Novel procedure for selective C-nitrosation of aminopyrimidine derivatives under neutral conditions. Scope and synthetic applications

Article abstract of DOI:10.1055/s-2002-19760

A novel simple method, based on treatment with isoamyl nitrite (IAN) in DMSO without any added acid, to produce selective C(5)-nitrosation of aminopyrimidine derivatives is described. It proved to be suitable for a multigram scale and applicable to a larger range of pyrimidine derivatives, including amino-dialkoxypyrimidines, than the procedures previously known. Its scope is analyzed and some example on the usefulness of the newly prepared substances as intermediates in the synthesis of fused heterobicyclic derivatives of potential biological interest is presented.

Full text of DOI:10.1055/s-2002-19760

LETTER
255
Novel Procedure for Selective C-Nitrosation of Aminopyrimidine Derivatives
Under Neutral Conditions. Scope and Synthetic Applications
a
a
a
a
b
N
A
ovel Procedure
f
n
or Selective
C
t
-
Nitro
o
sation of
A
m
n
inopyrimidi
i
ne
D
eri
o
vative
s
Marchal, Manuel Melguizo,* Manuel Nogueras, Adolfo Sánchez, John N. Low
a
Departamento de Química Inorgánica y Orgánica, Facultad de Ciencias Experimentales, Universidad de Jaén, 23071-Jaén, Spain
Fax +34(95)3012141; E-mail: mmelgui@ujaen.es
b
Department of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen, Aberdeen, AB24 3UE, Scotland
Received 16 November 2001
lead to a great variety of synthetically valuable 5-nitros-
opyrimidine derivatives conveniently functionalized with
different combinations of amino, alkylamino and alkoxy
Abstract: A novel simple method, based on treatment with isoamyl
nitrite (IAN) in DMSO without any added acid, to produce selective
C(5)-nitrosation of aminopyrimidine derivatives is described. It
proved to be suitable for a multigram scale and applicable to a larger groups.
range of pyrimidine derivatives, including amino-dialkoxypyrim-
However, there is no general procedure reported for ob-
taining such polyalkoxy-5-nitrosopyrimidines. The only
known precedent seems to be the preparation of 4-amino-
idines, than the procedures previously known. Its scope is analyzed
and some example on the usefulness of the newly prepared sub-
stances as intermediates in the synthesis of fused heterobicyclic de-
rivatives of potential biological interest is presented.
2
,6-dimethoxy-5-nitrosopyrimidine, in a poor 14% yield,
by direct nitrosation of the corresponding pyrimidine with
sodium nitrite in aqueous acid solution but, unfortunate-
Key words: electrophilic aromatic substitutions, heterocycles, C-
nitrosation, nucleoside analogues, pyrimidines
6
ly, this procedure proved to be ineffective while applied to
other dialkoxypyrimidine derivatives. The failure of the
sodium nitrite-aqueous acid procedure to perform syn-
thetically useful nitrosation of alkoxypyrimidines seems
to be connected not only with the smaller activation to-
wards aromatic nucleophilic substitution provided by the
alkoxy groups in comparison with other strongly activat-
ing groups (as amino or tautomerizable hydroxy-oxo
groups) but also with the propensity to suffer hydrolysis
shown by the alkoxy groups in alkoxy-5-nitrosopyrim-
Conveniently functionalized 6-amino-5-nitrosopyrim-
idines are useful intermediates in the synthesis of hetero-
bicyclic compounds of biological significance. Their
transformation, by direct cyclization or via reduction-cy-
clization, constitutes of a well established strategy which
has been widely employed in the syntheses of purine and
pteridine derivatives, including nucleosides and nucleo-
1
side analogues. Moreover, the recent discovery that sev-
5
idines. This latter feature is in accord with the reported
eral 4-alkoxy-6-amino-5-nitrosopyrimidines act as
2
rapid conversion of the firstly formed nitrosoaryl ethers
into nitrosophenols during nitrosation of aryl ethers under
aqueous acidic conditions.7
inhibitors of cyclin-dependent kinases (CDKs) and of the
DNA-repair protein O(6)-alkylguanine-DNA-alkyltrans-
3
ferase (AGT), add a renewed interest on the synthesis of
these pyrimidine derivatives as potential pharmacological Hence our initial interest was focused on the synthesis of
4
agents for cancer treatments.
the 5-nitroso derivatives of amino-dialkoxy- and -tri-
alkoxypyrimidines as a necessary previous step to explore
the aforementioned aminolysis reactions. Three com-
5
In a recent paper the authors described that the treat-
ment of 6-amino-3-methyl-2-methoxy-5-nitrosopyrimi-
din-4(3H)-one derivatives with different primary amines
produced aminolysis of the 2-methoxy group, leading to
the corresponding 2-aminopyrimidine derivatives in
good to excellent yields in a short time at room tempera-
ture. The easy substitution of such a poor leaving group
as is methoxide proved to be due to the strong electron
deficiency that the 5-nitroso group produces on the pyri-
8
pounds, 1a,b,c (Scheme 1 and Table 1) were selected as
model substrates to check the capability of a set of reac-
tion conditions to successfully perform the desired C-nit-
rosation. They bear the smallest alkoxy substituents
(
methoxy) and include the two possible combinations of
an amino group and two alkoxy groups as substituents at
positions C(2), C(4) and C(6) of a pyrimidine ring.
midine nucleus, thus favoring nucleophilic substitution As mentioned above, treatment of 1a–c with sodium ni-
at the pyrimidine C(2) position.
trite in water or ethanol under acidic conditions were inef-
fective to achieve the preparation of the desired C-nitroso
derivatives, as were also the combinations of isoamyl ni-
trite (IAN) with different organic solvents (acetone, ace-
tonitrile, ethanol, dimethylformamide, or glyme) under
both neutral or acidic conditions. In all cases when the
substrates were 1b or 1c, the reaction medium finally
showed a blue-green color, typically associated with pyri-
midine nitroso derivatives but reaction monitoring by
TLC revealed complex mixtures of no practical value for
These results prompted us to explore similar aminolysis
reactions on other 5-nitrosopyrimidines bearing two or
three alkoxy groups on C(2), C(4) and C(6), since multi-
ple successive substitutions of these alkoxy groups could
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1
©
437-2096,E;2002,0,02,0255,0258,ftx,en;G19601ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

2
56
A. Marchal et al.
LETTER
preparative purposes. On the other hand, no reaction was tomerizable) on the C(2) and/or C(4)/C(6) ring atoms,
observed for the trimethoxypyrimidine 1a under any of while substrates 1b–g bear only one strongly activating
the tested conditions.
amino group. Hence, treatment with IAN/DMSO is, to the
best of our knowledge, the first reported general proce-
dure to successfully produce selective C(5)-nitrosation of
the poorly activated amino-dialkoxypyrimidines.
However, treatment with a slight excess of IAN (1.2 mol
equivalents/mol substrate) in DMSO produced selective
clean C(5)-nitrosation reactions of 1b and 1c at room tem-
perature and, remarkably, under neutral conditions. Be- Unfortunately, the even less activated trialkoxypyrimi-
sides, easy workup was possible by simple addition of dine 1a did not react upon similar conditions. To further
water to the reaction medium, followed by vacuum filtra- explore the influence of the pyrimidine substituents on the
tion, washing and vacuum drying, what directly afforded ring susceptibility to suffer C-nitrosation by action of IAN
the desired nitroso derivatives 2b,c with the required in DMSO at room temperature, these conditions were ap-
9
13
grade of purity and in good yields (67% and 75%, respec- plied to compounds 1h–j (Scheme 1 and Table 1).
1
0
tively, Scheme 1 and Table 1). The same procedure was
successfully applied to several other amino-dialkoxypyri-
The 2-dibenzylamino (1h) and 2-methylthio (1i) deriva-
tives afforded the corresponding 5-nitroso pyrimidines 2h
and 2i in 66% and modest 32% yield, respectively. How-
ever, the 4-amino-6-methoxypyrimidine 1j did not suffer
C-nitrosation but slowly underwent 4-amino diazotation
followed by hydrolysis to produce 6-methoxypyrimidin-
1
1
midines, 1d–g, bearing different alkoxy substituents
which included benzyloxy, isopropoxy, and methoxy) to
(
give the corresponding 5-nitroso derivatives 2d–g in
yields ranging from 58% to 86% (Scheme 1 and Table 1).
The procedure proved to be suitable for a multigram scale
4
(3H)-one in 18% yield after 24 hours.
(
up to 5 g of 1b were nitrosated in one trial) without any
It can be concluded from the results above that the proce-
dure described here extends the range of pyrimidine deriv-
atives susceptible to be C(5)-nitrosated to substrates
possessing only one amino substituent on the ring carbon
atoms, but needs the presence of two other moderately -
electron-releasing substituents, such as methoxy or meth-
ylthio, on C(2) and/or C(4)/C(6) to successfully undergo
nitrosation. On the other hand, the formation of 2h in a
good yield proved that the amino substituent of the pyri-
midine ring can be a tertiary amine, thus eliminating the
participation of a hypothetical tautomerical imino form as
the key structure responsible for the nitrosation reaction.
significant loss in yields.
Y
Y
N
Z
N
isoamyl nitrite
DMSO, r.t.
N
O
X
N
Z
X
N
1
2
Scheme 1
Table 1 Synopsis for the Transformations of 1 into 2 Upon Treat-
ment with IAN/DMSO at Room Temperature
Reaction times (Table 1) showed a significant difference
in reactivity between pyrimidin-4-amines (1c–f) and pyri-
midin-2-amines (1b,g). This is consistent with previous
reports describing that 4(6)-amino groups produce higher
activation towards C(5)-nitrosation than do 2-amino
groups, as clearly illustrated by the contrast between the
effective C(5)-nitrosation of 4,6-pyrimidinediamine and
the low reactivity of its isomeric 2,4-pyrimidinediamine
Compds.
X
Y
Z
Reaction Yield
1, 2
time (h)
(%)
a
OCH3
OCH3
OCH3
No reaction
b
c
d
e
f
NH2
OCH3
OCH3
36
7
75
67
70
86
58
70
66
32
OCH3
OCH3
NH2
1
4
OCH3
Oi-Pr
OBn
NH2
5
when treated with sodium nitrite in aqueous acid.
OCH3
NH2
5
Several other pyrimidine derivatives, including 6-pyrim-
idinamine glycosides 3f–i, whose C(5)-nitrosation by
OBn
NH2
NBn2
SCH3
H
OBn
NH2
OBn
OCH3
NH2
NH2
4
treatment with sodium nitrite under acidic conditions was
previously reported,1
5–20
were as well nitrosated with IAN
g
h
i
OBn
25
20
100
in DMSO under neutral conditions in yields comparative
with those found in the literature (Scheme 2 and Table 2).
OCH3
OCH3
OCH3
O
O
j
Diazotation-hydrolysis
R
X
R
X
N
N
IAN
N
O
DMSO, r.t.
N
NH
R1
N
NH
R1
These results were considered particularly relevant be-
cause it seemed to be well established in the existing
literature that C(5)-nitrosation of pyrimidine derivatives
requires the presence of at least two strong -electron-re-
leasing substituents (e.g. amino, oxo or hydroxy-oxo tau-
1
2
3
4
Scheme 2
Synlett 2002, No. 2, 255–258 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Novel Procedure for Selective C-Nitrosation of Aminopyrimidine Derivatives
257
Table 2 Synopsis for the Transformations of 3 into 4 Upon Treatment with IAN/DMSO at Room Temperature; Comparison with Previously
Reported Results
Compounds
X
R
R1
Reaction
time (h)
Yield (%)
Literature results
3, 4
Reaction time (h) Yield (%)
Ref.
14
15
16
17
16
18
19
18
19
a
OH
H
H
24
4
78
24
24
24
24
24
12
24
96
24
quantitative
b
c
d
e
f
OCH3
SCH3
OCH3
SCH3
SCH3
SCH3
SCH3
SCH3
H
H
82
74
H
H
3.5
2.5
1
quantitative
quantitative
CH3
CH3
H
H
65
90
H
quantitative
quantitative
Xylo
5
91
87
91
90
90
92
75
89
g
h
i
H
Xylo(OAc)3
Gluco
4
CH3
CH3
24
2
Gluco(OAc)4
HO
Gluco = HO
HO
O
O
Xylo = HO
HO
OH
OH
The actual nitrosating species operating under the condi- ical significance, 9-(1-adamantyl)-6-methoxy-9H-purin-
tions described here remains unclear. Traces of water, dif- 2-amine (7) was obtained from the commercially avail-
ficult to remove from the highly hygroscopic DMSO or able pyrimidine 1b following the route depicted in
readily incorporated to the medium during solvent trans- Scheme 3. Compound 7 is the first 9-(1-adamantyl)purine
ferences or sampling for TLC monitoring, seem to play an derivative reported to date. Its preparation is based on
important role in these reactions. This statement is based the availability of compound 5 through nitrosation of 1b
upon the observation of a delay in the initiation of the ni- with IAN/DMSO and on the easy nucleophilic replace-
trosation reaction (marked by the appearance of the nitros- ment of one of its 4(6)-methoxy groups by primary
2
2
opyrimidine characteristic blue color) when mixtures of amines (1-adamantylamine in the present case). The
4
anhydrous DMSO and IAN were used, while the transfor- structure of N -1-adamantyl-6-methoxy-5-nitrosopyrimi-
mation immediately began when “wet” DMSO was used dine-2,4-diamine for compound 5 was unambiguously es-
as the reaction solvent. In connection with this observa- tablished through single crystal X-ray diffraction
1
13
23
tion, H and C NMR spectra of IAN measured in analysis. Reduction of 5 with sodium dithionite in meth-
DMSO-d at 25 ºC showed its ready transformation into anol–water, followed by cyclization employing formami-
6
24
isoamyl alcohol at the expense of the traces of water ini- dine acetate in 2-methoxyethanol under reflux afforded
tially present in the solvent, what consequently should the guanine derivative 7.
2
1
produce nitrous acid. Thence, it could be speculated that
In conclusion, the mixture of IAN and DMSO at room
the actual nitrosating species could be nitrous acid, pro-
duced in situ in small concentration by reaction between
IAN and the traces of water present in the medium.
temperature and without any added acid proved a nitrosat-
ing capacity and a C(5)- to N-selectivity superior to that
of other pyrimidine nitrosation procedures (as alkyl or in-
Finally, as an example of the synthetical usefulness of organic nitrites in acidic media), while the virtually neu-
amino-dialkoxypyrimidines 2 as intermediates in the tral conditions under which it operates enlarge its
preparation of binuclear heterocycles of potential biolog- synthetical usefulness to acid-sensitive substrates or
OCH3
N
OCH3
N
OCH3
N
NH
·
AcOH
N
N
NH2
N
N
Adamantylamine
N
Na2S2O4
N
H
NH2
N
O
H
2b
H
OH
DMSO/H2O
r.t., 36 h
MeOH/H2O
70 °C, 30 min
H2N
H2N
N
MeO
reflux, 24 h
H2N
5
(87 %)
6 (85 %)
7 (37 %)
Scheme 3
Synlett 2002, No. 2, 255–258 ISSN 0936-5214 © Thieme Stuttgart · New York

2
58
A. Marchal et al.
LETTER
products. It allows the preparation on a multigram scale of
the amino-dialkoxypyrimidines 2, which can find signifi-
cant application as synthetic intermediates in the prepara-
tion of binuclear fused pyrimidines of potential biological
interest.
A.; Tartakovsky, V. A. Eur. J. Org. Chem. 1999, 29; On the
other hand, all the 6-amino-5-nitroso-pyrimidine derivatives
show a strong intramolecular hydrogen bonding between the
5-nitroso oxygen atom and the neighbor 6-NH hydrogen,
which blocks the free rotation of the nitroso group and
results in a large downfield shifting for the 4(6)-NH proton
NMR signals (10–13 ppm in DMSO).
6
(
11) Compound 1d was obtained by selective O -alkylation of 6-
Acknowledgement
amino-2-methoxypyrimidin-4(3H)-one under Mitsunobu
conditions (i-PrOH/DEAD/Ph P) in acetonitrile; 1e was
prepared by treatment of 6-amino-2-methoxypyrimidin-
The authors acknowledge „Consejería de Educación y Ciencia de la
Junta de Andalucía“ for a research grant to A. Marchal and for fi-
nancial support, and Mr. Oscar del Pico for technical assistance.
3
4(3H)-one with benzyl chloride and potassium carbonate in
DMSO; 1f and 1g were prepared by nucleophilic
substitution with sodium benzylate in benzyl alcohol from 4-
amino-2,6-dichloropyrimidine and 2-amino-4,6-
dichloropyrimidine, respectively.
References and Notes
(
1) (a) Shaw, G. In Comprehensive Heterocyclic Chemistry,
Vol. 5; Potts, K. T.; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon Press: Oxford, 1984, 499. (b) Pfleiderer, W. In
Comprehensive Heterocyclic Chemistry II, Vol. 7;
(
12) (a) Brown, D. J. The Pyrimidines, In The Chemistry of
Heterocyclic Compounds, Vol. 52; Taylor, E. C.;
Weissberger, A., Eds.; John Wiley & Sons: New York, 1994,
305–306. (b) Brown, D. J. The Pyrimidines, In The
Ramsdem, D. A.; Katritzky, A. R.; Rees, C. W.; Scriven, E.
F. W., Eds.; Pergamon Press: Oxford, 1996, 679.
Chemistry of Heterocyclic Compounds, Suppl. I; Taylor, E.
C.; Weissberger, A., Eds.; John Wiley & Sons: New York,
(c) Melguizo, M.; Nogueras, M.; Sánchez, A. J. Org. Chem.
1970, 102–103. (c) Brown, D. J. The Pyrimidines, In The
1992, 57, 559.
Chemistry of Heterocyclic Compounds, Suppl. II; Taylor, E.
C.; Weissberger, A., Eds.; John Wiley & Sons: New York,
(
2) Arris, C. E.; Boyle, F. T.; Calvert, A. H.; Curtin, N. J.;
Endicott, J. A.; Garman, E. F.; Gibson, A. E.; Golding, B. T.;
Grant, S.; Griffin, R. J.; Dewsbury, P.; Johnson, L. N.;
Lawrie, A. M.; Newell, D. R.; Noble, M. E. M.; Sausville, E.
A.; Schultz, R.; Yu, W. J. Med. Chem. 2000, 43, 2797.
3) (a) Chae, M.-Y.; Swenn, K.; Kanugula, S.; Dolan, M.; Pegg,
A. E.; Moschel, R. C. J. Med. Chem. 1995, 38, 359.
1
985, 147–150.
13) (a) Compound 1h was obtained by treatment of 2-amino-
,6-dimethoxypyrimidine (1b) with benzyl chloride and
(
4
potassium hydroxide in toluene at 80 ºC. Compound 1i was
prepared by treatment of 6-amino-2-methylthiopyrimidin-
(
(
4
(3H)-one with dimethyl sulfate/NaOH according to:
Johns, C. O.; Hendrix, B. M. J. Biol. Chem. 1951, 20, 153.
b) Compound 1j was obtained by Raney-nickel
(b) Terashima, I.; Kohda, K. J. Med. Chem. 1998, 41, 503.
4) (a) Gray, N.; Detivaud, L.; Doerig, D.; Meijer, L. Curr. Med.
Chem. 1999, 6, 859. (b) Walker, D. H. Curr. Top.
Microbiol. Immunol. 1998, 227, 149. (c) Garrett, M. D.;
Fattaey, A. Curr. Opin. Genet. Dev. 1999, 9, 104.
5) Melguizo, M.; Marchal, A.; Nogueras, M.; Sánchez, A.;
Low, J. “Aminolysis of Methoxy Groups in Pyrimidine
Derivatives. Activation by 5-Nitroso Group”, J. Heterocycl.
Chem. in press.
(
desulfurization from pyrimidine 1i according to: Pfleiderer,
W.; Liedek, E. Ann. 1958, 612, 163.
(
(
14) (a) Lythgoe, B.; Todd, A. R.; Topham, A. J. Chem. Soc.
(
1944, 315. (b) Evans, R. M.; Jones, P. G.; Palmer, P. J.;
Stephens, E. F. J. Chem. Soc. 1956, 4106.
15) Zvilichovsky, G.; Feingers, J. J. Chem. Soc., Perkin Trans. 1
1976, 1507.
(
(
(
6) Ritzmann, G.; Ienaga, K.; Kiriasis, L.; Pfleiderer, W. Chem.
Ber.; 1980, 113, 1535.
7) Moodie, R. B.; O’Sullivan, B. J. Chem. Soc., Perkin Trans.
(
(
(
(
16) Pfleiderer, W. Chem. Ber. 1957, 90, 2272.
17) Schreider, H.-J.; Pfleiderer, W. Chem. Ber. 1974, 107, 3377.
18) Engelmann, M. Ber. Dtsch. Chem. Ges. 1909, 42, 177.
19) Sánchez, A.; Nogueras, M.; López, R.; Gutiérrez, M.;
Colacio, E. Thermochim. Acta 1988, 91, 173.
1995, 2, 205.
8) Compound 1a was obtained by treatment of 2,4,6-
trichloropyrimidine with sodium methoxide according to:
(
20) Nogueras, M.; López, R.; Gutiérrez, M. D. Sánchez, A. J.
(
(
a) Fox, J. J.; Shugar, D. Bull. Soc. Chim. Belg. 1952, 61, 44.
b) 1b was purchased from Adrich. 1c was prepared by
Therm. Anal. 1988, 34, 1335.
21) The 1H and 13C NMR signals of the newly formed species
(
treatment of 4-amino-2,6-dichloropyrimidine with sodium
methoxide according to: Bretschneider, H.; Klötzer, W.;
Spiteller, G. Monatsh. Chem. 1961, 92, 128.
coincided with those of an original sample of isoamyl
alcohol. On the other hand, the broad signal at 3.69 ppm
assigned to H O traces present in DMSO-d moved to 5.70
2
6
(
9) When the reaction was performed under the same conditions
but in the presence of a catalytic amount of acetic or
trifluoroacetic acid, a complex mixture of colored
compounds, synthetically useless, was obtained.
ppm (broad signal) assigned to the alcohol exchangeable
proton.
(
22) A study on the nucleophilic substitution of methoxide
groups of compounds 2 by different amines is currently
under preparation in our laboratory and will be the subject of
another report in near future. The easy substitution by the
bulky 1-adamantylamino group is here anticipated in order
to illustrate the synthetic potential of the products prepared
by the nitrosation procedure described here.
23) Low, J. N.; Marchal, A.; Nogueras, M.; Melguizo, M.;
Sánchez, A. Acta Crystallogr. 2001, C57, 178.
24) Melguizo, M.; Nogueras, M.; Sánchez, A. Synthesis 1992,
(
10) All the new prepared compounds were fully characterized by
1
13
spectroscopic methods (IR, UV/Vis, MS, H and C NMR)
and elemental analysis (C 0.3, H 0.3, N 0.4%). A
relevant feature of the 2-amino-4,6-dialkoxy-5-nitroso-
1
3
pyrimidines 2b,g,h is the particularly broad C NMR signal
= 161–164 ppm in DMSO) for carbons C(4) and C(6) as
(
(
(
a consequence of the free rotation of the nitroso group that
makes these carbon atoms chemically equivalent. A similar
observation on benzene nitroso derivatives can be found in:
Lipilin, D. L.; Churakov, A. M.; Ioffe, S. L.; Strelenko, Y.
491.
Synlett 2002, No. 2, 255–258 ISSN 0936-5214 © Thieme Stuttgart · New York