Efficient synthesis of N-3-substituted 6-aminouracil derivatives, via N6-[(dimethylamino)methylene] protection

Article abstract of DOI:10.1055/s-2001-11449

A convenient synthetic procedure has been developed to introduce different functional groups at position 3 of 6-amino-1-benzyl- or 6-amino-1-methyluracil based on N⁶-[(dimethylamino) methylene] protection. This method allows for the smooth substitution at N-3 even when base-labile or heat sensitive halide reagents are employed.

Full text of DOI:10.1055/s-2001-11449

478
PAPER
Efficient Synthesis of N-3-Substituted 6-Aminouracil Derivatives via
N6-[(Dimethylamino)methylene] Protection
Eva-María Priego, María-José Camarasa, María-Jesús Pérez-Pérez*
Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, E-28006 Madrid, Spain
Fax +34-91-5644853; E-mail: mjperez@iqm.csic.es
Received 24 October 2000; revised 18 November 2000
O
O
N
O
N
Abstract: A convenient synthetic procedure has been developed to
introduce different functional groups at position 3 of 6-amino-1-
benzyl- or 6-amino-1-methyluracil based on N6-[(dimethylamino)
methylene] protection. This method allows for the smooth substitu-
tion at N-3 even when base-labile or heat sensitive halide reagents
are employed.
4
HN3
a
5
6
HN
N
2
+
1
N
O
NH2
O
N
CH N
O
N
CH N
Ph
Ph
Ph
2
3
1
a) CH3CH2CH2I/K2CO3/DMF, 80 ºC, 2 (8%) and 3 (35%)
Key words: alkylations, heterocycles, protecting groups, nucleo-
bases
Scheme 1
The fact that the N-3 alkylated product 3 showed concom-
itant transformation of the 6-amino function into the for-
mamidino, led us to consider whether "masking" the
exocyclic amino function with a (dimethylamino)methyl-
ene moiety could favor the alkylation at position 3. There-
fore, we decided to study this reaction in detail and here
we report our results on the functionalization at position 3
of 1-substituted-6-aminouracils via N6-[(dimethylami-
no)methylene] protection. This procedure represents a
smooth alternative to previously described methods for N-
3 substitution of 6-aminouracil derivatives. Despite its
common use as a protecting group in the purine chemis-
try,6 to the best of our knowledge a [(dimethylamino)me-
thylene] moiety has not been used with this purpose on 6-
aminouracil.7
6-Aminouracils are key intermediates in the synthesis of
different families of heterocyclic compounds.1 Their key
role in the synthesis of xanthines and analogues, com-
pounds that show well established biological activities as
adenosine receptor antagonists, diuretics, antiinflammato-
ry agents, etc. is well known.2 Despite the versatility of
6-aminouracils in heterocyclic chemistry, most of the re-
actions described have been performed on 1,3-dimethyl-
6-aminouracil, and this, somehow, limits the interest of
the final heterocyclic compounds for biological evalua-
tion. This can be partially explained by the difficulties en-
countered to alkylate the N-3 position of 6-aminouracil,
especially when the N-1 position is already substituted.
The classical approach of 15% NaOH in refluxing EtOH,3
affords, in general, low yields of the N-3 substituted com-
pound and cannot be employed with basic labile or heat
sensitive alkylating agents, such as propargyl bromide.
Attempts to increase the reactivity of 6-amino-1-methylu-
racil by silylation, an approach that has afforded good re-
sults in the free base,4 gave only low yields of the desired
6-amino-1-methyl-3-propragyluracil.5
As starting materials, we chose either 6-amino-1-
benzyluracil3,8 (1) or 6-amino-1-methyluracil3,9 (4)
(Scheme 2) which were quantitatively transformed into
the corresponding formamidines 2 or 5, respectively, by
reaction with DMF-dimethyl acetal (DMF-DMA) in
DMF at 40 ºC. This reaction can be easily followed by
TLC. Then, addition of K2CO3 and the corresponding
alkyl halide and heating to 80 ºC, gave the corresponding
N-3 alkyl derivatives 3, 6 9 in good to excellent yields.
(Table, entries 1 5). In this reaction no deprotection of
the formamidino moiety was observed and the only side
product detected was the protected starting material 2 or
5. Moreover, no O-4 alkylated derivatives were detected.
It should be emphasised that this strategy allows the reac-
tion with base-labile alkylating agents such as 4-(methox-
ycarbonyl)butyl bromide (Table, entries 3 and 4) or N-(3-
bromopropyl)phthalimide (Table, entry 5), substituents
that could not be introduced under the classical vigorous
ethanolic sodium hydroxide conditions.3
In the course of our research on purines, we were interest-
ed in introducing different substituents at the N-3 position
of 6-amino-1-benzyluracil (1) under smooth conditions.
Thus, we tried the alkylation of 1 with propyl iodide in the
presence of K2CO3 in different solvents at 80 ºC. Among
the solvents tested (acetone, acetonitrile, DMF, or ni-
tromethane) only DMF allowed significant transforma-
tion of the starting material into two new products
(Scheme 1). However, to our surprise, when these two
new compounds were characterized, their 1H NMR spec-
tra showed the absence of the 6-NH2 signal, and the pres-
ence of two new singlets at 3.03 ppm and 3.10 ppm,
respectively, each of them corresponding to three H-at-
oms, and an extra singlet at 7.62 ppm. These two com-
pounds were finally identified as the formamidino
derivatives 2 and 3.
From these experiments it was clear that the (dimethy-
lamino)methylene protection causes a marked increase in
the 3-N-alkylation of 1-substituted-6-aminouracils. Next,
and in order to prove the validity of this approach, it was
Synthesis 2001, No. 3, 478–482 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of N-3-Substituted 6-Aminouracil Derivatives
479
Table Synthesis of 3-Substituted 6-[(Dimethylamino)methylene]aminouracil Derivatives
Entry
1
Substrate
Halide Reagent
CH3CH2CH2I
Reaction Conditions
Product
Yield (%)
69
mp (°C)
119
2
5
2
5
2
2
2
2
2
2
2
DMF/DMF-DMA/K2CO3; 80 ºC
DMF/DMF-DMA/K2CO3; 80 ºC
DMF/DMF-DMA/K2CO3; 80 ºC
DMF/DMF-DMA/K2CO3; 80 ºC
DMF/DMF-DMA/K2CO3; 80 ºC
DMF/DMF-DMA/K2CO3; 80 ºC
DMF/K2CO3/TBAI; r.t.
3
6
2
CH3CH2CH2I
68
110
3
MeO2C(CH2)4Br
MeO2C(CH2)4Br
PhtN(CH2)3Br
HC≡CCH2Br
7
72
134
4
8
71
126
5
9
97
245
6
13
13
13
13
16
16
15b
15
7a
8a
9a
10
11a
HC≡CCH2Br
HC≡CCH2Br
acetone/K2CO3/I2; r.t.
37
HC≡CCH2Br
MeCN/DBU; 80 ºC
62
166
136
p-MeOC4H6CH2Cl
DMF/DMF-DMA/K2CO3/I2; 80 ºC
30
p-MeOC4H6CH2Cl
MeCN/DBU; 80 ºC
68
a The excess of DMF-DMA was distilled off in vacuo previous to the addition of the alkylating agent.
b Compound 14 was also obtained in 20% yield.
imperative to efficiently remove the N,N-dimethylami- methoxycarbonyl)butyl derivative 12 was obtained in
nomethylene moiety under conditions that do not affect 90% yield.
the substituents. Thus, removal of the formamidino moi-
Particularly interesting compounds are 6-amino-3-propar-
gyluracils, key intermediates in the synthesis of 1-propar-
gyl xanthines, compounds that show important
ety in compounds 3 and 6 was performed by treatment
with aqueous ammonia in methanol at room temperature,6
affording the desired 6-amino derivatives 10 and 113 in
pharmacological properties, but have proven to be diffi-
92% and 94% yields, respectively (Scheme 3). On the oth-
cult to obtain.11 These facts led us to assay our strategy for
er hand, compound 8 was deprotected by treatment with
the introduction of the propargyl moiety. Following an
analogous procedure to that described above, that is, pro-
ZnCl2 in refluxing methanol6,10 in order to avoid transfor-
mation of the methoxycarbonyl group into the corre-
tection of the exocyclic amino function with DMF-DMA,
sponding
amide.
Thus,
the
6-amino-3-(4-
followed by in situ reaction with K2CO3 and propargyl
bromide (Table, entry 6), the desired 3-propargyl deriva-
O
N
O
N
R1
N
CH N
3 R1=CH2Ph
b
6 R1=CH3
O
O
O
O
a
HN
HN
O
N
c
O
N
NH2
O
N
N
CH N
O
N
N
CH N
R1
R1
R1
d
7 R1=CH2Ph
8 R1=CH3
2 R1=CH2Ph
5 R1=CH3
1 R1=CH2Ph
4 R1=CH3
O
O
N
N
O
N
N
CH N
O
R1
9 R1=CH2Ph
a) DMF-DMA/DMF, 40 ºC; b) CH3CH2CH2I/K2CO3, 80 ºC, 3 (69%), 6 (68%); c) CH3O2C(CH2)4Br/K2CO3, 80 ºC, 7 (72%), 8 (71%); d)
PhtN(CH2)3Br/K2CO3, 80 ºC, 9 (97%)
Scheme 2
Synthesis 2001, No. 3, 478–482 ISSN 0039-7881 © Thieme Stuttgart · New York

480
E.-M. Priego et al.
PAPER
O
at 80 ºC gave only a poor yield of the 3-N-(4-methoxyben-
zyl) derivative 16, even after addition of iodine (Scheme
4). However, treatment of the crude protected 2 with DBU
O
N
N
a
O
N
R1
NH2
O
N
R1
N
CH N
in acetonitrile (Table, entry 11), afforded the desired
4-
10 R1=CH2Ph
11 R1=CH3
3 R1=CH2Ph
6 R1=CH3
methoxybenzyl derivative 16 in 68% yield.
In conclusion, protection of 1-substituted 6-aminouracils
with a N6-[(dimethylamino)methylene] moiety allows the
introduction of a variety of functional groups at position 3
under smooth conditions in good to excellent yields. The
present method offers an alternative over the previously
described procedures that required either harsh
conditions3 or resulted in poor yields.4 Therefore, the
present synthetic procedure could be of interest to obtain
heterocyclic compounds, including pharmacologically ac-
tive xanthine derivatives. Moreover, the here described
compounds can be useful scaffolds for combinatorial
chemistry.
O
O
O
N
O
N
O
O
b
O
N
CH3
NH2
O
N
CH3
N
CH N
8
12
a) NH3 (aq)/MeOH, r.t., 10 (92%), 11 (94%); b) ZnCl2/MeOH, re-
flux, 12 (90%)
Scheme 3
tive 13 was isolated in a 15% yield, together with a second
compound that was identified as the N-3 methyl derivative
14 (Scheme 4). It seems that the excess of the protective
reagent DMF-DMA present in the reaction media, under
basic conditions (K2CO3), behaves as a methylating
agent.12,13 Therefore, to avoid this undesired methylation,
the excess of DMF-DMA was removed prior to treatment
with the carbonate. Reaction of the crude protected deriv-
ative 2 with propargyl bromide and K2CO3 in acetone/
DMF led to a poor transformation into the propargyl de-
rivative 13, even in the presence of a phase-transfer cata-
lyst (Bu4NI) (Table, entry 7). Addition of iodine (Table,
entry 8) allowed a slight increase in the yield of the 3-pro-
pargyl derivative (37%). Finally, when different basic
conditions were tested, it was found that treatment of 2
with DBU in acetonitrile (Table, entry 9) gave the best re-
sults allowing a 62% yield of the desired 1-benzyl-3-pro-
pargyl-6-formamidino derivative 13. Deprotection with
aqueous ammonia in methanol afforded the 6-amino-
derivative 15 in 75% yield.
Melting points were obtained on a Reichert-Jung Kofler apparatus
and are uncorrected. Microanalyses were obtained with a Heraeus
CHN-O-RAPID instrument. Electrospray mass spectra were mea-
sured on a quadrupole mass spectrometer equipped with an electro-
spray source (Hewlett-Packard, LC/MS HP 1100). 1H and 13C NMR
spectra were recorded on a Varian Gemini operating at 200 MHz
(1H) and 50 MHz (13C), respectively, on a Varian INOVA 300 op-
erating at 299 MHz (1H) and 75 MHz (13C), respectively, and Varian
INOVA-400 operating at 399 MHz (1H) and 99 MHz (13C), respec-
1
tively. Monodimensional H and 13C spectra were obtained using
standard conditions. 2D inverse proton detected heteronuclear one-
bond shift correlation spectra were obtained using the Pulsed Field
Gradient HSQC pulse sequence. Data were collected in a
2048 î 512 matrix with a spectral width of 3460 Hz in the proton
domain and 22500 Hz in the carbon domain, and processed in a
2048 î 1024 matrix. The experiment was optimized for one bond
heteronuclear coupling constant of 150 Hz. 2D inverse proton de-
tected heteronuclear long range shift correlation spectra were ob-
tained using the Pulsed Field Gradient HMBC pulse sequence. The
HMBC experiment was acquired under the same conditions that of
HSQC experiment and optimized for long range coupling constants
of 7 Hz. Analytical TLC was performed on silica gel 60 F254 (Mer-
ck) precoated plates (0.2 mm). Spots were detected under UV light
(254 nm) and/or by charring with phosphomolybdic acid. Separa-
tions on silica gel were performed by preparative centrifugal circu-
lar thin-layer chromatography (CCTLC) on a Chromatotron®
(Kiesegel 60 PF254 gipshaltig (Merck)), layer thickness (1 or 2 mm),
flow rate (4 or 8 mL/min, respectively). Flash column chromatogra-
phy was performed with silica gel 60 (230 400 mesh) (Merck).
Finally, we decided to extend the reaction to benzyl sub-
stituents. Treatment of 2 in the DMF-DMA medium (Ta-
ble, entry 10), with 4-methoxybenzyl chloride and K2CO3
O
N
O
N
NH2
15
Reaction of 6-Amino-1-benzyluracil with Propyl Iodide in DMF
To a suspension of 1 (217 mg, 1.0 mmol) in anhyd DMF (8 mL)
were added K2CO3 (208 mg, 1.50 mmol) and propyl iodide
(0.14 mL, 1.50 mmol), and the mixture was heated at 80 ºC for 4 h.
Volatiles were removed in vacuo and the residue was treated with
EtOAc (50 mL) and filtered through Celite. Evaporation of the fil-
trate followed by purification by CCTLC on the Chromatotrom
(mixtures of CH2Cl2/MeOH) afforded 22 mg (8%) of 2 and 110 mg
(35%) of 3.
Ph
b
O
N
O
O
N
HN
N
N
a
O
N
CH N
+
CH N
O
N
O
N
N
O
N
CH N
Ph
2
14
13
Ph
N
Ph
c
O
O
N
CH N
1-Benzyl-6-(dimethylaminomethylene)aminouracil (2)
16
Ph
Mp 213 ºC.
a) See Table, entries 6 9; b) NH3(aq)/MeOH; r.t., 15 (75%); c) See
Table, entries 10 and 11
MS (ES, positive mode): m/z = 273 (M + 1)+, 295 (M + Na)+.
Scheme 4
Synthesis 2001, No. 3, 478–482 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of N-3-Substituted 6-Aminouracil Derivatives
481
1H NMR (CDCl3): = 3.03, 3.10 [2 s, 6 H, N(CH3)2], 4.98 (s, 1 H,
H-5), 5.19 (s, 2 H, N-1-CH2), 7.22 7.33 (m, 5 H, C6H5), 7.62 (s, 1
H, N=CH), 8.11 (br s, 1 H, NH-3).
MS (ES, positive mode): m/z = 311.2 (M + 1)+, 333.3 (M + Na)+.
1H NMR (CDCl3): = 1.65 1.72 [m, 4 H, (CH2)2], 2.35 (t, 2 H,
J = 7.0 Hz, CH2CO), 3.07, 3.12 [2 s, 6 H, N(CH3)2], 3.39 (s, 3 H, N-
1-CH3), 3.65 (s, 3 H, OCH3), 3.96 (t, 2 H, J = 7.0 Hz, N-3-CH2),
5.02 (s, 1 H, H-5), 7.65 (s, 1 H, N=CH).
1-Benzyl-6-(dimethylaminomethylene)amino-3-propyluracil
(3)
Mp 119 ºC.
MS (ES, positive mode): m/z = 315 (M + 1)+.
1H NMR (CDCl3): = 0.93 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.66 (m,
2 H, CH2CH3), 3.03, 3.08 [2 s, 6 H, N(CH3)2], 3.89 (t, J = 7.0 Hz, 2
H, N-3-CH2), 5.05 (s, 1 H, H-5), 5.22 (s, 2 H, N-1-CH2), 7.24 7.34
(m, 5 H, C6H5), 7.62 (s, 1 H, N=CH).
13C NMR (CDCl3): = 22.29, 27.34 (CH2), 29.95 (N-1-CH3), 33.78
(CH2CO), 34.86, 40.42, 40.84 [N(CH3)2, N-3-CH2], 51.43 (OCH3),
83.56 (C-5), 152.46 (C-2), 153.90 (N=CH), 159.42, 163.42 (C-4, C-
6), 173.95 (CH3O ).
2
1-Benzyl-6-(dimethylaminomethylene)amino-3-(3-phthalimi-
dopropyl)uracil (9)
Starting from 1 (100 mg), 205 mg (97%) of 9 was obtained as a
white solid; mp (see Table).
MS (ES, positive mode): m/z = 460.1 (M + H)+, 482.1 (M + Na)+.
13C NMR (CDCl3): = 11.31 (CH2CH3), 21.11 (CH2CH3), 34.98,
40.81 [N(CH3)2], 42.65 (N-3-CH2), 46.03 (N-1-CH2), 83.73 (C-5),
127.08, 127.68, 128.30, 138.17 (C6H5), 152.46 (C-2), 154.08
(N=CH), 159.01 (C-6), 163.48 (C-4).
1H NMR (CDCl3): = 2.04 (q, J = 7.0 Hz, 2 H, CH2), 3.02, 3.08 [2
s, 6 H, N(CH3)2], 3.75 (t, J = 7.2 Hz, 2 H, NPht-CH2), 4.02 (t,
J = 7.0 Hz, 2 H, N-3-CH2), 5.03 (s, 1 H, H-5), 5.20 (s, 2 H, N-1-
CH2), 7.23 (m, 5 H, C6H5), 7.62 (s, 1 H, N=CH), 7.68 (m, 2 H,
C6H4), 7.82 (m, 2 H, C6H4).
13C NMR (CDCl3): = 27.30 (CH2), 35.01 [N(CH3)2], 36.06 (NPht-
CH2), 38.87 (N-3-CH2), 40.87 [N(CH3)2], 46.06 (N-1-CH2), 83.66
(C-5), 123.16, 127.08, 127.52, 128.35, 132.21, 133.76, 138.02
(C6H4, C6H5), 152.34 (C-2), 154.06, 159.15 (N=CH, C6), 163.27
(C-4), 168.29 (COPht).
3-N-Alkyl-6-(dimethylaminomethylene)amino-1-benzyl or -1-
methyluracil (3, 6-9); General Procedure
A suspension containing 6-amino-1-benzyl (1) or 6-amino-1-meth-
yluracil (4) (0.5 mmol) in anhyd DMF (2.5 mL) and DMF-DMA
(0.27 mL, 2.0 mmol) was warmed at 40 ºC till disappearance of
starting material (typically 45-60 min; TLC: CH2Cl2/MeOH, 10:1).
Then K2CO3 (104 mg, 0.75 mmol) and the corresponding alkyl ha-
lide (0.75 mmol) were added and the mixture was heated to 80 ºC.
After 4 h, solvents were removed, the residue was dissolved in
EtOAc (50 mL) and filtered through Celite. The filtrate was evapo-
rated and purified by CCTLC on the Chromatotron using CH2Cl2/
MeOH (20:1).
Removal of the Formamidino Group; Synthesis of 10 and 11;
General Procedure
A solution of the corresponding formamidino derivative (0.3 mmol)
in MeOH (2 mL) was treated with aq ammonia (4 mL) at r.t. for
1 to 3 days. Solvents were evaporated and the resulting residue was
purified by CCTLC on the Chromatotron eluting with CH2Cl2/
MeOH (15:1).
1-Benzyl-6-(dimethylaminomethylene)amino-3-propyluracil
(3)
Following this general procedure and starting from 1 (100 mg),
100 mg (69%) of 3 was obtained.
6-(Dimethylaminomethylene)amino-1-methyl-3-propyluracil
(6)
Starting from 4 (150 mg), 172 mg (68%) of 6 was obtained as a
white solid; mp (see Table).
6-Amino-1-benzyl-3-propyluracil (10)
Starting from 3 (94 mg), 76 mg (92%) of 10 was obtained as a white
solid.
Mp 169 ºC.
MS (ES, positive mode): m/z = 239.1 (M + 1)+.
1H NMR (DMSO-d6): = 0.79 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.46
(m, 2 H, CH2CH3), 3.66 (t, J = 6.8 Hz, 2 H, N-3-CH2), 4.69 (s, 1 H,
H-5), 5.04 (s, 2 H, N-1-CH2), 7.17 (br s, 2 H, NH2), 7.23 7.34 (m,
5 H, C6H5).
1H NMR (CDCl3): = 0.91 (t, J = 7.5 Hz, 3 H, CH3), 1.65 (m, 2 H,
CH2), 3.05, 3.10 [2 s, 6 H, N(CH3)2], 3.37 (s, 3 H, N-1-CH3), 3.86
(m, 2 H, N-3-CH2), 5.01 (s, 1 H, H-5), 7.63 (s, 1 H, N=CH).
13C NMR (CDCl3): = 11.30 (CH3), 21.11 (CH2), 29.93 (N-1-CH3),
34.85, 40.77 [N(CH3)2], 42.58 (N-3-CH2), 83.72 (C-5), 152.58 (C-
2), 153.89, 159.36 (N=CH, C-6), 163.52 (C-4).
6-Amino-1-methyl-3-propyluracil (11)
Starting from 6 (72 mg), 57 mg (94%) of 11 was obtained.
Mp 80 ºC.
1-Benzyl-6-(dimethylaminomethylene)amino-3-[4-(methoxy-
carbonyl)butyl]uracil (7)
MS (ES, positive mode): m/z = 184.1 (M + 1)+, 206.0 (M + Na)+.
1H NMR (acetone-d6): = 0.84 (t, J = 7.5 Hz, 3 H, CH3), 1.49 1.61
(m, 2 H, CH2), 3.38 (s, 3 H, N-1-CH3), 3.75 (t, J = 7.5 Hz, 2 H, N-
3-CH2), 4.82 (s, 1 H, H-5), 6.13 (br s, 2 H, NH2).
Starting from 1 (100 mg), 128 mg (72%) of 7 was obtained as a
white solid; mp (see Table).
MS (ES, positive mode): m/z = 387.1 (M + 1)+.
13C NMR (acetone-d6): = 11.52 (CH3), 21.90 (CH2), 29.03 (N-1-
CH3), 42.58 (N-3-CH2), 77.05 (C-5), 152.58 (C-2), 155.78 (C-6),
162.61 (C-4).
1H NMR (CDCl3): = 1.69 [m, 4 H, (CH2)2], 2.33 (m, 2 H, CH2CO),
3.04, 3.10 [2 s, 6 H, N(CH3)2], 3.95 (m, 2 H, N-3-CH2), 5.06 (s, 1 H,
H-5), 5.22 (s, 2 H, N-1-CH2), 7.25 7.32 (m, 5 H, C6H5), 7.64 (s, 1
H, N=CH).
13C NMR (CDCl3): = 22.30, 27.34 (CH2), 33.77 (CH2CO), 34,98,
40.83 [N(CH3)2], 40.50 (N-1-CH2), 46.01 (N-3-CH2), 51.41
(OCH3), 83.63 (C-5), 127.08, 127.63, 128.29, 138.05 (C6H5),
152.37 (C-2), 154.04, 159.03 (N=CH, C-6), 163.34 (C-4), 173.91
(CO2CH3).
6-Amino-3-[4-(methoxycarbonyl)butyl]-1-methyluracil (12)
To a solution of 8 (60 mg, 0.19 mmol) in MeOH (3 mL) was added
ZnCl2 (111mg, 0.81 mmol), and the mixture was refluxed for 2 d.
Then the mixture was partitioned between H2O (20 mL) and EtOAc
(20 mL). The aqueous phase was extracted with EtOAc (3 î 20
mL). The combined organic phases were dried (Na2SO4), filtered,
evaporated, and the resulting residue was purified by CCTLC on the
Chromatotron using CH2Cl2/MeOH (15:1) to yield 45 mg (90%) of
12 as white solid; mp 165 ºC.
6-(Dimethylaminomethylene)amino-3-[4-(methoxycarbon-
yl)butyl]-1-methyluracil (8)
Starting from 4 (100 mg), 128 mg (72%) of 8 was obtained as a
white solid; mp (see Table).
MS (ES, positive mode): m/z = 256.1(M + 1)+, 278.0 (M + Na)+.
Synthesis 2001, No. 3, 478–482 ISSN 0039-7881 © Thieme Stuttgart · New York

482
E.-M. Priego et al.
PAPER
1H NMR (DMSO-d6): = 1.44 1.48 [m, 4 H, (CH2)2], 2.29 (t,
J = 7.0 Hz, 2 H, CH2CO), 3.22 (s, 3 H, N-1-CH3), 3.55 (s, 3 H,
OCH3), 3.69 (t, 2 H, J = 7.0 Hz, N-3-CH2), 4.66 (s, 1 H, H-5), 6.75
(br s, 2 H, NH2).
1H NMR (CDCl3): = 3.01, 3.08 [2 s, 6 H, N(CH3)2], 3.76 (s, 3 H,
OCH3), 5.05 (s, 2 H, N-3-CH2), 5.07 (s, 1 H, H-5), 5.19 (s, 2 H, N-
1-CH2), 6.81 (d, J = 8.4 Hz, 2 H, C6H4), 7.24 7.41 (m, 5 H, C6H5),
7.43 (d, J = 8.4 Hz, 2 H, C6H4) 7.61 (s, 1 H, N=CH).
13C NMR (DMSO-d6): = 21.71, 26.98 (CH2), 29.10 (N-1-CH3),
32.86 (CH2CO), 40.75 (N-3-CH2), 51.02 (OCH3), 74.95 (C-5),
151.31 (C-2), 154.85 (C-6), 161.15 (C-4), 173.09 (C=O).
13C NMR (CDCl3): = 34.96, 40.81 [N(CH3)2], 43.54 (N-3-CH2),
46.05 (N-1-CH2), 55.18 (OCH3), 83.71 (C-5), 113.57, 130.04,
130.27, 158.74 (C6H4), 127.06, 127.58, 128.28, 138.03 (C6H5),
152.46 (C-2), 154.03 (N=CH), 159.09 (C-6), 163.31 (C-4).
1-Benzyl-6-(dimethylaminomethylene)amino-3-propargylu-
racil (13).
A suspension containing 6-amino-1-benzyluracil (1) (108 mg,
0.5 mmol) in dry DMF (2.5 mL) and DMF-DMA (0.27 mL, 2.0
mmol) was warmed at 40 ºC till disappearance of starting material
(TLC: CH2Cl2/MeOH, 10:1). It was cooled to r.t. and volatiles were
removed by distillation in vacuo. The crude residue containing 2
was dissolved in anhyd MeCN (4 mL) and DMF (0.5 mL), and then
treated with DBU (0.30 mL, 1 mmol) and propargyl bromide
(0.10 mL, 0.9 mmol). The mixture was heated at 80 ºC for 4 h. Then
it was cooled and neutralized by the addition of AcOH. Solvents
were removed, and the residue was treated with aq NaHCO3 solu-
tion (20 mL) and EtOAc (30 mL). The aqueous phase was further
extracted with EtOAc (2 î 30 mL). The combined organic phases
were dried (Na2SO4), filtered, and evaporated. The residue was pu-
rified by flash column chromatography using CH2Cl2/acetone (6:1)
as eluent to yield 96 mg (62%) of 13 as a white solid; mp (see Ta-
ble).
Acknowledgement
Financial support from the Spanish CICYT (SAF 2000-0153-C02-
01) is gratefully acknowledged.
References
(1) Wamhoff, H.; Dzenis, J.; Hirota, K. Adv. Heterocycl. Chem.
1992, 55, 153.
(2) Jacobson, K. A. In Comprehensive Medicinal Chemistry;
Emmet, J. C., Ed.; Pergamon Press: Oxford, 1990; Vol. 3., p
625.
(3) Papesch, V.; Schroeder, E. F. J. Org. Chem. 1951, 16, 1879.
(4) Müller, C. E. Tetrahedron Lett. 1991, 45, 6539.
(5) Müller, C. E.; Shi, D.; Manning, M. Jr.; Daly, J. W. J. Med.
Chem. 1993, 36, 3341.
(6) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: New York, 1999; p 588.
(7) There are only a few reports on 6-[(dimethylamino)-
methylene]amino-1,3-dimethyluracil as substrate for
cycloaddtion and Michael-type reactions:
(a) Walsh, E. B.; Nai-Jue, Z.; Fang, G.; Wamhoff, H.
Tetrahedron Lett. 1988, 29; 4401.
MS (ES, positive mode): m/z = 311 (M + 1)+, 333 (M + Na)+.
1H NMR (CDCl3): = 2.17 (t, 1 H, J = 2.6 Hz, C CH), 3.07, 3.13
[2 s, 6 H, N(CH3)2], 4.73 (d, 2 H, N-3-CH2), 5.12 (s, 1 H, H-5), 5.26
(s, 2 H, N-1-CH2), 7.26 7.36 (m, 5 H, C6H5), 7.67 (s, 1 H, N=CH).
13C NMR (CDCl3): = 30.17 (N-3-CH2), 35.06, 40.91 [N(CH3)2],
46.14 (N-1-CH2), 69.99 (C CH), 78.95 (C CH), 83.28 (C-5),
127.18, 127.82, 128.28, 138.79 (C6H5), 151.81 (C-2), 154.29
(N=CH), 159.46 (C-6), 162.23 (C-4).
(b) Turchi, S.; Giomi, D.; Nesi, R.; Paoli, P. Tetrahedron
1995, 51, 7085.
(c) Nesi, R.; Turchi, S.; Giomi, D. J. Org. Chem. 1996, 61;
7933.
(8) Hutzenlaub, W.; Pfleiderer, W. Liebigs Ann. Chem. 1979,
1847.
(9) Sun, H.; Zhi, C; Wright, G. E.; Ubiali, D.; Pregnolato, M.;
Verri, A.; Focher, F.; Spadari, S. J. Med. Chem. 1999, 42,
2344.
(10) Toste, D.; McNulty, J.; Still, I. W. J. Synth. Commun. 1994,
24, 1617.
6-Amino-1-benzyl-3-propargyluracil (15)
Following the general procedure for the removal of the formamidi-
no group, compound 13 (93 mg, mmol) was treated with aq ammo-
nia in MeOH. Filtration of the reaction mixture and washing with
MeOH afforded 58 mg (75%) of 13 as a white solid; mp 225 ºC.
MS (ES, positive mode): m/z = 256.1 (M + 1)+, 274.1 (M + Na)+.
1H NMR (DMSO-d6): = 3.20 (s, 1 H, HC C), 4.45 (d, 2 H, J = 2.2
Hz, N-3-CH2), 4.74 (s, 1 H, H-5), 5.08 (s, 2 H, N-1-CH2), 6.95 (s, 2
H, NH2), 7.18 7.36 (m, 5 H, C6H5).
13C NMR (DMSO-d6): = 29.29 (N-3-CH2), 44.77 (N-1-CH2),
72.47 (HC C), 74.85 (HC C), 80.14 (C-5), 126.40, 127.31, 128.57,
136.30 (C6H5), 151.04 (C-2), 154.68(C-6), 160.22 (C-4).
(11) (a) Müller, C. E.; Geis, U.; Hipp, J.; Schobert, U.; Frobenius,
W.; Pawlowski, M.; Suzuki, F.; Sandoval-Ramírez, J. J. Med.
Chem. 1997, 40, 4396.
(b) Müller, C.E.; Deters, D.; Dominik, A.; Pawlowski, M.
Synthesis 1998, 1428.
1-Benzyl-6-(dimethylaminomethylene)amino-3-(4-methoxy-
benzyl)uracil (16)
(12) This methylated product was never detected with the
alkylating reagents described in entries 1 5.
(13) For DMF-DMA as a methylating agent see:
(a) Abdulla, R. F.; Brinkmeyer, R. S. Tetrahedron 1979, 35,
1675.
Starting from 1 (100 mg, 0.46 mmol), and following an analogous
procedure to that described for the synthesis of 13, compound 16
(123 mg, 68%) was obtained after purification by CCTLC in the
Chromatotron using CH2Cl2/MeOH (25:1) as eluent; mp (see Ta-
ble).
(b) Pinto, J. C.; Fryer, R. I. J. Heterocycl. Chem. 1993, 30,
939.
MS (ES, positive mode): m/z = 393.1 (M + 1)+; 415.0 (M + Na)+.
Article Identifier:
1437-210X,E;2001,0,03,0478,0482,ftx,en;Z10300SS.pdf
Synthesis 2001, No. 3, 478–482 ISSN 0039-7881 © Thieme Stuttgart · New York