A novel and efficient synthesis of 6-dialkylamino-9-benzyl-8-methoxypurines and 6-dialkylamino-9-benzylpurin-8-ones by reaction of methyl N-benzyl-N-(6-dialkylamino-5-nitropyrimidin-4-yl)glycinates with sodium alkoxides

Article abstract of DOI:10.1055/s-2006-941566

A novel and simple synthesis of 6-dialkylamino-9-benzyl-8-methoxypurines and 6-dialkylamino-9-benzylpurin-8-ones by reaction of methyl N-benzyl-N-(6-dialkylamino-5-nitropyrimidin-4-yl)glycinates with sodium alkoxides is described. Georg Thieme Verlag Stut

Full text of DOI:10.1055/s-2006-941566

1422
LETTER
A Novel and Efficient Synthesis of 6-Dialkylamino-9-benzyl-8-methoxypurines
and 6-Dialkylamino-9-benzylpurin-8-ones by Reaction of Methyl N-Benzyl-N-
(6-dialkylamino-5-nitropyrimidin-4-yl)glycinates with Sodium Alkoxides
S
ynthesi
n
s
of Purine
s
g
a
N
-Benzyl-
N
-(6-d
S
ialkylamino-5
u
-nitropyrimid
s
in-4-yl)g
v
s
ilo, Algirdas Brukstus, Sigitas Tumkevicius*
Vilnius University, Faculty of Chemistry, Department of Organic Chemistry, Naugarduko 24, 03225 Vilnius, Lithuania
Fax +370(5)23309 87; E-mail: sigitas.tumkevicius@chf.vu.lt
Received 20 February 2006
(entries 1–3), other alkoxides such as EtONa, EtOLi,
Abstract: A novel and simple synthesis of 6-dialkylamino-9-benz-
yl-8-methoxypurines and 6-dialkylamino-9-benzylpurin-8-ones by
reaction of methyl N-benzyl-N-(6-dialkylamino-5-nitropyrimidin-
4-yl)glycinates with sodium alkoxides is described.
EtOK, PrONa or NaOCH2CH2F in the appropriate alco-
hols cause the transformation of 2c into purin-8-one 4c
(entries 6–9, 12). However, potassium tert-butoxide in
t-BuOH and sodium 2,2,3,3-tetrafluoropropoxide in
2,2,3,3-tetrafluoropropanol – the most and least basic
alkoxides among the employed ones (entries 10, 13) did
not initiate the transformations of 2c. Performing the reac-
tion in aprotic solvents (MeONa in benzene or DMF at
room or elevated temperature or LDA in THF; entries 4,
5, 11) also did not give satisfactory results: in all cases af-
ter the work-up of the reaction mixtures the initial com-
pounds were recovered.
Key words: methyl N-benzyl-N-(6-dialkylamino-5-nitropyrimi-
din-4-yl)glycinates, 8-methoxypurines, purin-8-ones, cyclisation,
rearrangement
Due to interest in synthetic purines as mediators of vari-
ous biological processes1 a number of solution and solid-
phase synthesis procedures have recently been advanced.2
A literature survey revealed that 5-aminopyrimidines with
suitable substituents are the most often used starting com-
pounds for this purpose.3 However, to the best of our
knowledge, no work has been done on the synthesis of
purines from 5-nitropyrimidines under non-reductive con-
ditions. Recently, we have reported on the unexpected
transformations of methyl N-methyl-N-(5-nitropyrimidin-
4-yl)glycinates into 5-nitroso-4-methylaminopyrimidines
or purinones.4a As continuation of our ongoing program
aimed on the study of reactions of 5-nitropyrimidines4 we
report herein on a novel and very simple synthesis of 6-di-
alkylamino-9-benzyl-8-methoxypurines and 6-dialkyl-
amino-9-benzylpurin-8-ones from the corresponding
methyl N-benzyl-N-(5-nitropyrimidin-4-yl)glycinates.
NR2
NR2
NO2
NO2
N
i
N
N
N
CO2Me
N
Cl
1a–e
2a–e
Ph
iii
ii
NR2
NR2
H
N
N
N
N
N
O
OMe
N
N
N
Ph
Ph
The starting materials – methyl N-benzyl-N-(6-dialkyl-
amino-5-nitropyrimidin-4-yl)glycinates 2a–e – were syn-
thesised by the reaction of the readily available 4-
dialkylamino-6-chloro-5-nitropyrimidines 1a–e5 with
methyl N-benzylglycinate in the presence of
triethylamine6 (Scheme 1). Treatment of 2a–e with an
equivalent amount of sodium methoxide in methanol at
room temperature led to the formation of corresponding 8-
methoxy-9H-purines 3a–e in good yields,7 whereas sodi-
um ethoxide in ethanol caused a transformation of 2a–e
into 6-dialkylamino-9-benzylpurin-8-ones 4a–e.7 This
rather unexpected result emboldened to study the reaction
of 2a–e with various alkoxides as it is exemplified by
the results of reaction 2c with various bases in Table 1.
The data obtained indicate that only methoxides in meth-
anol gave 6-dialkylamino-9-benzyl-8-methoxypurines 3
3a–e
4a–e
O
N
NR2
1–4
a
b
c
d
e
N(CH2)4
N(CH2)5
N(CH2)4O
N(CH2)4NMe
N(CH2)6
N
N
N
OCD3
N
Ph
5
Scheme 1 Reagents and conditions: i) PhCH2NHCH2CO2Me (1
equiv), Et3N (1 equiv), MeOH, reflux, 1 h; ii) NaOMe (1 equiv),
MeOH, 2 h, r.t.; iii) NaOEt (1 equiv), EtOH, 2 h, r.t.
The reaction of 2c sodium deuteriomethoxide in deuterat-
ed methanol gave the labeled product 5 (Scheme 1), what
indicates that methoxy group in 3a–e comes from the sol-
vent and not from an ester group of compounds 2a–e.
SYNLETT 2006, No. 9, pp 1422–1424
Advanced online publication: 22.05.2006
DOI: 10.1055/s-2006-941566; Art ID: G06906ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
6.
2
0
0
6
These data indicate that protic solvents – alcohols (excep-
tion is t-BuOH) and rather strong, sterically unhindered

LETTER
Synthesis of Purines from Methyl N-Benzyl-N-(6-dialkylamino-5-nitropyrimidin-4-yl)glycinates
1423
Table 1 Reaction of Compound 2c with Basesa
Entry
1
Base
Time (h)
Product
Yield (%)b
NaOMe/MeOH
LiOMe/MeOH
KOMe/MeOH
NaOMe/C6H6
2
3c
91
57
83
2
5
3c
3
0.5
3c
4
No reaction
5
NaOMe/DMF
No reaction
6
NaOEt/EtOH
2
4c
81
45
79
60
7
LiOEt/EtOH
5
4c
8
KOEt/EtOH
0.5
2
4c
9
NaOPr/PrOH
4c
10
11
12
13
KOt-Bu/t-BuOH
LDA/THF
No reaction
No reaction
4c
NaOCH2CH2F/FCH2CH2OH
NaOCH2CF2CHF2/CHF2CF2CH2OH
2
78
No reaction
a 1 Equiv of base is used at r.t.
b Isolated yield.
bases – have to be used to perform the observed transfor- Taking into account that benzyl, oxo and methoxy groups
mations of methyl N-benzyl-N-(6-dialkylamino-5-nitro- in the molecules can be removed or undergo further trans-
pyrimidin-4-yl)glycinates 2 into the purine derivatives 3 formations this method for the synthesis of the title com-
and 4. Counterion in alkoxides does not have influence on pounds should be useful for the preparation of various
the reaction direction. Nevertheless, reactions with lithi- biologically important 6,8,9-trisubstituted purine deriva-
um alkoxides appeared to be slower and with potassium tives.
alkoxides – faster than using the corresponding sodium
alkoxides. For example, duration of the reaction of 2c
with MeOLi in methanol to give 3c is 5 hours, while the
Acknowledgment
We express our gratitude to M. Kreneviciene and A. Karosiene for
the recording of NMR and IR spectra, to E. Kersuliene and M.
Gavrilova for the elemental analyses.
The work was supported by Lithuanian Science and Study Founda-
tion, Grant No. T-05292.
same reaction using MeOK and MeONa is over already
after 30 minutes and two hours, respectively. The synthe-
sis of the title compounds using sodium alkoxides seems
to be more economic and convenient than the synthesis
using lithium or potassium alkoxides.
Formation of compounds 3a–e, probably, proceeds during
Dieckmann’s type cyclisation of 2a–e and subsequent
reactions of intermediates – purine 7-oxides with metha-
nol.4a Transformation of 2a–e into purin-8-ones 4a–e can
occur by two competitive mechanisms: by an abnormal
addition and elimination of water to purine 7-oxides4a or
by bimolecular rearrangement of purine 7-oxides analo-
gously to that proposed for benzimidazole N-oxides.9
References and Notes
(1) (a) Wu, X.; Ding, S.; Ding, Q.; Gray, N. S.; Schultz, P. G. J.
Am. Chem. Soc. 2002, 14520. (b) Beck, J. P.; Arvanitis, A.
G.; Curry, M. A.; Rescinito, J. T.; Fitzgerald, L. W.;
Gilligan, P. J.; Zaczek, R.; Trainor, G. L. Bioorg. Med.
Chem. Lett. 1999, 967. (c) Perez, O. D.; Chang, Y.-T.;
Rosania, G.; Sutherlin, D.; Schultz, P. G. Chemistry and
Biology 2002, 475.
(2) (a) Hammarstrom, L. G. J.; Smith, D. B.; Talamas, F. X.;
Labadie, S. S.; Krauss, N. E. Tetrahedron Lett. 2002, 8071.
(b) Dang, Q.; Brown, B. S.; Erion, M. D. Tetrahedron Lett.
2000, 6559. (c) Austin, R. E.; Okonya, J. F.; Bond, D. R. F.;
Al-Obeidi, F. Tetrahedron Lett. 2002, 6169.
In conclusion, we have developed a very simple, efficient,
and straightforward synthesis of 6-dialkylamino-9-ben-
zyl-8-methoxy-9H-purines and 9H-purin-8-ones through
reactions of methyl N-benzyl-N-(6-dialkylamino-5-nitro-
pyrimidin-4-yl)glycinates with sodium alkoxides. This is
the first example for preparing of the title compounds
from nitropyrimidines under non-reductive conditions.
(d) Bakkestuen, A. K.; Gundersen, L.-L.; Langli, G.; Lui, F.;
Nolsoe, J. M. J. Bioorg. Med. Chem. Lett. 2000, 1207.
Synlett 2006, No. 9, 1422–1424 © Thieme Stuttgart · New York

1424
I. Susvilo et al.
LETTER
(3) (a) Makara, G. M.; Ewing, W.; Ma, Y.; Wintner, E. J. Org.
Chem. 2001, 5783. (b) Martin, A.; Butters, T. D.; Fleet, G.
W. Chem. Commun. 1998, 2119. (c) Hammarstrom, L. G.
J.; Meyer, M. E.; Smith, D. B.; Talamas, F. X. Tetrahedron
Lett. 2003, 8361. (d) Guan, H.-P.; Ksebati, M. B.; Cheng,
Y.-C.; Drach, J. C.; Kern, E. R.; Zemlicka, J. J. Org. Chem.
2000, 1280.
(4) (a) Susvilo, I.; Brukstus, A.; Tumkevicius, S. Tetrahedron
Lett. 2005, 1841. (b) Susvilo, I.; Brukstus, A.; Tumkevicius,
S. Synlett 2003, 1151.
(5) (a) Clark, J. J. Chem. Soc., Perkin Trans. 1 1974, 1611.
(b) Clark, J. J. Chem. Soc., Perkin Trans. 1 1970, 494.
(6) Typical Procedure for the Preparation of Methyl N-
Benzyl-N-(6-dialkylamino-5-nitropyrimidin-4-
yl)glycinates 2a–e.
The precipitate was filtered off and recrystallised to give
3a–e or 4a–e.
Compound 3a: yield 80%, mp 139–140 °C (from EtOH).8
Compound 3b: yield 79%, mp 143–145 °C (from i-PrOH).8
Compound 3c: yield 91%, mp 142–144 °C (from MeOH).
1H NMR (300 MHz, CDCl3): d = 3.79–3.81 [4 H, m,
N(CH2)2], 4.12 (3 H, s, OMe), 4.17–4.20 [4 H, m, O(CH2)2],
5.17 (2 H, s, NCH2Ph), 7.29 (5 H, s, ArH), 8.30 (1 H, s, C2-
H) ppm. 13C NMR (CDCl3): d = 43.6, 45.1, 57.0, 66.0,
115.0, 127.0, 127.4, 128.4, 136.3, 150.2, 150.3, 151.2, 153.4
ppm. MS (%): m/z = 325 (30) [M+]. Anal. Calcd for
C17H19N5O2: C, 62.75; H, 5.89; N, 21.52. Found: C, 62.86;
H, 5.74; N, 21.17.
Compound 3d: yield 85%, mp 150–151 °C (from hexane).8
Compound 3e: yield 76%, mp 127–128 °C (from i-PrOH).8
Compound 4a: yield 82% (using NaOEt in EtOH). Yield
62% (using NaOPr in PrOH), mp 254–255 °C (from
MeOH).8
A solution of compound 1a–e (5 mmol), benzylamino acetic
acid methyl ester (0.9 g, 5 mmol), Et3N (0.5 g, 5 mmol) in
MeOH (10 mL) was refluxed for 1 h. After cooling to r.t. the
precipitate was filtered off and recrystallised to give 2a–e.
Compound 2a: yield 80%, mp 98–100 °C (from MeOH). IR
(nujol): nmax = 1748 (CO2Me), 1563 (NO2) cm–1. 1H NMR
(300 MHz, CDCl3): d = 1.88–1.92 [4 H, m, (CH2)2], 3.37–
3.41 [4 H, m, N(CH2)2], 3.76 (3 H, s, OMe), 4.23 (2 H, s,
NCH2CO), 4.96 (2 H, s, NCH2Ph), 7.30 (5 H, s, ArH), 8.02
(1 H, s, C2-H) ppm. Anal. Calcd for C18H21N5O4: C, 58.21;
H, 5.70; N, 18.86. Found: C, 58.37; H, 5.67; N, 18.79.
Compound 2c: yield 87%, mp 140–142 °C (from MeOH).
IR (nujol): nmax = 1747 (CO2Me), 1567 (NO2) cm–1. 1H
NMR (300 MHz, CDCl3): d = 3.30–3.34 [4 H, m, N(CH2)2],
3.48–3.52 [4 H, m, O(CH2)2], 3.71 (3 H, s, OMe), 4.51 (2 H,
s, NCH2CO), 4.96 (2 H, s, NCH2Ph), 7.30 (5 H, s, ArH), 7.97
(1 H, s, C2-H) ppm. Anal. Calcd for C18H21N5O5: C, 55.81;
H, 5.46; N, 18.08. Found: C, 55.89; H, 5.27; N, 18.15.
Compound 2e: yield 83%, mp 125–126 °C (from i-PrOH).
IR (nujol): nmax = 1762 (CO2Me), 1578 (NO2) cm–1. 1H
NMR (300 MHz, CDCl3): d = 1.21–1.48 [8 H, m, (CH2)2],
3.20–3.51 [4 H, m, N(CH2)2], 3.76 (3 H, s, OMe), 4.36 (2 H,
s, NCH2CO), 5.00 (2 H, s, NCH2Ph), 7.24–7.29 (5 H, m,
ArH), 7.91 (1 H, s, C2-H) ppm. Anal. Calcd for C20H25N5O4:
C, 60.14; H, 6.36; N, 17.53. Found: C, 60.29; H, 6.28; N,
17.71.
Compound 4b: yield 80% (using NaOEt in EtOH), mp 215–
216 °C (from MeOH).8
Compound 4c: yield 81% (using NaOEt in EtOH), mp 259–
260 °C (from MeOH). IR (nujol): nmax = 3116 (NH), 1715
(CO) cm–1. 1H NMR (300 MHz, DMSO-d6): d = 3.52–3.56
[4 H, m, N(CH2)2], 3.68–3.71 [4 H, m, O(CH2)2], 4.98 (2 H,
s, NCH2Ph), 7.32 (5 H, s, ArH), 8.19 (1 H, s, C2-H), 11.16 (1
H, br s, NH) ppm. 13C NMR (75 MHz, DMSO-d6): d = 43.1,
46.6, 66.7, 105.9, 128.1, 128.2, 129.2, 137.7, 147.7, 149.7,
150.9, 153.5 ppm. MS (%): m/z = 311 (40) [M+]. Anal.
Calcd for C16H17N5O2: C, 61.72; H, 5.50; N, 22.49. Found:
C, 61.87; H, 5.47; N, 22.52.
Compound 4d: yield 82% (using NaOEt in EtOH), mp 222–
223 °C (from MeOH).8
Compound 4e: yield 77% (using NaOEt in EtOH), yield
59% (using NaOPr in PrOH), mp 249–250 °C (from
i-PrOH).8
Compound 5: yield 93%, mp 128–129 °C (from MeOH). 1H
NMR (300 MHz, CDCl3): d = 3.78–3.80 [4 H, m, N(CH2)2],
4.19–4.21 [4 H, m, O(CH2)2], 5.17 (2 H, s, NCH2Ph), 7.28 (5
H, s, ArH), 8.29 (1 H, s, C2-H) ppm. 13C NMR (75 MHz,
CDCl3): d = 44.7, 45.9, 56.2, 67.3, 116.3, 127.8, 127.9,
128.9, 136.5, 150.9, 151.2, 152.3, 154.2 ppm. Anal. Calcd
for C17H16D3N5O2: C, 62.18; H/D, 6.75; N, 21.33. Found: C,
62.05; H/D, 6.74; N, 21.52.
(7) Typical Procedure for the Preparation of 6-Dialkyl-
amino-9-benzyl-8-methoxypurines (3a–e) and 6-
Dialkylamino-9-benzylpurin-8-ones (4a–e).
(8) Compounds 2b,d, 3a,b,d,e and 4a,b,d,e were also fully
characterised by IR, 1H NMR, 13C NMR spectroscopic and
microanalytical data.
(9) Benzimidazoles and Congeneric Tricyclic Compounds;
Preston, P. N.; Smith, D. M.; Gettennant, G., Eds.; Wiley
Interscience: New York, 1981, 313.
To a suspension of the corresponding compound 2a–e
(5 mmol) in an alcohol (5 mL) a solution of the sodium
alkoxide, prepared from sodium (0.115 g, 5 mmol) and
appropriate alcohol (3 mL), was added dropwise under
stirring. The reaction mixture was stirred at r.t. for 2 h.
Synlett 2006, No. 9, 1422–1424 © Thieme Stuttgart · New York