyrimidin-6-yl]methyl)-N,N’,N’-trimethylsulfamide 7 as a white solid. Mp 156-157 °C. IR (KBr): ν 3146,
1
3000-2800, 1593, 1351, 1153 cm-1; H-NMR (CDCl3+D2O) δ 2.71 (s, 3H, CH2-N-CH3), 2.91 (s, 6H,
N(CH3)2), 3.88 (s, 3H, N-CH3), 4.54 (s, 2H, CH2-N-SO2), 4.90 (s, 2H, CH2OH), 6.53 (s, 1H, H5), 8.87 (s,
13
1H, H4); C-NMR (CDCl3) 28.9 (N-CH3), 34.9 (CH2-N-CH3), 38.7 (N(CH3)2), 47.5 (CH2-N-SO2), 65.0
(CH2OH), 101.4 (C5), 117.2 (Cq), 136.2 (Cq), 149.1 (C4), 152.9 (Cq), 161.9 (Cq); MS (IE) m/z = 314
(M+1); Anal. Calcd for C12H19N5O3S: C, 45.99; H, 6.11; N, 22.35; S, 10.23. Found: C, 46.18; H, 6.05; N,
22.55; S, 10.09.
1.38. 6-(Azidomethyl)-7-(2-bromoethyl)-2-(methoxymethyl)pyrrolo[2,3-d]pyrimidine 44
A solution of 40 (0.670 g, 3.1 mmol), 1,2-dibromoethane (8.7 mL, 101.0 mmol) and tetrabutylammonium
bromide (0.050 g, 0.16 mmol) was added to a 7M NaOH aqueous solution (8.7 mL). The reaction was
then stirred at rt for 18 h. The mixture was extracted with EtOAc and the combined organic layers were
washed with water, a saturated aqueous NaCl solution then dried over anhydrous MgSO4, filtered and
concentrated in vacuo. The crude was purified on silica gel (eluent: light petroleum/EtOAc, 1/9) to
1
provide 44 (0.649 g, 65%) as a pink oil. IR (film): ν 3000-2800, 2102, 1591 cm-1; H-NMR (CDCl3) δ
3.55 (s, 1H, OCH3), 3.82 (t, 2H, J = 6.5 Hz, CH2Br), 4.60 (s, 2H, CH2N3), 4.65 (t, 2H, J = 6.5 Hz, NCH2),
4.75 (s, 2H, OCH2), 6.57 (s, 1H, H5), 8.96 (s, 1H, H4); 13C-NMR (CDCl3) 30.5 (CH2-Br), 44.7 (N-CH2),
47.7 (Ar-CH2-N3), 59.8 (O-CH3), 76.7 (O-CH2), 101.9 (C5), 117.6 (Cq), 135.8 (Cq), 150.7 (C4), 153.1
79
81
(Cq), 161.1 (Cq); MS (IE) m/z = 325 (M+1 for Br), 327 (M+1 for Br); Calcd for C11H13BrN6O: C,
40.63; H, 4.03; N, 25.85. Found: C, 40.72; H, 4.38; N, 25.39.
1.39. 2-(Methoxymethyl)-6,7,8,9-tetrahydropyrazino [2’,1’:5,1]pyrrolo[2,3-d]pyrimidine 45
A solution of compound 44 (0.620 g, 1.9 mmol) in EtOH (7 mL) was hydrogenated under pressure (15
psi) over Lindlar palladium catalyst (93 mg) for 1 h at rt. After filtration of the catalyst over Celite the
filtrate was concentrated in vacuo. The crude was purified on silica gel (eluent: MeOH/CH2Cl2, 1/9) to

HETEROCYCLES, Vol. 75, No. 5, 2008
1187
give the title compound 45 (0.382 g, 92%) as a yellow oil. IR (film): ν 3416, 3000-2800, 1593 cm-1;
1H-NMR (CDCl3 + D2O) 3.34 (t, 2H, J = 5.6 Hz, N-CH2-CH2-NH), 3.54 (s, 3H, OCH3), 4.23 (m, 4H,
N-CH2-CH2-NH and CH2-NH), 4.74 (s, 2H, OCH2), 6.20 (s, 1H, H5), 8.85 (s, 1H, H4); 13C-NMR (CDCl3
42.1 (N-CH2-CH2-NH), 43.5 (N-CH2-CH2-NH), 44.6 (Ar-CH2-NH), 59.3 (O-CH3), 76.4 (O-CH2),
94.2( C5), 117.9 (Cq), 136.9 (Cq), 148.5 (C4), 152.3 (Cq), 158.7 (Cq); MS (IE) m/z = 219 (M+1); Calcd for
C11H14N4O: C, 60.53; H, 6.47; N, 25.67. Found: C, 60.72; H, 6.58; N, 25.39.
1.40. N,N-Dimethyl-2-(methoxymethyl)-6,7,8,9-tetrahydropyrazino[2’,1’:5,1]pyrrolo[2,3-d]-
pyrimidine-7-sulfonamide 46
Under an inert atmosphere, a solution of N,N-dimethylsulfamoyl chloride (0.24 mL, 2.2 mmol) in dry
CH2Cl2 (5 mL) was added dropwise to a solution of 45 (0.245 g, 1.1 mmol) and triethylamine (0.31 mL,
2.2 mmol) in dry CH2Cl2 (8 mL). The reaction was then stirred at rt for 15 h. After completion of the
reaction, the mixture was hydrolysed and extracted with CH2Cl2. The combined organic layers were dried
over anhydrous MgSO4 and evaporated in vacuo. The crude was purified on silica gel (eluent:
MeOH/EtOAc, 3/97) to provide 46 (0.230 g, 63%) as a yellow oil. IR (film): ν 3000-2800, 1592, 1148
1
cm-1; H-NMR (CDCl3) δ 2.89 (s, 6H, N(CH3)2), 3.56 (s, 3H, OCH3), 3.78 (t, 2H, J = 5.6 Hz,
N-CH2-CH2-N-SO2), 4.37 (t, 2H, J = 5.6 Hz, N-CH2-CH2-N-SO2), 4.64 (s, 2H, CH2-N-SO2), 4.75 (s, 2H,
OCH3), 6.32 (s, 1H, H5), 8.90 (s, 1H, H4); 13C-NMR (CDCl3) 38.6 (N(CH3)2), 41.2 (N-CH2), 44.3
(CH2-CH2-N-SO2), 44.8 (Ar-CH2-N-SO2), 59.4 (O-CH3), 76.3 (O-CH2), 95.5 (C5), 117.9 (Cq), 133.4 (Cq),
149.2 (C4), 151.5 (Cq), 159.4 (Cq); MS (IE) m/z = 326 (M+1); Calcd for C13H19N5O3: C, 47.99; H, 5.89;
N, 21.52. Found: C, 47.65; H, 5.90; N, 21.67.
1.41. N,N-Dimethyl-2-(hydroxymethyl)-6,7,8,9-tetrahydropyrazino[2’,1’:5,1]pyrrolo[2,3-d]-
pyrimidine-7-sulfonamide 8
Under an inert atmosphere, compound 46 (0.220 g, 0.68 mmol) was dissolved in dry CH2Cl2 (8 mL). The
mixture was then cooled to 0°C and a solution of BBr3 (0.32 mL, 3.4 mmol) in dry CH2Cl2 (3 mL) was
added dropwise. After 2 h stirring at 0 °C, the reaction was hydrolysed, basified with saturated aqueous
NaHCO3 solution and extracted with CH2Cl2. The combined organic layers were dried over anhydrous
MgSO4 and concentrated in vacuo. Finally, purification by flash chromatography on silica gel using 3%
methanol in dichloromethane as eluent gave 0.172 g (82%) of N,N-dimethyl-2-(hydroxymethyl)-
6,7,8,9-tetrahydropyrazino[2’,1’:5,1]pyrrolo[2,3-d]pyrimidine-7-sulfonamide 8 as a yellow solid. Mp
160 °C; IR (KBr): ν 3170, 3000-2800, 1593, 1361, 1161 cm-1; 1H-NMR (CDCl3) δ 2.89 (s, 6H, N(CH3)2),
3.79 (t, 2H, J = 5.6 Hz, N-CH2-CH2-N), 3.85 (sb, 1H, CH2OH), 4.34 (t, 2H, J = 5.6 Hz,
N-CH2-CH2-N-SO2), 4.65 (s, 2H, CH2-N-SO2), 4.89 (s, 2H, OCH2), 6.34 (s, 1H, H5), 8.87 (s, 1H, H4);
13C-NMR (CDCl3) 38.2 (N(CH3)2), 40.8 (N-CH2), 43.9 (CH2-CH2-N-SO2), 44.5 (Ar-CH2-N-SO2), 64.6

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(CH2-OH), 95.3 (C5), 117.6 (Cq), 132.9 (Cq), 148.5 (C4), 150.8 (Cq), 160.6 (Cq); MS (IE) m/z = 312
(M+1); Anal. Calcd for C12H17N5O3S: C, 46.29; H, 5.50; N, 22.49; S, 10.30. Found: C, 46.55; H, 5.52; N,
22.41; S, 10.22.
ACKNOWLEDGEMENTS
We thank the society ADIR (Courbevoie, France) for its multiform supports.
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