An improved procedure for the preparation of 8-substituted guanines

Article abstract of DOI:10.1039/b302529b

The preparation of 8-substituted guanines using a new phosphorus(III)-mediated cyclisation of 4-acylamino-5-nitrosopyrimidines as the key step is described.

Full text of DOI:10.1039/b302529b

An improved procedure for the preparation of 8-substituted guanines†
Ming Xu, Fabio De Giacomo, Duncan E. Paterson, Tesmol G. George and Andrea Vasella*
Laboratorium für Organische Chemie, ETH-Hönggerberg, CH-8093 Zürich, Switzerland.
E-mail: vasella@org.chem.ethz.ch; Fax: +41 1632 1136; Tel: +41 1632 5130
Received (in Cambridge, UK) 6th March 2003, Accepted 17th April 2003
First published as an Advance Article on the web 20th May 2003
The preparation of 8-substituted guanines using a new
phosphorus(III)-mediated cyclisation of 4-acylamino-5-
nitrosopyrimidines as the key step is described.
The synthesis of purines and purine nucleosides continue to
attract medicinal interest1 due to their antimicrobial properties2
and their interaction with adenosine receptors.3 The double
condensation of 4,5-diaminopyrimidines with one-carbon elec-
trophiles (Traube synthesis) and related methods4 remain by far
the most important routes for the construction of purines,
although closure of the imidazole ring to give C(8)-substituted
derivatives is generally more difficult than in the case of C(8)-
unsubstituted purines. In recent years, however, the direct
transformation of 4-amino- or 4-acylamino-5-nitrosopyrimi-
dines into purines by thermally driven processes5 or reduc-
Scheme 2 Reagents and conditions: i. XNOCOi-Bu, CH2Cl2 solution of
mixed anhydride at 0° treated with pyridine solution of 4; ii: X = Cl, THF
solution of 4 at rt treated with 1.1 eq. acyl chloride and K2CO3 or Et3N; iii:
2.2 eq. Ph3P, o-xylene, reflux; iv: 10 mol% Pd(OAc)2, 6 bar H2, MeOH, rt;
tions,6 without isolation of the 5-amino derivatives have been
reported. Such nitroso compounds also react with Mannich
bases,7 Vilsmeier-Haak reagents8 and 1,1-dimethylhydra-
v: 10% Pd/C, HCO2H, MeOH, reflux.
zones,9 to form fused imidazole rings. We wish to report an
improved procedure for the reductive cyclisation of 4-acyla-
mino-5-nitrosopyrimidines to give 8-substituted guanines.
amount of carbamate co-product 6 in some cases. However,
reaction of 4 with an acyl chloride in THF in the presence of
K2CO3 or triethylamine gave consistently higher yields of
amide 1 than the mixed anhydride method.
When acylation of the corresponding non-nitrosated pyr-
imidine 5 was attempted, the above methods gave little (using
acyl chloride) or no (mixed anhydride) products. Clearly, the
neighbouring nitrosyl group of 4 participates in the amide-
forming reaction. It is plausible that the nitroso group first
undergoes O-acylation and that migration of the acyl moiety to
the adjacent amino group follows (Scheme 3). Indeed, there is
precedent for this type of reaction in uracil systems: in the case
of 4-amino-2,6-dioxo-5-nitrosopyrimidines it has been shown
that both the nitroso and amine functions are efficiently acylated
by a variety of acyl chlorides and that both of these acyl groups
can be transferred to nucleophiles.12
Scheme 1 5a Reagents and conditions: i. Raney Ni, H2, EtOH; ii. Raney Ni,
H2, EtOH, AcOH; iii. AcOH, EtOH, reflux.
In the context of ongoing research we prepared C(8)-
substituted guanine derivatives using the methodology de-
scribed by Pfleiderer5a (Scheme 1). This entailed the prepara-
tion of 4 in two steps10 from commercially available
6-chloro-2,4-diaminopyrimidine followed by regioselective
acylation with either an acid anhydride or acyl chloride to give
1 (57–67%) and then reduction to the triamine 2 (51–68%) or
direct reduction to purine 3 using a catalytic amount of Raney
nickel and hydrogen in the presence of acetic acid.5a In our
hands, imidazole ring-closure to give the protected guanine 3
could be effected by heat or treatment with SOCl2 but in only
65% or 48% yield, respectively.11
Scheme
3 Acylation of the 4-amino group may proceed via the
In an effort to improve the efficiency of this synthesis, we
reasoned that treatment of the o-nitrosoamide 1 with a
phosphorus(III) reagent might accomplish the direct transforma-
tion of 1 into the desired guanine derivative 3. Upon testing this
hypothesis on a number of substrates we found that the
conversion of 1 into 3 using two molar equivalents of
triphenylphosphine does indeed occur in high yield (Table 1).
Two procedures for the N4-acylation of 4 were investigated.
The first involved treatment with a mixed anhydride, prepared
in situ from the corresponding carboxylic acid, iso-butyl-
chloroformate and N-methylmorpholine. This procedure did not
prove satisfactory. Yields were variable and poor for sterically
hindered acids and, in addition, we observed a significant
5-acyloxyimino intermediate 8.
Phosphorus(III)-mediated reductive cyclisation of amides 1
proceeded most conveniently in xylene at reflux.‡ Reactions
also worked well in toluene but gave slightly lower yields. In
many cases, the product precipitated from solution upon cooling
and could be isolated in analytically pure form by filtration.§
Otherwise, products were separated from the phosphine oxide,
the only other product observed, by column chromatography of
the reaction mixture. In cases where removal of triphenyl- or
tributylphosphine oxide proved problematic, 1 molar equivalent
of 1,2-bis(triphenylphosphino)ethane (DPPE) was the reagent
of choice due to the quantitative precipitation of its bis-oxide
from the reaction medium. The yields of purine derivatives 3 are
generally good to excellent and compare well with those already
reported for alternative methods for this transformation.
† Electronic supplementary information (ESI) available: characterisation of
new compounds. See http://www.rsc.org/suppdata/cc/b3/b302529b/
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CHEM. COMMUN., 2003, 1452–1453
This journal is © The Royal Society of Chemistry 2003

Table 1 Preparation of 8-substituted guanines from 4 according to Scheme 2.
Cyclisation
conditionsa
Debenzylation
conditionsb
Yield of
7
Entry
R
X
Yield of 1
Yield of 3
a
b
c
d
e
f
Me
OCOi–Bu
Cl
OCOi–Bu
Cl
OCOi–Bu
Cl
OCOi–Bu
Cl
OCOi–Bu
Cl
OCOi–Bu
Cl
OCOi–Bu
Cl
OCOi–Bu
Cl
71
73
34
68
35
73
59
49
41
57
71
75
68
79
71
87
20
90
60
61
A
A
A
A
A
A
A
A
B
82
95
58
90
40
86
94
86
92
D
D
D
D
D
E
E
E
E
E
95c
95 c
95 c
95 c
70 c
96
i-Pr
t–Bu
Ph
Ph2CH
C17H35
g
h
i
2-Furyl
94
2-Styryl
3-Pyridyl
91d
85
OCOi–Bu
Cl
OCOi–Bu
Cl
j
B
C
75
80
83
a A: 2.2 eq. PPh3, o-xylene, reflux, 24 h; B: 2.2 eq. Bu3P, o-xylene, reflux, 24 h. C: DPPE, toluene, reflux. b D: Pd(OAc)2, HCO2H, 12 h; E: H2, Pd/C, MeOH,
12 h. c Isolated as the formate salt. d Double bond was also reduced to give 8-phenethylguanine.
Aliphatic, aromatic and heteroaromatic substituents are all
tolerated and the availability of the 8-tert-butyl and benzhydryl
derivatives, albeit in lower yields, is notable. Reductive
cleavage of the O6-benzyl group13 yielded the desired 8-substi-
tuted guanines 7 in high yield.
Notes and references
‡
On addition of two molar equivalents of triphenylphosphine to a
solution of the amide 1 in o-xylene at 23 °C, a colour change from blue to
green then yellow was observed over 10–20 min. At this point TLC showed
that the substrate had been completely consumed and converted into a more
polar compound and that all the phosphine had also disappeared. Upon
heating at reflux for up to 24 h, this intermediate was slowly converted into
the purine 3.
§
All new compounds were characterised by their 1H and 13C NMR, IR
and mass spectra and elemental analysis.†
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Scheme 4 Possible mechanism of phosphorus(III)-mediated reductive
cyclisation.
Although mechanistic studies of the cyclisation step have not
been carried out, a plausible pathway is shown in Scheme 4.
Nucleophilic addition of a trialkylphosphine to the nitroso
group of 1 is expected to lead to a zwitterion 9 which is then
converted into the iminophosphorane 10 by a second equivalent
of phosphine, either by substitution or elimination–addition.
This should be followed by an “aza-Wittig” process leading to
the guanine 3. This transformation is analogous to the synthesis
of indoles from o-acylaminobenzyltriphenylphosphonium salts
reported by Le Corré et al.14
In conclusion, this method can be used to prepare a variety of
novel 8-substituted guanines from the readily available ni-
trosopyrimidine 4 in good to excellent overall yields. The key
phosphorus-mediated cyclisation step is a simple and efficient
alternative to existing methodology which typically yields less
than 50% of the desired product. We are currently applying this
method to other substrates.
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14 M. Le Corré, A. Hercouet and H. Le Baron, J. Chem. Soc., Chem.
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