Synthetic strategies to 9-substituted 8-oxoadenines

Article abstract of DOI:10.1080/00397911.2011.642051

Three synthetic routes to 9-substituted 8-oxoadenines have been studied: bromination of adenine followed by N-9-alkylation/arylation and finally hydrolysis; bromination of adenine, hydrolysis, and N-functionalization as the last step; and N-9-alkylation of adenine, halogenation, and finally hydrolysis. As long as the N-9-functional group is compatible with conditions required for introduction of the halogen, the latter strategy was the most efficient. Also, a strategy starting from 5-amino-4,6-dichloropyrimidine was found to be a very good alternative for synthesis of 9-substituted 8-oxoadenines. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications1 to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

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Synthetic Strategies to 9-Substituted 8-
Oxoadenines
Huey-San Melanie Siah a & Lise-Lotte Gundersen a
a Department of Chemistry, University of Oslo, Oslo, Norway
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to 9-Substituted 8-Oxoadenines, Synthetic Communications: An International Journal for Rapid
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Synthetic Communications1, 43: 1469–1476, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.642051
SYNTHETIC STRATEGIES TO 9-SUBSTITUTED
8-OXOADENINES
Huey-San Melanie Siah and Lise-Lotte Gundersen
Department of Chemistry, University of Oslo, Oslo, Norway
GRAPHICAL ABSTRACT
Abstract Three synthetic routes to 9-substituted 8-oxoadenines have been studied: bromin-
ation of adenine followed by N-9-alkylation/arylation and finally hydrolysis; bromination
of adenine, hydrolysis, and N-functionalization as the last step; and N-9-alkylation of ade-
nine, halogenation, and finally hydrolysis. As long as the N-9-functional group is compatible
with conditions required for introduction of the halogen, the latter strategy was the most
efficient. Also, a strategy starting from 5-amino-4,6-dichloropyrimidine was found to be
a very good alternative for synthesis of 9-substituted 8-oxoadenines.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Halogenation; hydrolysis; N-alkylation; 8-oxoadenine
INTRODUCTION
N-9-Substituted 8-oxoadenine derivatives may display a variety of biological
properties including binding affinity to the corticotropin-releasing hormone
receptor,[1] binding affinity to the benzodiazepine receptor,[2] antirhinovirus
activity,[3] and interferon-inducing activity.[4–7] Further work on the interferon
Received November 4, 2011.
Address correspondence to Lise-Lotte Gundersen, Department of Chemistry, University of Oslo,
P.O. Box 1033, Blindern, N-0314 Oslo, Norway. E-mail: l.l.gundersen@kjemi.uio.no
1469

1470
H.-S. M. SIAH AND L.-L. GUNDERSEN
inducers suggested the TLR7 agonizing activity as the molecular basis of the
biological action of 8-oxoadenine derivative,[8–9] and 8-oxoadenine derivatives as
TLR7 agonists inducing dendritic cell maturation has also been reported.[10]
8-Oxoadenine derivatives are also found in nature.[11] Furthermore, 8-oxoadenine
is found as an oxidized metabolite of DNA lesions,[12] and 8-oxoadenine derivatives
may have potential in cancer therapy as inhibitors of DNA repair enzymes.
N-9-Substituted 8-oxoadenines may be synthesized with a ring-closing step
starting from imidazole[4,5,13,14] or pyrimidine,[15] but adenine itself (or 6-chloropur-
ine) may be regarded as a more convenient starting point. From adenine the following
transformations must be included in the synthesis: Introduction of a functional group
(for instance, halogen) at C-8, which can be hydrolyzed, and (selective) N-9-
functionalization. The aim of the current study is to examine in which sequence the
functionalization is most efficiently carried out.
RESULTS AND DISCUSSION
As target compounds 8-oxoadenines 4a–d were selected (Scheme 1). The
N-9-substituents were chosen so that the N-functionalization step would include
alkylation with primary, secondary, and benzylic halide as well as N-arylation.
Initially three synthetic sequences were evaluated: (1) bromination of adenine (1) fol-
lowed by N-9-alkylation=arylation and finally hydrolysis; (2) bromination of adenine
(1), hydrolysis, and N-functionalization as the last step; and (3) N-9-alkylation=
arylation of adenine, halogenation, and finally hydrolysis.
Scheme 1.

SYNTHESIS OF 8-OXOADENINES
1471
Adenine (1) can easily be brominated at C-8 by a literature procedure.[16] How-
ever, we recently reported that benzylation of 8-bromoadenine (2) mainly afforded
the N-3-benzylated isomer and that compound 3a was isolated in only 15% yield.[17]
Also, N-9-alkylation with (bromomethyl)cyclohexane was inefficient; compound 3b
was isolated in 13% yield (Table 1). Hence this synthetic route was abandoned.
8-Bromoadenine (2) was hydrolyzed to the 8-oxo analog 5 by treatment with
formic acid.[18] Synthesis of targets compounds 4 by N-9-alkylation of compound 5
was an attractive strategy because all diversity is introduced in the last step, but unfor-
tunately the yields of 4a–c were only modest, mainly because also 7,9-dialkylated
8-oxopurines also were formed (but not isolated in pure form). N-9-Arylation of
compound 5 was not attempted.
N-Alkylation of adenine (1) gave the 9-substituted compounds 6a–c as the
major products, but in all cases some N-3-alkylated isomer 7 was formed. The N-9-
selectivity, however, is much better compared to what was obtained in alkylations of
8-bromoadenine (2). The structural elucidation of compounds 6 and 7 were done by
various two-dimensional (2D) NMR techniques, and as reported for 3-benzyl-8-
bromoadenine before,[17] restricted rotation around the C–6–N[6] bond was also
observed for 7a–c. It is worth noting that benzylation (and other alkylations) of
adenine (1) under essentially identical reaction conditions previously was reported
to give the N-7-benzyladenine (and other N-7-alkylated adenines).[19] However,
the reported spectral data strongly indicate that also in this case the N-3-alkylated
adenine was the minor isomer.
We previously found that N-arylation of adenine was not successful with phe-
nylboronic acid in the presence of phenanthroline and anhydrous copper(II) acetate
in CH2Cl2,[20] but later others have published a modified procedure [PhB(OH)2,
Cu(OAc)2, TMEDA, MeOH, H2O] for efficient N-9-phenylation of adenine (1).[21]
Phenyladenine is also easily available by N-arylation of 6-chloropurine[20] followed
by aminolysis of compound 8.
9-Alkyladenines 6a–c could be brominated by N-bromosuccinimide (NBS) or
Br2 (Table 1) to give the 8-bromopurines 3a–3c in reasonably good yields. We and
others have shown that C-8 halogenation of purines often can be achieved in good
yields when the parent purine is lithiated with lithium diisopropylamide (LDA) and
Table 1. C-8 halogenation of adenines
Starting material
Reaction conditions
Product
R
X
Yielda (%)
2
PhCH2Br, K2CO3, DMF
NBS, DMF
3a
3a
3b
3b
3c
3d
3e
3f
CH2Ph
CH2Ph
CH2-c-hex
CH2-c-hex
c-pent
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
15b
42
13
66
67
6a
2
c-hexCH2Br, K2CO3, DMF
Br2, H2O
6b
6c
6a
6b
6c
6d
Br2, H2O
b
(1) LDA, (2) C2Cl6, THF, ꢀ78 ꢁC
(1) LDA, (2) C2Cl6, THF, ꢀ78 ꢁC
(1) LDA, (2) C2Cl6, THF, ꢀ78 ꢁC
(1) LDA, (2) C2Cl6, THF, ꢀ78 ꢁC
CH2Ph
CH2-c-hex
c-pent
—
68
69
67
3g
Ph
aIsolated yields
bTaken from Ref. 17.

1472
H.-S. M. SIAH AND L.-L. GUNDERSEN
trapped with a halogen donor.[22,23] Hence, we first treated the compounds 6
with LDA followed by CBrCl2CBrCl2. Extensive decomposition (and probably
debenzylation) took place when 9-benzyladenine 6a was reacted with LDA. Also,
9-benzyl-6-chloropurine, but not certain substituted benzylpurines, decomposes when
treated with LDA.[23] The other purines 6 tolerated LDA well and gave the corre-
sponding 8-bromopurines in good yield (data not shown) after trapping with
CBrCl2CBrCl2. However, careful inspection of the NMR and MS spectra revealed
that the product in fact was a mixture of the 8-bromo- and 8-chloropurine with the
former as the major product. Hence we decided to trap lithiated purines 6b–d with
C2Cl6, and the 8-chloropurines 3e-g were isolated in good yields (Table 1).
Finally, the 8-haloadenines 3 were efficiently hydrolyzed to the 8-oxoadenines 4
in refluxing formic acid. The yields from the chloropurines were slightly greater than
from the bromopurines.
Even though 8-oxo-9-phenyladenine (4d) could be synthesized efficiently
as shown in Scheme 1, we also explored an alternative route. The commercially
available dichloropyrimidine 9 was reacted with aniline according to a literature
procedure,[24] and ring closing to the 8-oxopurine 11 in an excellent yield was
achieved with carbonyldiimidazole (CDI) (Scheme 2). In contrast, a recent attempt
to synthesize compound 11 by a one-step substitution–ring-closing reaction on the
methyl carbamate of 9 failed.[15] We first treated the chloropurine 11 with con-
centrated NH3 (aqueous), but even after 7 days at 130 ꢁC, the conversion to the
desired amine 4d was only slightly more than 50%. The substitution was expected
to be difficult because deprotonation (removal of the NH proton) was believed
to take place before the substitution. Benzylamines are more nucleophilic than
ammonia,[25] and we tried substitution on the chloropurine 11 with the electron-rich
p-methoxybenzylamine. Conversion to the aminopurine 12 was almost quantitative,
and crude 12 was reacted directly in the TFA-mediated debenzylation to give target
compound 4d in 75%yield over two steps. We envisage that many 9-substituted
8-oxoadenines will be available by the route depicted in Scheme 2 as long as the
amine needed as nucleophile in the first step is available.
Three synthetic routes to 9-substituted 8-oxoadenines have been compared.
As long as the N-9-functional group is compatible with conditions required for
introduction of the halogen, N-9-alkylation=arylation followed by C-8-halogenation
and finally hydrolysis is the most efficient route. Also a strategy starting from
5-amino-4,6-dichloropyrimidine was found to be a very good alternative for synthesis
of 9-substituted 8-oxoadenines.
Scheme 2.

SYNTHESIS OF 8-OXOADENINES
1473
EXPERIMENTAL
The 1H NMR spectra were recorded at 600 MHz with a Bruker AV 600
instrument, at 400 MHz with a Bruker AVII 400 instrument, at 300 MHz with a
Bruker Avance DPX 300 instrument, or at 200 MHz with a Bruker Avance DPX
200 instrument. The decoupled 13C NMR spectra were recorded at 150, 100, or
75 MHz using instruments mentioned previously. Mass spectra under electron-impact
conditions were recorded with a VG Prospec instrument at 70-eV ionizing voltage,
and are presented as m=z (% rel. int.). Melting points were determined with a Buchi
¨
melting-point B-545 apparatus and are uncorrected. Dry dimethylformamide (DMF)
and tetrahydrofuran (THF) were obtained from a solvent purification system,
MB SPS-800, from MBraun, Garching, Germany. Diisopropylamine was distilled
from CaH2. All other reagents were commercially available and used as received.
All flash chromatography was performed with silica gel from Merck, Darmstadt,
Germany (Merck No. 09385). Compounds available by literature methods were
8-bromoadenine (2),[16] 9-benzyl-8-bromo-9H-purin-6-amine (3a) from compound
2,[17] 8-oxoadenine (5),[18] 6-chloro-9-phenyl-9H-purine (8),[20] and 6-chloro-N4-
phenylpyrimidine-4,5-diamine (10).[24]
N-Alkylation of 8-Bromoadenine: 9-(Cyclohexylmethyl)-8-bromo-9H-
purin-6-amine (3b)
A mixture of 8-bromoadenine (2) (217 mg, 1.06 mmol) andK2CO3 (280 mg,
2.01 mmol) in dry DMF (5 mL) was stirred under N2 at ambient temperature for
20 min. (Bromomethyl)cyclohexane (0.28 mL, 2.0 mmol) was added, and the mixture
was stirred for 20 h. The mixture was filtered, and the solvent was evaporated in
vacuo. The residue was purified by flash chromatography eluting with 0–10% MeOH
in CH2Cl2; yield 43 mg (13%), mp 228–230 ꢁC, colorless powdery crystals.1H NMR
(DMSO-d6, 300 MHz) 8.11 (s, 1H, H-2), 7.35 (br s, 2H, NH2), 3.94 (d, J ¼ 7.5 Hz,
2H, NCH2), 1.90 (ddd, J ¼ 10.6, 7.3, 3.4 Hz, 1H, CH in c-hex), 1.78 ꢀ 1.36 (m,
5H, c-hex), 1.36 ꢀ 0.91 (m, 5H, c-hex); 13C NMR (DMSO-d6, 75 MHz) 154.7
(C-6), 152.8 (C-2), 151.0 (C-4), 126.6 (C-8), 118.9 (C-5), 49.5 (NCH2), 37.3 (CH in
c-hex), 30.0 (CH2 in c-hex), 25.7 (CH2 in c-hex), 25.1 (CH2 in c-hex); MS EI m=z
(rel. %) 311=309 (2=2, Mþ), 231 (39), 230 (100), 227 (10), 215=213 (28=26), 148
(40). HRMS found 309.0587; calculated for C12H16BrN5309.0589.
Direct Bromination of N-Substituted Adenine: 9-(Cyclohexylmethyl)-
8-bromo-9H-purin-6-amine (3b)
A solution of bromine (0.20 mL, 3.9 mmol) and distilled water (15 mL) was
added to a flask containing 9-(cyclohexylmethyl)adenine (6b) (146 mg, 0.631 mmol).
The flask was fitted with a condenser and the resulting mixture was stirred at
ambient temperature for 17 h. The flask was left open in the fumehood until most
of the Br2 was evaporated, and the solvent was removed in vacuo. The residue
was purified by flash chromatography eluting with 0–100% EtOAc in hexane; yield
126 mg (66%).

1474
H.-S. M. SIAH AND L.-L. GUNDERSEN
General Procedure for Lithiation and Subsequent Chlorination of
9-Substituted Adenines 6
Lithium diisopropylamide (LDA) was generated from n-BuLi in hexanes and
dry diisopropylamine by cooling diisopropylamine (ca. 2.6 mmol) in dry THF
(5 mL) to ꢀ78 ꢁC under Ar. n-BuLi in hexanes (ca. 2.5 mmol) was added dropwise,
and the mixture was stirred for 1 h under these conditions. The appropriate 9-substi-
tuted adenine 6 (0.500 mmol) was dissolved in dry THF (10 mL) and added dropwise
to the LDA solution. The mixture was stirred for 1 h before hexachloroethane
(1.50 mmol) and dry THF (2 mL) were added dropwise, and the reaction was stirred
for a further 4 h. The reaction was quenched with saturated aqueous NH4Cl (0.5 mL)
and warmed to ambient temperature. The mixture was transferred to a separatory
funnel and saturated aqueous NH4Cl (15 mL) was added. The phases were separated,
and the water phase was extracted with EtOAc (3 ꢂ 15 mL). The organic phases were
combined, washed with brine (15 mL), dried (MgSO4), and evaporated in vacuo. The
residue was purified by flash chromatography, eluting with 0–100% EtOAc in hexane
to give compounds 3e–3g.
8-Chloro-9-(cyclohexylmethyl)-9H-purin-6-amine (3e)
Yield 90 mg (68%), mp 229–230 ꢁC, colorless powdery crystals. 1H NMR
(DMSO-d6, 400 MHz) 8.13 (s, 1H, H-2), 7.36 (s, 2H, NH2), 3.96 (d, J ¼ 7.4 Hz,
2H, NCH2), 1.87 (ddd, J ¼ 10.9, 7.4, 3.5 Hz, 1H, CH in c-hex), 1.75 ꢀ 1.30 (m, 5H,
c-hex), 1.13 ꢀ 0.99 (m, 5H, c-hex); 13C NMR (DMSO-d6, 150 MHz) 154.8 (C-6),
152.9 (C-2), 150.6 (C-4), 136.8 (C-8), 117.4 (C-5), 48.7 (NCH2), 37.1 (CH in
c-hex), 29.9 (CH2 in c-hex), 25.7 (CH2 in c-hex), 25.0 (CH2 in c-hex); MS EI m=z
(rel. %) 267=265 (2=8, Mþ), 230 (100), 185=183 (7=21), 184=182 (8=19), 171=169
(14=43), 148 (15), 142 (8). HRMS Found 265.1098, calculated for C12H16ClN5
265.1094.
N-Alkylation of 8-Oxoadenines: 6-Amino-9-(cyclohexylmethyl)-7H-
purin-8(9H)-one (4b)
A mixture of 8-oxoadenine (5) (128 mg, 0.847 mmol) and K2CO3 (238 mg,
1.73 mmol) in dry DMF (5 mL) was stirred under N2 at 50 ꢁC for 20 min. (Bromo-
methyl)cyclohexane (0.14 mL, 1.013 mmol) was added, and the mixture was stirred
at 70 ꢁC for 24 h. The mixture was filtered, and the solvent was evaporated in vacuo.
The residue was purified by flash chromatography (see method A); yield 51 mg
1
(28%), mp 287–289 ꢁC, colorless powdery crystals. H NMR (DMSO-d6, 300 MHz)
10.11 (s, 1H, NH), 8.00 (s, 1H, H-2), 6.39 (s, 2H, NH2), 3.55 (d, J ¼ 7.3 Hz, 2H,
NCH2), 1.80 (ddd, J ¼ 10.7, 7.3, 3.4 Hz, 1H, CH in c-hex), 1.63 ꢀ 1.51 (m, 5H,
c-hex), 1.32 ꢀ 0.74 (m, 5H, c-hex); 13C NMR (DMSO-d6, 75 MHz) 152.3 (C-8),
150.9 (C-2), 147.8 (C-4), 146.5 (C-6), 103.1 (C-5), 45.1 (NCH2), 36.3 (CH in c-hex),
30.1 (CH2 in c-hex), 25.9 (CH2 in c-hex), 25.1 (CH2 in c-hex); MS EIm=z (rel. %)
247 (48, Mþ), 231 (49), 165 (53), 151 (100), 136 (31). HRMS found 247.1422, calcu-
lated for C12H17N5O 247.1433.

SYNTHESIS OF 8-OXOADENINES
1475
Hydrolysis of 8-Haloadenines: 6-Amino-9-(cyclohexylmethyl)-7H-
purin-8(9H)-one (4b)
A mixture of 9-(cyclohexylmethyl)-8-bromoadenine (3b) (129 mg, 0.42 mmol)
in concentrated HCO2H (10 mL), or of 9-(cyclohexylmethyl)-8-chloroadenine (3e)
(180 mg, 0.678 mmol) in concentrated HCO2H (20 mL), was stirred at reflux for
16 h. The HCO2H was co-evaporated with water (3 ꢂ 20 mL), and the residue was
dried in vacuo. The product was purified by flash chromatography, eluting with
3–5% MeOH in CH2Cl2; yield 199 mg (78%) from 3b and 151 mg (90%) from 3e.
Synthesis of 8-Oxo-adenines from 6-Chloro-8-oxopurines: 6-Amino-
9-phenyl-7H-purin-8(9H)-one (4d)
6-Chloro-9-phenyl-7H-purin-8(9H)-one (11) (249 mg, 1.01 mmol) and para-
methoxybenzylamine (0.55 mL, 4.2 mmol) were refluxed in n-butanol (20 mL) for
24 h. The solvent was evaporated in vacuo, and the residue was purified by flash
chromatography (see method A); yield 345 mg of crude compound 12, which was
heated in TFA (5 mL) at 60 ꢁC for 2 h. The acid was evaporated in vacuo, and the
residue was purified by flash chromatography eluting with 0–10% MeOH in CH2Cl2;
yield 171 mg (75% from 3g), mp 300 ꢁC (dec.; lit.[14] > 300 ꢁC), colorless powdery
crystals. NMR and MS data were in good agreement with those reported before.[14]
N-Alkylation of Adenine: 9-(Cyclohexylmethyl)-9H-purin-6-amine
(6b) and 3-(Cyclohexylmethyl)-3H-purin-6-amine (7b)
A mixture of adenine (1) (135 mg, 1.00 mmol) and K2CO3 (314 mg, 2.28 mmol)
in dry DMF (5 mL) was stirred under N2 at 65 ꢁC for 30 min. (Bromomethyl)cyclo-
hexane (0.21 mL, 1.5 mmol) was added and the mixture was stirred for 72 h. The
mixture was filtered, and the solvent was evaporated in vacuo. The residue was
purified by flash chromatography, eluting with 0–10% MeOH in CH2Cl2; yield
720 mg (70%) of 6b and 30 mg (13%) of 7b.
9-(Cyclohexylmethyl)-9H-purin-6-amine (6b). Mp 224–226 ꢁC, colorless
1
powdery crystals. H NMR,[26] 13C NMR,[27] and MS[27] data were in good agree-
ment with those reported before.
3-(Cyclohexylmethyl)-3H-purin-6-amine (7b). Mp 220–252 ꢁC, colorless
1
powdery crystals. H NMR (DMSO-d6, 600 MHz) 8.29 (s, 1H, H-2), 7.98 (br s,
1H, HA in NH2), 7.92 (br s, 1H, HB in NH2), 7.77 (s, 1H, H-8), 4.12 (d, J ¼ 7.4 Hz,
Hz, 2H, NCH2), 2.01 (dtt, J ¼ 15.0, 7.5, 3.8 Hz, CH in c-hex), 1.63 ꢀ 1.45 (m, 5H,
c-hex), 1.10 ꢀ 0.97 (m, 5H, c-hex); 13C NMR (DMSO-d6, 150 MHz) 155.0 (C-6),
152.3 (C-2), 149.8 (C-4), 143.9 (C-8), 120.2 (C-5), 55.1 (NCH2), 36.4 (CH in
c-hex), 29.8 (CH2 in c-hex), 25.9 (CH2 in c-hex), 25.1 (CH2 in c-hex); MS EIm=z
(rel. %) 231 (72, Mþ), 188 (12), 149 (100), 148 (76), 136 (22), 135 (80), 108 (15).
HRMS found 231.1479; calculated for C12H17N5 231.1484.

1476
H.-S. M. SIAH AND L.-L. GUNDERSEN
ACKNOWLEDGMENT
The Norwegian Research Council is gratefully acknowledged for partial finan-
cing of the Bruker Avance instruments used in this study.
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