Alkoxy-5-nitrosopyrimidines: Useful building block for the generation of biologically active compounds

Article abstract of DOI:10.1002/ejoc.201000195

Several alkoxy-5-nitrosopyrimidines were synthesised and high regioselective and sequential nucleophilic aromatic substitution of methoxy groups in 2-am:ino-4,6-d.imetho;xy-5nitrosopyrimidine was observed. The approach was applied to the synthesis of valu

Full text of DOI:10.1002/ejoc.201000195

FULL PAPER
DOI: 10.1002/ejoc.201000195
Alkoxy-5-nitrosopyrimidines: Useful Building Block for the Generation of
Biologically Active Compounds
Antonio Marchal,[a] Manuel Nogueras,[a] Adolfo Sánchez,[a] John N. Low,[b] Lieve Naesens,[c]
Erik De Clercq,[c] and Manuel Melguizo*[a]
Keywords: Nitrogen heterocycles / Nitrosation / Amination / Nucleophilic substitution / Antiviral agents
Several alkoxy-5-nitrosopyrimidines were synthesised and
high regioselective and sequential nucleophilic aromatic
substitution of methoxy groups in 2-amino-4,6-dimethoxy-5-
idines capable of mimicking fused heterobicyclic derivatives
of biological interest. In addition, new compounds were
evaluated as antivirals and their usefulness as synthetic in-
nitrosopyrimidine was observed. The approach was applied termediates was demonstrated.
to the synthesis of valuable polyfunctionalised aminopyrim-
different primary amines led to aminolysis of the 2-methoxy
Introduction
group and to the corresponding 2-aminopyrimidine deriva-
tives II in good to excellent yields in a short time at room
temperature.[10] The easy substitution of a poor leaving
group, such as methoxide, proved to be due to the strong
electron deficiency that the 5-nitroso group imposes on the
pyrimidine nucleus,[11] thus favouring nucleophilic substitu-
tion at the pyrimidine C(2) position.[12]
Aminopyrimidines constitute a class of biologically rel-
evant molecules, as well as important intermediates for the
design and synthesis of fused polycyclic pharmaceutical tar-
gets, such as purines, pteridines and nucleoside analogues.[1]
The highly electron-deficient nature of the pyrimidine ring
renders the nucleophilic aromatic substitution reaction
(SNAr) a general approach for the synthesis, both in solu-
tion[2] and more recently in the solid phase,[3] of a large
number of aminopyrimidine derivatives, especially from
readily available polyhalo-pyrimidines. Unfortunately from
a synthetic point of view, the nucleophilic substitution reac-
tions of 2,4- and/or 6-halopyrimidines are only moderately
selective and a mixture of 2- and 4-monosubstituted prod-
ucts are frequently obtained.[4–6] In addition, once the first
group has been introduced, the reactivity of the resultant 2/
4-aminopyrimidine toward a second SNAr is greatly dimin-
ished, thus restricting the use of poor nucleophiles, such as
anilines, or requiring high temperatures for hours or days[7]
and high concentrations of these nucleophiles to drive reac-
tions to completion.[8] However, microwave irradiation can
facilitate the synthesis of aminopyrimidines through micro-
wave-assisted aromatic nucleophilic substitution.[9] In fact,
we found that the treatment of pyrimidine I (Figure 1) with
Figure 1. Derivation of pyrimidines through sequential alkoxy ami-
nolysis.
[a] Inorganic and Organic Chemistry Department, University of
Jaén,
These results encouraged us to explore similar aminolysis
reactions with other 5-nitrosopyrimidines (III–V), carrying
three or two alkoxy groups on C(2), C(4) and C(6), as an
alternative to classical derivation of polyhalo-pyrimidines.
Furthermore, multiple and sequential substitution of alk-
oxy groups in this kind of pyrimidine could lead to a great
variety of valuable and conveniently functionalised 4-alk-
oxy-5-nitrosopyrimidine derivatives (Figure 2) some of
which exhibit activity as inhibitors of cyclin-dependent kin-
Campus Las Lagunillas s/n, 23071 Jaén, Spain
Fax: +34-953-211876
E-mail: mmelgui@ujaen.es
[b] Department of Chemistry, University of Aberdeen,
Meston Walk, Old Aberdeen, Aberdeen, AB24 3UE, Scotland,
UK
[c] Rega Institute for Medical Research, Katholieke Universiteit
Leuven,
3000 Leuven, Belgium
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000195.
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M. Melguizo et al.
FULL PAPER
ases (CDKs)[13] and of the DNA-repair protein O(6)-alkyl-
guanine-DNA-alkyltransferase (AGT),[14] leading to a re-
newed interest in the synthesis of these pyrimidine deriva-
tives.
Figure 2. Biologically active 4-amino-5-nitrosopyrimidines.
With this idea in mind, several polyalkoxy-5-nitrosopyr-
imidines were synthesised[15] and then assayed against a
range of amines. Here, we report on the very high activation
towards aminolysis of methoxy groups found in symmetri-
cal 2-amino-4,6-dimethoxy-5-nitrosopyrimidine (1).
Figure 3. Dialkoxy-5-nitrosopyrimidines synthesised under neutral
conditions with IAN and DMSO.
Results and Discussion
In a previous paper[10] we described how the treatment
of several amino-dialkoxypyrimidines with a slight excess of
isoamyl nitrite (IAN; 1.2 mol/mol pyrimidine) in dimethyl
sulfoxide (DMSO) at room temperature, led to selective and
clean C(5)-nitrosation of the pyrimidine nucleus. Isolation
of the resulting 5-nitrosopyrimidines was accomplished
through an easy work up consisting of water addition, fol-
lowed by vacuum filtration, washing and vacuum drying,
to afford the desired nitroso derivatives in good yields (65–
75%). These results were considered particularly relevant
because there is no general procedure reported in the litera-
ture to prepare such polyalkoxy-5-nitrosopyrimidines. The
only known precedent is the preparation of 4-amino-2,6-
dimethoxy-5-nitrosopyrimidine (3; Figure 3), which has
been prepared by direct nitrosation of the corresponding
pyrimidine with sodium nitrite in aqueous acid solution[16]
but in a poor 14% yield, surely due to the propensity of the
alkoxy groups to suffer hydrolysis under acidic condi-
tions.[17] It is interesting to note that C(5)-nitrosation of
2,4,6-trimethoxypyrimidine was not achieved under any
conditions. Thus, it may be concluded that the nitrosation
procedure based on treatment with IAN in DMSO without
any added acid extends the range of pyrimidine derivatives
susceptible to C(5)-nitrosation from highly activated poly-
hydroxy or polyamino-pyrimidines to less active pyrimid-
ines possessing only one amino substituent and two moder-
ately π-electron-releasing substituents (alkoxy or alkylthio)
on C(2) and/or C(4)/C(6) carbon atoms.
with the starting material when water or methanol were
used as solvent; the latter result suggested that lower selec-
tivities were obtained when protic solvents were employed.
No traces of di-substitution products were detected by TLC
when anhydrous aprotic solvents such as DMSO, CH2Cl2
or CH3CN were used and mono-substitution product 7a
(Table 1, entries 1–3) could be isolated by simple filtration
without further purification after a short time. With the
amine/methoxy displacement chemistry established, we
then examined the scope of reaction of 1 with amines of
diverse electron density and steric bulk (Table 1). These ex-
periments were conducted under the same reaction condi-
tions as described above, i.e., non-hydroxylic media at room
temperature, however, some of the reactions were sluggish
and required the addition of more amine or a protic solvent
to achieve reasonable rates. All the reactions proceeded in
suspension except when DMSO was used and, once the re-
action was judged to be complete by TLC, the mixture was
worked up and usually purified by simple filtration, wash-
Table 1. Synopsis of reaction conditions and yields for the aminoly-
sis reaction of 1.
Entry
7
R1
Solvent
Time [h] Yield [%]
1
2
3
4
5
6
7
8
a
a
a
b
c
d
e
f
g
h
i
j
k
l
Bu
Bu
Bu
Cy
Ad
DMSO
CH2Cl2
MeCN
DMSO
H2O/DMSO
1
24
3
3.5
36
20
8
75
65
80
80
87
66
94
76
70
95
95
50
84
66
60
85
CH2CH=CH2 CH2Cl2
CH2CH2OH CH2Cl2
(CH2CH2O)2H MeCN
Bn
Ph
4-HO2CC6H4
3-ClC6H4
CH2CO2Et
CH2CH2CO2Et DMSO
CHCH3CO2Et EtOH
With several-5-nitrosopyrimidines to hand, preliminary
aminolysis studies on pyrimidine 1 were undertaken to es-
tablish whether milder conditions could bring about the se-
quential displacement of methoxy groups. Thus, an equi-
molar mixture of 1 and n-butylamine was stirred in both
protic and aprotic polar solvents at room temperature. Af-
ter stirring for 30 min, TLC analysis revealed that two new,
coloured compounds, resulting from the mono- and double-
displacement of methoxy groups, were present, together
8
7
9
MeCN
H2O
H2O
H2O
CH2Cl2
10
11
12
13
14
15
16
0.8
20
48
72
10
120
20
m
n
CHBnCO2Et
H2O
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Alkoxy-5-nitrosopyrimidine Building Blocks
ing and recrystallisation. The simpler primary alkylamines of the neighbouring NH group, which blocks the nitroso
(entries 1–9), all reacted selectively at room temperature, group rotation observed in the precursor[19] and results in
with only the highly hindered 1-adamantylamine requiring the NMR signal of the involved NH proton being displaced
a larger excess of amine (1.5 mol/mol pyrimidine) and water up to 10.84–13.49 ppm ([D6]DMSO, see Exp. Sect.). On the
as solvent to push the reaction to completion. The results other hand, X-ray crystallographic analysis of compound
were clean nucleophilic substitutions affording the corre- 7c (Figure 4) confirmed the predicted structure[20] and
sponding 2,4-diaminopyrimidine derivatives 7a–g in good showed that, in the solid state, the molecule adopts a con-
to very good yields (65–94%) after reaction times ranging formation in which the methoxy group is directed away
from 1 to 36 h (Scheme 1).
from the nitroso group which, in turn, is turned towards
the adamantyl substituent. The distance N(4)···O(5), and
the angle N(4)–H(4)–O(5), were found to be 2.589 Å and
138°, respectively, indicating again that an intramolecular
hydrogen bond exists between the oxygen of the nitroso
group and the hydrogen of the adamantylamino group in
7c. This strong hydrogen bond has been studied in several
4-amino-5-nitrosopyrimidine series[21] and it has been found
that this link enables these compounds to mimic fused het-
ero-bicyclic systems such as purines to deliver new lead
compounds of great biological interest with comparable
pharmacological potency.[13d]
Scheme 1. Synthesis of 4-alkylamino-6-methoxy-5-nitrosopyrimid-
ines 7.
The less nucleophilic aromatic amines (entries 10–12)
were unable to displace one methoxy group in aprotic sol-
vents, however, this was achieved with excellent yield using
a larger excess of amine (2.5 mol/mol pyrimidine) and water
as solvent at room temperature. Like the reaction with 1-
adamantylamine, in this case, neither contamination by dis-
ubstitution nor hydrolysis by-products were observed. A
longer reaction time was required when less activated ani-
lines were assayed (entries 11 and 12). Finally, reaction with
α-amino esters (entries 13–16) offered the best results in a
shorter reaction time when carried out in highly polar di-
methyl sulfoxide solution. Water was also found to be a
good solvent in some cases (entry 16), however, in general,
long reaction times and high temperatures must be avoided
to minimise ester hydrolysis by-products. α-Amino acid
salts were also selectively linked to the nitrosopyrimidine
nucleus after 16 h reaction at room temperature even in
water as solvent. Unfortunately, all attempts to precipitate
pyrimidinecarboxylate salts were unprofitable and con-
trolled acidification of the reaction media led to a mixture
of acids and methoxy-hydrolysed pyrimidine derivatives. Fi-
nally, the medium was acidified to induce total hydrolysis of
the methoxy group in C(6) and to isolate only one product
(Scheme 2). Single-crystal diffraction analysis of compound
8c confirmed the predicted structure.[18]
Figure 4. ORTEP drawing of 7c.
Especially significant from a synthetic point of view is
the fact that all the evaluated primary amines displaced the
first methoxy group much faster than the second. Con-
versely, treatment of 1 with equimolar amounts of second-
ary amines (e.g., pyrrolidine, piperidine or morpholine) did
not produce sequential displacement of their methoxy
groups, and only starting material together with disubstitu-
tion products were detected by TLC and subsequently iso-
lated after a very short reaction times, even for reactions in
aprotic solvents (Scheme 3).
Scheme 3. Reaction of 1 with secondary amines to give 9: (a) X
= –, 0.2 h, 84%; (b) X = CH2, 0.3 h, 64%; (c) X = O, 5 h, 65%.
Scheme 2. Synthesis of N4-(6-oxopyrimidin-4-yl)--amino acids 8.
R and isolated yield (%): (a) R = H (90%); (b) R = Me (62%); (c)
R = CH(CH3)Et (83%); (d) R = CH2Ph (72%); (e) R = CH2OH
(40%); (f) R = CH2CO2H (76%).
This different selectivity of primary and secondary
amines could be rationalised by considering the more nucle-
ophilic character of secondary amines and the additional
A remarkable structural feature of compounds 7 and 8 is stability of nitrosopyrimidines 7 associated with planar de-
the strong intramolecular hydrogen bond that is established localised structures A–E (Figure 5), which were deduced
between the oxygen of the nitroso group and the hydrogen through X-ray analysis.[21e] In addition, it has been ob-
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M. Melguizo et al.
FULL PAPER
served that the planarity of the pyrimidine nucleus is lost
when a secondary amine is introduced,[21c,21d] which means
that charge delocalisation is not so effective as with primary
amines and, therefore, the remaining methoxy group is
more activated towards subsequent nucleophilic substitu-
tion.
Scheme 4. Synthesis of 4,6-bis(alkylamino)-5-nitrosopyrimidines
10.
The one-pot syntheses of non-symmetrical 2,4,6-tris(alk-
ylamino)-5-nitrosopyrimidines were carried out by adding
a protic solvent to crude 7 or, even better, by removing the
original solvent (CH2Cl2 or MeCN) and adding water or a
mixture of MeOH/H2O (4:1, v/v) to gain solubility at room
temperature. The influence of the amine bulk on the substi-
tution rate is evident from the data shown in Table 2. In the
most extreme case, the double displacement by the bulky 1-
adamantylamine (entry 21) was not possible. Instead, the
corresponding product obtained through monosubstitution
and subsequent hydrolysis was isolated after two days in
Figure 5. Resonance forms attributed to compounds 7 according
to the results of X-ray analysis.
We next explored the ability of compounds 7 to undergo refluxing water. The same behaviour was observed when the
a second methoxy displacement to prepare symmetrical and secondary amines pyrrolidine and morpholine were used in
non-symmetrical 2,4,6-tris(alkylamino)-5-nitrosopyrimid- an attempt to displace the second methoxy group from the
ines, in which the different amines would be incorporated monosubstituted products, i.e., C(6)-methoxy hydrolysis oc-
independently in a time-saving, one-pot procedure without curred instead of aminolysis. Nevertheless, the aminolysis
requiring isolation or purification of the reaction intermedi- products 10d and 10i (entries 20 and 25) were finally iso-
ates (Scheme 4). When the reactions were carried out in the lated in good yields after long reaction times in refluxing
same aprotic solvents used for the first methoxy displace- methanol. In this respect, the longer reaction time required
ment, the substitution of the second methoxy group re- by secondary amines in comparison to primary amines de-
quired rather long reaction times and the addition of a large spite the more nucleophilic character of the former is worth
excess (3–4 equiv.) of the second amine. Use of a protic sol- noting.[22] Steric effects and the instability of non-planar
vent or heating the reaction medium was necessary to reaction intermediates can be suggested as possible causes
achieve complete displacement of the methoxy group in 7. of this lower reactivity.[23] Finally, the monosubstituted ani-
According to this understanding, symmetrical 2,4,6-tris(al- line derivatives (entries 30–32) were reactive enough to un-
kylamino)-5-nitrosopyrimidines were easily synthesised in dergo a second methoxy displacement by aliphatic amines
one-pot by adding a slight excess of amine (2.2 mol/mol as well as by α-amino esters, but not by less nucleophilic
pyrimidine) to an aqueous suspension of pyrimidine 1 anilines. In this case, the less basic character of aniline had
(Table 2, entries 17, 19, 22–24 and 29).
the result that the hydrolysis side reaction was not competi-
Table 2. Reaction conditions and yields of 4,6-bis(alkylamino)-5-nitrosopyrimidines 10.
Entry
10
R1
R2
Conditions
Time [h]
Isolated yield [%]
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
Bu
Bu
Cy
Cy
NHBu
NHBn
NHCy
NPyr
H2O/r.t.
H2O/r.t.
H2O/r.t.
MeOH/∆
H2O/∆
H2O/r.t.
H2O/r.t.
H2O/r.t.
1.5
24
96
120
48
8
99
80
65
64
53
79
95
84
82
87
67
86
75
77
60
76
Ad
OH
CH2CH=CH2
(CH2)3NMe2
CH2CH2OH
CH2CH2OH
CH2CH2OH
Bn
Bn
Bn
Ph
Ph
NHCH2CH=CH2
NH(CH2)3NMe2
NHCH2CH2OH
NMor
NHBn
NHMe
NHiPr
NHBn
NHBu
NHCH2CH2CO2Et
NHiPr
8
3.5
36
0.75
4
MeOH/∆
MeOH/∆
MeOH/H2O/r.t.
MeOH/H2O/r.t.
H2O/r.t.
MeOH/H2O/r.t.
DMF/80 °C
MeOH/H2O/r.t.
4
36
24
24
48
3-ClC6H4
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Eur. J. Org. Chem. 2010, 3823–3830

Alkoxy-5-nitrosopyrimidine Building Blocks
tive enough and only the starting material was recovered
even after prolonged heating in water, ethanol or dimethyl
sulfoxide with a large excess of aniline.
1H and 13C NMR spectra of non-symmetrically substi-
tuted compounds 10 showed two sets of signals, indicating
that, in solution, these compounds exist as two rotamers
1
10α and 10β in equilibrium (Figure 6). The H NMR spec-
trum in CDCl3 showed the α/β ratio of the equilibrium mix-
ture to be 87:13 as determined by integration of PhCH2N
and CH3N signals in compound 10k, however, this ratio
changed to 50:50 in [D6]DMSO (see Figures S85 and S87
in the Supporting Information). No significant changes in
1
the H NMR spectrum (i.e., broadening or coalescence of
Figure 6. Rotamers of non-symmetrically substituted 5-nitrosopyr-
signals) were observed between 25 and 120 °C, which is
consistent with a high rotational barrier around the C(5)–
NO bond,[24] as a result of the high strength of the intramo-
imidines 10 and mimicked purine analogues.
lecular, resonance-assisted, N=O···H–N hydrogen bonds temperature range of +20 to –20 °C, in particular, the
existing in both rotamers. This might have significant con- 507 nm band changed neither its position nor its intensity
sequences from a biological point of view since a non-sym- significantly.
metrically substituted nitrosopyrimidine 10 could be able to
mimic two potentially active purines.
Aromatic nitroso compounds are characterised by a
weak nǞp* transition that appears in the visible region
between 480 nm and 760 nm (ε = 40–70), which is sensitive
to solvent polarity (Figure 7).[25] The spectrum of 10k in
methanol, for example, shows peaks at λmax 295 (ε = 9060),
331 (ε = 15120), 507 nm (ε = 68), which is consistent with
the presence of a nitroso group or a mixture of nitroso de-
rivatives (10α and 10β). On the other hand, in ethyl acetate,
the compound absorbs at λmax 278 (ε = 8540), 340 (ε =
Figure 7. Solvent effect on the colour of 5-nitrosopyrimidine solu-
tions.
Finally, to demonstrate the synthetic usefulness of
15200) and 578 nm (ε = 67). Finally, no changes were ob- amino-5-nitrosopyrimidines 7 as intermediates in the prepa-
served when the spectra were recorded in methanol over a ration of binuclear heterocycles of potential biological sig-
Scheme 5. Application of 5-nitrosopyrimidine aminolysis to the synthesis of fused polyazaheterocycles.
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M. Melguizo et al.
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1586, 1402, 1255 cm–1. MS (EI, 70 eV): m/z (%) = 184 (14) [M]+·,
96 (16), 69 (40), 57 (57), 43 (100). UV/Vis (MeOH): λmax [logε] =
237 [3.91], 338 [4.41], 651 [1.77] nm. C6H8N4O3 (184.15): calcd. C
39.13, H 4.38, N 30.42; found C 39.06, H 4.52, N 30.46.
nificance, several fused pyrimidine derivatives were synthe-
sised from the alkoxy-5-nitrosopyrimidines 7c, 7n and 7h,
following the routes depicted in Scheme 5.[26–29]
General Procedure (B) for the Synthesis of 2-Amino-4-alkylamino-
6-methoxy-5-nitrosopyrimidines 7: To a suspension of 1 in a suitable
solvent (10 mL/mol pyrimidine), amine (1.0 mol/mol pyrimidine)
was added. When ethyl amino acid ester hydrochloride was used,
Et3N (2.0 mol/mol pyrimidine) was added to neutralised the hydro-
chloride. The mixture was stirred at r.t. and the reaction was moni-
tored by TLC (silica; CH2Cl2/MeOH, 9:1, v/v) until no starting
material was observed. The mixture was evaporated to dryness and
the residue was suspended in water. The precipitate was filtered,
washed with water and finally dried in a vacuum desiccator over
potassium hydroxide pellets.
Antiviral Activity
Most of the compounds described herein were evaluated
for antiinfluenza virus activity.[30] Convincing activity was
noted for the reference compounds oseltamivir carboxylate
(the active form of Tamiflu), ribavirin, amantadine and rim-
antidine (the latter two are only active against influenza A
virus). Unfortunately, none of the test compounds displayed
antiinfluenza virus activity at subtoxic concentrations or
the highest concentration tested (100 µg/mL). Activity stud-
ies against other viruses are in progress and will be the sub-
ject of another report in the near future.
2-Amino-4-(butylamino)-6-methoxy-5-nitrosopyrimidine (7a): Fol-
lowing general procedure B, starting from pyrimidine 1 (184 mg,
1.00 mmol) and n-BuNH2 in MeCN, 7a was obtained after 3 h of
reaction time as a violet solid (180 mg, 80%). M.p. 102–104 (de-
1
comp.). H NMR (300 MHz, CDCl3, 25 °C): δ = 11.65 (br. s, 1 H,
Conclusions
NH), 5.66 (m, 2 H, NCH2), 4.15 (s, 3 H, OMe), 3.46–3.40 (m, 2
H, CH2), 1.62–1.52 (m, 2 H, CH2), 1.45–1.35 (m, 2 H, CH2), 0.93
(t, J = 7.3 Hz, 3 H, Me) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 172.3 (s), 163.6 (s), 151.0 (s), 139.2 (s), 54.9 (q), 39.5 (t), 30.9
The introduction of a nitroso group on C(5) of a pyrim-
idine nucleus highly activates it towards nucleophilic substi-
tution. This enables easy and selective displacement of
methoxy groups in 2-amino-4,6-dimethoxy-5-nitrosopyrim-
idine by a large range of amines under mild conditions, al-
lowing efficient, time-saving, one-pot preparations of sym-
metrical and non-symmetrical 2,4,6-tris(alkylamino)-5-ni-
trosopyrimidines, which are useful as intermediates in com-
mon synthetic routes to hetero-bicyclic systems of great bio-
logical interest such as purines, pteridines or diazepines.
Unfortunately, none of the test compounds displayed anti-
influenza virus activity; nevertheless, additional activity
evaluation of the synthesised compounds are in progress
and, in accord with the initial results, further investigations
to assess the applicability of the methoxy aminolysis strat-
egy to automated solid-phase synthesis of large 5-nitroso-
pyrimidines libraries will be undertaken.
(t), 20.1 (t), 13.7 (q) ppm. IR (KBr): ν = 3333, 3159, 2934, 1650,
˜
1582, 1211 cm–1. MS (EI, 70 eV): m/z (%) = 225 (93) [M]+·, 208
(100), 179 (38), 154 (89), 127 (33), 68 (32), 57 (43), 43 (70). UV/
Vis (MeOH): λmax [logε] = 231 [3.86], 328 [4.36], 538 [1.83] nm.
C9H15N5O2 (225.25): calcd. C 55.59, H 5.05, N 27.01; found C
55.64, H 5.06, N 26.68.
N-(2-Amino-6-methoxy-5-nitrosopyrimidin-4-yl)ethyl Glycinate (7k):
Following general procedure B, starting from pyrimidine 1 (184 mg,
1.00 mmol), GlyOEt·HCl and Et3N in CH2Cl2, 7k was obtained
after 72 h of reaction time as a blue solid (220 mg, 84%). M.p. 150–
152 °C (decomp.). 1H NMR (300 MHz, [D6]DMSO, 25 °C): δ =
11.22 (br. s, 1 H, NH), 8.07 (br. s, 1 H, NH2), 8.01 (br. s, 1 H,
NH2), 4.19 (d, J = 5.6 Hz, 2 H, NCH2), 4.12 (q, J = 7.1 Hz, 2 H,
COCH2), 4.07 (s, 3 H, OCH3), 1.20 (t, J = 7.0 Hz, 3 H, CH3) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 171.1 (s), 169.0 (s), 163.2
(s), 150.0 (s), 138.9 (s), 60.8 (t), 54.4 (q), 41.3 (t), 14.0 (q) ppm. IR
(KBr): ν = 3426, 3296, 3162, 2976, 1729, 1643, 1214 cm–1. MS (EI,
˜
70 eV): m/z (%) = 255 (94) [M]+·, 166 (63), 154 (100), 127 (42), 57
(30), 43 (29). UV/Vis (MeOH): λmax [logε] = 234 [3.85], 333 [4.39],
549 [1.84] nm. C9H13N5O4 (255.23): calcd. C 42.35, H 5.13, N
27.44; found C 42.42, H 5.14, N 27.39.
Experimental Section
General Procedure (A) for the Synthesis of Amino-dialkoxy-5-ni-
trosopyrimidines 1–6: The aminopyrimidine was dissolved in
DMSO (2.5 mL/mmol pyrimidine) and isoamyl nitrite (1.1 mol/mol
pyrimidine) was added. The reaction mixture was stirred at r.t. until
the starting pyrimidine could no longer be detected by TLC (silica;
CH2Cl2/MeOH, 9:1, v/v). Then, a double volume of water was
added dropwise under continuous stirring and the suspension was
stirred for 2 h. The product was isolated by vacuum filtration,
washed several times with water and finally dried in a vacuum des-
iccator over potassium hydroxide pellets.
General Procedure (C) for the Synthesis of N4-(2-Amino-1,6-dihy-
dro-5-nitroso-6-oxopyrimidin-4-yl)-L-amino Acids 8: To a suspen-
sion of 1 (0.092 mg, 0.5 mmol) in MeCN (5 mL), a solution of -
amino acid (0.6 mmol) in Na2CO3 (1 , 0.6 mL) was added. The
total volume was increased by the addition of water (4.4 mL) and
the final mixture was stirred at r.t. until the initial nitrosopyrimid-
ine was no longer detected by TLC (silica; MeOH). The solvent
was distilled off and the residue was suspended water (5 mL) and
acidified with concentrated HCl to pH 2–3. The solvent was re-
moved in a vacuum evaporator and the red residue obtained was
suspended in water (5 mL), filtered off and finally dried in a vac-
uum desiccator over potassium hydroxide pellets.
2-Amino-4,6-dimethoxy-5-nitrosopyrimidine (1): Following general
procedure A, starting from commercial 2-amino-4,6-dimethoxypyr-
imidine (1.00 g, 6.44 mmol), compound 1 was obtained after 36 h
of reaction time as a green solid (0.866 g, 75%). Crystals suitable
for single-crystal X-ray diffraction were obtained by slow evapora-
N-(2-Amino-1,6-dihydro-5-nitroso-6-oxopyrimidin-4-yl)-L-isoleucine
tion in acetone.[31] M.p. 190–192 °C (decomp.). 1H NMR (8c): Following general procedure C, starting from pyrimidine 1
(300 MHz, [D6]DMSO, 25 °C): δ = 8.33 (br. s, 2 H, NH2), 3.98 (s,
and -isoleucine, 8c was obtained as a red solid (97 mg, 72%).
Crystals suitable for X-ray diffraction were obtained by slow evapo-
ration in water.[21] M.p. 190–192 °C (decomp.). 1H NMR
6 H, 2 ϫ OMe) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 173.0
(s), 163.5 (s), 141.9 (s), 54.9 (q) ppm. IR (KBr): ν = 3328, 1673,
˜
3828
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3823–3830

Alkoxy-5-nitrosopyrimidine Building Blocks
(300 MHz, [D6]DMSO, 25 °C): δ = 12.87 (d, J = 8.4 Hz, 1 H, NH),
the precipitate was filtered, washed with water and dried in a vac-
10.94 (br. s, 1 H, NH), 8.29 (br. s, 1 H, NH2), 7.01 (br. s, 1 H, uum desiccator over potassium hydroxide pellets.
NH2), 4.70 (dd, J = 8.5, 4.5 Hz, 1 H, NCH), 1.98–1.85 (m, 1 H,
2-Amino-4-benzylamino-6-methylamino-5-nitrosopyrimidine (10k):
CH), 1.51–1.37 (m, 1 H, CH2), 1.27–1.13 (m, 1 H, CH2), 0.91 (d,
Following general procedure E, starting from pyrimidine 7g
(138 mg, 0.53 mmol) and MeNH2 in MeOH/H2O (4:1, v/v), 10k
was obtained as a red solid (92 mg, 67%). M.p. 160–162 °C. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 12.01, 7.87 (br. s, 1 H, NH),
11.64, 7.62 (br. s, 1 H, NH), 7.33 (m, 5 H, Ph), 5.55 (br. s, 2 H,
NH2), 4.74, 4.64 (d, J = 6.0 Hz, 2 H, NCH2), 3.09, 2.95 (d, J =
4.9 Hz, 3 H, NCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.9
(s), 163.7 (s), 152.0 (s), 137.6 (s), 136.4 (s), 128.8 (d), 128.7 (d),
J = 7.3 Hz, 3 H, CH3CH), 0.85 (q, J = 7.3 Hz, CH3CH2) ppm. 13
C
NMR (100 MHz, [D6]DMSO): δ = 171.5 (s), 161.1 (s), 156.3 (s),
151.8 (s), 140.5 (s), 56.6 (d), 36.7 (s), 24.7 (t), 15.5 (q), 11.4 (q)
ppm. IR (KBr): ν = 3369, 1736, 1656 cm–1. UV (H O): λmax [logε)]
˜
2
= 267 [4.07], 320 [3.98] nm. C10H15N5O4·1/4H2O (273.76): calcd. C
43.87, H 5.71, N 25.58; found C 43.87, H 5.81, N 25.44.
General Procedure (D) for the Synthesis of Symmetrically Substi-
tuted 2-Amino-4,6-bis(alkylamino)-5-nitrosopyrimidines 9–10: To a
suspension of 1 in water (10 mL/mmol), the corresponding amine
(2.2 mol/mol pyrimidine) was added. The mixture was stirred at r.t.
and monitored by TLC (silica; CH2Cl2/MeOH, 9:1, v/v) until no
starting material was observed. The mixture was evaporated to dry-
ness and the residue was suspended in water (diethyl ether when
secondary amines were used). The precipitate was filtered, washed
and dried in a vacuum desiccator over potassium hydroxide pellets.
127.5 (d), 44.6 (t), 26.1 (q) ppm. IR (KBr): ν = 3321, 3174, 1573,
˜
1360, 1182 cm–1. MS (EI, 70 eV): m/z (%) = 258 (9) [M]+·, 241
(100), 224 (32), 153 (32), 91 (71), 65 (30), 43 (28). UV/Vis (MeOH):
λmax [logε] = 228 [sh], 295 [sh], 331 [4.18], 507 [1.83]. C12H14N6O
(258.28): calcd. C 55.80, H 5.46, N 32.54; found C 55.87, H 5.69,
N 32.51.
Supporting Information (see also the footnote on the first page of
this article): Material and methods, experimental procedures, char-
acterisation data and copies of 1H, 13C, DEPT NMR spectra of all
the synthesised compounds as well as the data for the antiinfluenza
virus activity and cytotoxicity in MDCK cell cultures with some of
synthesised compounds are available.
2-Amino-5-nitroso-4,6-bis(pyrrolidin-1-yl)pyrimidine (9a): Following
general procedure D, starting from pyrimidine
1 (92 mg,
0.50 mmol) and pyrrolidine, 9a was obtained after 0.2 h of reaction
time as a red solid (110 mg, 84%). Red crystals suitable for X-ray
diffraction were obtained by slow evaporation from CH3CN.[21e]
M.p. 192–195 °C. 1H NMR (300 MHz, [D6]DMSO, 25 °C): δ =
6.99 (br. s, 2 H, NH2), 3.87 (br. s, 2 H, NCH2), 3.68 (br. s, 2 H,
NCH2), 3.46 (t, J = 6.7 Hz, 2 H, NCH2), 3.08 (t, J = 6.3 Hz, 2 H,
NCH2), 1.91 (br. s, 4 H, 2CH2), 1.88–1.74 (m, 4 H, 2CH2) ppm.
13C NMR (100, MHz, [D6]DMSO): δ = 163.1 (s), 161.4 (s), 151.6
(s), 142.0 (s), 51.9 (t), 50.7 (t), 48.2 (t), 47.7 (t), 25.9 (t), 25.2 (t),
Acknowledgments
The authors are grateful to Regional Government (Junta de Andal-
ucia) for financial support and staff of CICT-UJA for technical
assistance.
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and references cited therein.
23.7 (t) ppm. IR (KBr): ν = 3341, 2975, 1651, 1577, 1352, 1074
˜
cm–1. MS (EI, 70 eV): m/z (%) = 262 (4) [M]+·, 245 (100), 203 (12),
174 (14), 55 (24), 41 (100). UV/Vis (MeOH): λmax [logε] = 280
[4.17], 336 [4.26], 470 [1.97] nm. C12H18N6O·1/2H2O (271.15):
calcd. C 53.12, H 7.06, N 30.97; found C 53.25, H 7.14, N 30.80.
2-Amino-4,6-bis(benzylamino)-5-nitrosopyrimidine (10m): Following
general procedure D, starting from pyrimidine
1 (184 mg,
1.00 mmol) and BnNH2, 10m was obtained after 36 h of reaction
time as a red solid (240 mg, 75%). Crystals suitable for single-crys-
tal X-ray diffraction were obtained by slow evaporation in MeCN/
1
DMSO (5:1, v/v).[21c] M.p. 160–162 °C. H NMR (300 MHz, [D6]-
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DMSO, 25 °C): δ = 11.95 (t, J = 5.9 Hz, 1 H, NH), 9.26 (t, J =
6.4 Hz, 1 H, NH), 7.51 (br. s, 2 H, NH2), 7.40–7.23 (m, 10 H, 2Ph),
4.89 (d, J = 6.4 Hz, 2 H, NCH2), 4.62 (d, J = 5.9 Hz, 2 H, NCH2)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 164.3 (s), 163.0 (s),
150.6 (s), 139.3 (s), 138.1 (s), 136.1 (s), 128.4 (d), 128.1 (d), 127.5
(d), 127.3 (d), 127.0 (d), 126.6 (d), 42.9 (t), 42.1 (t) ppm. IR (KBr):
ν = 3310, 1631, 1592, 1496, 1360, 1173 cm–1. MS (EI, 70 eV): m/z
˜
(%) = 334 (7) [M]+·, 317 (45), 226 (40), 91 (100). UV/Vis (MeOH):
λmax [logε]: 231 [sh], 296 [sh], 329 [4.33], 504 [2.03]. C18H18N6O
(334.38): calcd. C 64.66, H 5.43, N 25.13; found C 64.75, H 5.52,
N 25.10.
General Procedure (E) for the Synthesis of Non-Symmetrically Sub-
stituted 2-Amino-4,6-bis(alkylamino)-5-nitrosopyrimidines 10: Gene-
ral procedure B for the synthesis of pyrimidines 7 was followed
until compound 1 was no longer observed by TLC. The solvent
was removed, the residue was suspended in a suitable solvent (ca.
10 mL/mmol pyrimidine) and a second amine (1.5 mol/mol pyrim-
idine) was added. The mixture was stirred until compound 7 was
no longer observed by TLC (silica; CH2Cl2/MeOH, 9:1, v/v), then
Eur. J. Org. Chem. 2010, 3823–3830
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Melguizo et al.
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Published Online: May 19, 2010
3830
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3823–3830