Trifluoroethanol solvent facilitates selective N-7 methylation of purines

Article abstract of DOI:10.1039/c3ob27473j

Purines protected at N-9 by p-methoxybenzyl are methylated or ethylated in 2,2,2-trifluoroethanol at N-7 by trimethyl- or triethyl-oxonium borofluorate, respectively. Subjecting the resulting cationic species to microwave irradiation releases an N⁷

Full text of DOI:10.1039/c3ob27473j

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Trifluoroethanol solvent facilitates selective
N-7 methylation of purines†
Cite this: Org. Biomol. Chem., 2013, 11,
1874
Honorine Lebraud, Celine Cano, Benoit Carbain, Ian R. Hardcastle,
Ross W. Harrington, Roger J. Griffin* and Bernard T. Golding*
Received 20th December 2012,
Accepted 29th January 2013
Purines protected at N-9 by p-methoxybenzyl are methylated or ethylated in 2,2,2-trifluoroethanol at N-7
by trimethyl- or triethyl-oxonium borofluorate, respectively. Subjecting the resulting cationic species to
microwave irradiation releases an N7-methyl- or ethyl-purine. This one-pot procedure is an efficient
regiospecific method applicable to diverse substrates.
DOI: 10.1039/c3ob27473j
www.rsc.org/obc
In a drug discovery program aimed at developing inhibitors1,2 exposure to alkylating agents.13 Such genotoxic lesions, if not
of the Nek2 kinase,3–5 we required a series of purines in which repaired,14 lead to depurination of DNA.15,16 Among the alky-
N-7 was methylated or ethylated. Such compounds lack a key lating agents are S-adenosylmethionine, a ubiquitous cellular
component (N9-H) of the donor–acceptor–donor motif (2-NH, component, as well as xenobiotic toxins, e.g. the methyldi-
N-3 and N9-H) characteristic of many purine kinase inhibitors, azonium ion derived from nitrosoamines found in tobacco
which enables the formation of a triplet of hydrogen bonds and contributory to lung cancer,17 as well as other methylating
between the heterocycle and ATP-binding domain of the agents.18 The common way to methylate guanine residues in
kinase.6 Alkylation of N-7 removes the hydrogen atom at N-9 DNA selectively at the N-7 position uses dimethyl sulfate, as in
and abolishes one hydrogen bond donor. We reasoned that the Maxam–Gilbert procedure for DNA sequencing.19
achieving selectivity amongst the several hundred known
Kohda et al.20 methylated N-7 with MeI, whilst N-9 was pro-
kinases7,8 might be possible with N-7 alkylated purines pro- tected by a ribose moiety, which was subsequently cleaved by
vided the alkyl group was small and despite the loss of one acidic hydrolysis. However, only one example of this method
hydrogen bond. In this paper we describe a versatile and was provided for the purine scaffold. Moreover, acidic con-
efficient method to synthesise N7-methyl- and N7-ethyl- ditions can be problematic for certain functionalities such as
purines.
the cyano group. Similar strategies have been described in
The most common method for synthesising alkylated which the N-9 protecting group is acetyl,21 diphenylmethyl,22
purines is by the direct reaction with an alkylating agent, e.g. trimethylsilyl,23 trityl24 or a solid-supported 2-(alkoxycarbonyl)-
iodomethane (MeI with K2CO3 or NaH10) or diazomethane.11 ethyl moiety.25 In a related approach Kotek et al.26,27 protected
9
The regioselectivity of this method usually favours N-9 alkyl- N-9 with t-butyloxycarbonyl (BOC) and then reduced the imida-
ation, with the N-7 isomer representing only ∼20% of the N-7/ zole ring prior to alkylating N-7. Finally, N-9 was deprotected
N-9 mixture. However, rare cases are known where alkylation with trifluoroacetic acid (TFA) and the 7,8-dihydropurine was
at N-7 is the exclusive outcome, e.g. from reaction of N6- re-oxidised. Despite selective N-7 alkylation being achieved in
[(dimethylamino)methylene]adenine with 1,1,1-trifluoro-2- good yields, this 5-step procedure is compromised by the
iodo-ethane in the presence of NaH in tetrahydrofuran.12
instability of the reduced purine, especially when electron-
Several methods for accessing N7-alkylated purines have donating groups are present, which limits the substitution
been devised based on transient protection at N-9. This possible at the 2- and 6-positions. In a different approach,
approach mimics N-7 alkylation of guanine residues in DNA, Dalby et al.28 coordinated methyl(aquo)cobaloxime to purine
which is a common DNA damaging process arising from N-3, thereby creating a hydrogen bond between N-9 and the
dimethylglyoximato oxyanion. The complex thus formed pre-
vented attack on N-9 and directed alkylation to N-7. However,
this strategy had limited application, with the reaction only
being performed on 6-chloropurine and 2,6-dichloropurine,
and failing with 2-amino-6-chloropurine.
Regardless of the methods described above, a mild, general
and selective process for achieving N-7 over N-9 alkylation of
purines has not been developed to date. To obtain
Newcastle Cancer Centre, Northern Institute for Cancer Research, School of
Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU,
United Kingdom. E-mail: bernard.golding@newcastle.ac.uk;
Fax: +44 (0)191 2226929; Tel: +44 (0)191 2226647
†Electronic supplementary information (ESI) available. CCDC 905716. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob27473j
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N7-methylpurines selectively, we have devised a new biomi-
metic method for which trimethyloxonium tetrafluoroborate
was selected as methylating agent, owing to its ease of hand-
ling compared to other reagents (MeI, Me2SO4, methyl trifluoro-
methanesulfonate). p-Methoxybenzyl (PMB) was chosen as a
more practical protecting group for N-9 of a purine, compared
with other groups (see above). For the methylation of N9-PMB-
protected purines, 2,2,2-trifluoroethanol (TFE)29 was employed
because of its several advantages over any other solvent:
(i) ability to solubilise numerous polar compounds, in this
case both trimethyloxonium tetrafluoroborate and the purine;
(ii) non-nucleophilic character avoiding any interference with
the highly reactive trimethyloxonium species; (iii) slightly
acidic character (TFE pKa 12.4),30 which may assist the PMB
deprotection after N-7 methylation; (iv) suitability for heating
with microwave irradiation. We have already exploited the
manifold distinctive properties of TFE to facilitate SNAr reac-
tions in purines and other heterocycles.31,32
Scheme 1 PMB protection of 2-amino-6-chloropurine (1).
Table 2 Selective N-7 methylation of 9-tetrahydropyranyl-purines
Starting material
X
Y
Product
Isolated yield [%]
5a
5b
H
F
F
6a
4l
57
41
TIPS–u
To validate this approach for selective N7-methylation of
purines, our new conditions were applied as a one-pot process
to a range of 2,6-disubstituted purines (Table 1). The common
starting material for entries 3a–3l was synthesised by PMB pro-
tection of 2-amino-6-chloropurine (1) [reaction with 4-methoxy-
benzyl chloride in the presence of Cs2CO3 in
dimethylformamide: Scheme 1].33 Diversity at the 6-position
was introduced using either cyanation in the presence of 1,4-
diazabicyclo[2.2.2]-octane,34 by an SNAr reaction,35 or by Sono-
gashira coupling.36 At the 2-position, iodination37 and
fluorination35 were performed on the amino group. Cyana-
tion38 and addition of an amino side chain (Table 1, entry 3c)
by Buchwald coupling39 were carried out on the 2-iodo deriva-
tives. The alternative starting material 5a (Table 2) was syn-
thesised by protection of 2-fluoro-6-chloropurine with
tetrahydropyranyl (THP) group.40
a
The one-pot process offers moderate to good overall yields
(42–73%) of pure products when PMB is used as an N-9 pro-
tecting group. With the new conditions, synthetically challeng-
ing compounds that are N7-methylated were obtained in very
satisfactory yields. There is high tolerance towards steric hin-
drance (Table 1, entries 3e–3g and 3j–3l) and the method is
clearly an improvement for the selective N7-methylation of
purines. Note that methylation of 2-amino-6-cyanopurine with
MeI only afforded the N-9 regioisomer, whereas methylation of
3a with trimethyloxonium tetrafluoroborate in TFE led to the
N-7 regioisomer 4a.
Table 1 Selective N-7 methylation of diverse 9-(4-methoxybenzyl)-purines
In one case (3d), addition of TFA to TFE was required to
effect the deprotection of the PMB group. Pappo and
Kashman22 investigated PMB as a potential protecting group
for purine N-7, but found it difficult to remove selectively
under acidic conditions. By the use of microwave heating in
TFE, we have solved this problem.
Starting
material
Isolated
Product yield [%]
X
Y
3a
3b
3c
CN
CN
CN
NH2
I
4a
4b
4c
65
66
56
The method was also investigated with THP instead of PMB
as protecting group. With THP, it appeared that methylation
was sufficient to trigger the deprotection and microwave
heating was not required (Table 2). However, the THP group is
less stable than PMB under the reaction conditions and this
led to by-products that caused difficult purifications and there-
fore lower yields.
3da,b
3e
Cl
NH2
NH2
4d
4e
68
60
3f
I
4f
45
70
3g
CN
4g
Using the process described, three compounds were
3h
3i
3j
3k
3l
OEt
OEt
TIPS–u
TIPS–u
TIPS–u
NH2
I
NH2
I
4h
4i
4j
4k
4l
66
73
43
58
42
obtained from
a common intermediate, 2-(3-((6-cyano-9-
(4-methoxybenzyl)-9H-purin-2-yl)amino)phenyl)acetamide (7)
(Scheme 2). N7-Methylated compound 4c was isolated in good
yield following the procedure developed, whereas the
N9-methylated compound 9 was obtained using a standard
methylation procedure starting from 2-(3-((6-cyano-9H-purin-2-
F
a 10% TFA in TFE was required for the deprotection step. b The TFA
salt was obtained; TIPS = triisopropylsilyl.
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and angles were within expected ranges, whilst weak intermo-
lecular C–H⋯N interactions to N-3 and N-9 linked the mol-
ecules of 4f into a 1-dimensional non-bonded tape.
Conclusions
We have established a rapid and convenient one-pot process
for the selective N-7 methylation and ethylation of purines.
This method, which generally gives good yields, can be
applied to a wide range of purine substrates having different
groups either at the 2- or 6-positions. The presence of a small
alkyl group at the N-7 position of the purine, in tandem with
deletion of N9-H, may be useful in drug discovery, as we have
suggested in the context of designing inhibitors of kinases.
Several existing drugs and natural products contain an alkyl
group at the N-7 position of a purine. These include agel-
asines, 7,9-dialkylpurinium salts isolated from a marine source,
which have a diterpenoid chain at the N-7 position and exhibit
anti-mycobacterial activity.41 Asmarines are also marine
natural products, which are 7-substituted purines with anti-
tumour properties.22 Another example is the 7-methylpurin-
8-ones, which possess affinity for corticotropin releasing
hormone receptor 1, secretion of which is linked with neuro-
psychiatric diseases.42
Scheme 2 Synthetic approach to N-7 and N-9 methylated purines.
Table 3 Selective N-7 ethylation of 9-(4-methoxybenzyl)-purines
Starting material
X
Y
Product
Isolated yield [%]
3a
3e
CN
NH2
NH2
10a
10b
28
40
Varying the substituents at the 2, 6, and 8 positions, as well
as the N-7 and N-9 positions of purines, is key to the develop-
ment of new small molecule chemotherapeutic agents. This
paper presents an efficient solution to the problem of selective
methylation and ethylation at N-7.
3h
3j
OEt
TIPS–u
NH2
NH2
10c
10d
58
0
Experimental section
General information
1H, 19F and 13C nuclear magnetic resonance (NMR) spectra
were obtained as DMSO-d6 solutions and recorded at
500 MHz, 470 MHz and 125 MHz, respectively, on a Bruker
Avance III 500 spectrometer. Chemical shifts are reported in
parts per million (δ) referenced to the appropriate deuterated
solvent employed. Multiplicities are indicated by s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), b (broad) or
combinations thereof. LCMS was carried out on a Waters
Acquity SQD operating in positive and negative ion electro-
spray mode, employing a 50 × 2.1 mm, Waters Acquity UPLC
BEH C18, 1.7 μm column and a 1.5 min gradient elution of
0.1% formic acid and acetonitrile (5–95%) running at a flow
rate of 0.6 mL min−1. High resolution mass spectrometry were
measured using a Finnigan MAT 95 XP or a Finnigan MAT 900
XLT by the EPSRC National Mass Spectrometry Service Centre,
University of Wales (Swansea), Singleton Park, Swansea, SA2
8PP. Infrared (IR) spectra were recorded on a Bio-Rad FTS
3000MX diamond ATR as a neat sample. UV spectra were
obtained using a U-2001 Hitachi Spectrophotometer with the
sample dissolved in ethanol. Thin layer chromatography for
monitoring reaction progress was conducted on plates
Fig. 1 View of the molecular structure of 4f with 50% probability displace-
ment ellipsoids.
yl)amino)phenyl)acetamide (8). These results demonstrate
further the utility of our method for selective N-7 methylation.
In an extension to the method, trimethyloxonium tetra-
fluoroborate was replaced by triethyloxonium tetrafluoro-
borate, which enabled selective N7-ethylation (Table 3). By
comparison with methylation, ethylation appears to be more
difficult when a cyano group is at the purine 6-position
(Table 1, 3a compared to Table 3, 3a), whilst steric factors pre-
vented ethylation when a TIPS-ethynyl group was at C-6
(Table 3, 3j).
Product structures were confirmed by analytical and spectro-
scopic techniques including an X-ray crystal structure of com-
pound 4f (Fig. 1). The purine system is essentially planar and
the cyclohexyl ring has a chair conformation; bond lengths
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pre-coated with silica gel (Merck 60F254). The eluent was as
2-Fluoro-7-methyl-6-((triisopropylsilyl)ethynyl)-7H-purine
stated (where this consisted of more than one solvent, the (4l). The title compound was synthesised following general
ratio is stated as volume : volume) and visualisation was by procedure B using 2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-6-((tri-
ultraviolet light. The products were purified by medium isopropylsilyl)ethynyl)-9H-purine 5b (150 mg, 0.37 mmol) and
pressure liquid chromatography (MPLC), using the Varian trimethyloxonium tetrafluoroborate (54 mg, 0.37 mmol). The
automated purification system. All commercial reagents and crude product was purified by MPLC on silica (DCM : MeOH
solvents were purchased from reputable suppliers. The chemi- 95 : 5) to give the product 4l as a yellow solid (51 mg,
cals were of the highest available purity and were used as sup- 0.15 mmol, 42%); mp 97–99 °C; Rf 0.18 (petrol : EtOAc 60 : 40);
plied unless otherwise stated. Anhydrous solvents were stored 1H NMR (500 MHz, DMSO-d6) ppm 1.13–1.18 (21H, m, 3 × CH
under nitrogen. Petrol refers to the fraction with a boiling (CH3)2), 4.11 (3H, s, NCH3), 8.79 (1H, s, H-8); 13C NMR
point between 40 and 60 °C. Reactions needing microwave (125 MHz, DMSO-d6) ppm 10.6, 18.3, 33.2, 99.9, 102.4, 124.7
irradiation were carried out in a Biotage Initiator™ Sixty (J = 4 Hz), 133.8 (J = 18 Hz), 153.4, 157.0 (J = 207 Hz), 164.0; 19
reactor.
F
NMR (470 MHz, DMSO-d6) ppm −52.58; IR (cm−1) 2940, 2870,
1560, 1460, 1430, 1295; λmax 310 nm (in EtOH); HRMS (ES+)
m/z 333.1911 [M + H]+ (calcd for C17H25N4FSi 333.1905).
6-Ethoxy-7-ethyl-7H-purin-2-amine (10c). The title com-
pound was synthesised following general procedure C using
6-ethoxy-9-(4-methoxybenzyl)-9H-purin-2-amine 3h (90 mg,
0.30 mmol) and triethyloxonium tetrafluoroborate (57 mg,
Caution
Trifluoroethanol should only be used in an efficient fume-cup-
board and the operator should wear protective ‘nitrile’ gloves.
General procedure A
The 9H-purine-6-carbonitrile (67 mg, 0.16 mmol) and tri- 0.30 mmol). The reaction was heated for 10 min at 100 °C. The
methyloxonium tetrafluoroborate (28 mg, 0.19 mmol) were crude product was purified by MPLC on silica (DCM : MeOH
solubilised in TFE (2 mL). The resulting solution was stirred at 90 : 10) to give the product 20 as a colourless oil (36 mg,
room temperature for 2 hours. The reaction was purged with 0.17 mmol, 58%); mp 159 °C; Rf 0.43 (DCM : MeOH 90 : 10); 1H
nitrogen, sealed and heated under microwaves at 100 °C. The NMR (500 MHz, DMSO-d6) 1.36–1.39 (6H, m, 2 × CH3), 4.20
solvent was removed in vacuo and the crude product was puri- (2H, q, J = 7.2 Hz, OCH2), 4.46 (2H, q, J = 7.1 Hz, OCH2), 6.18
fied as indicated.
(2H, s, ArNH2), 8.11 (1H, s, H-8); 13C NMR (125 MHz, DMSO-
d6) ppm 14.4, 16.4, 41.7, 61.7, 105.6, 144.7, 156.7, 159.4, 163.2;
IR (cm−1) 3451, 3178, 2828, 1569, 1382, 1255; λmax 258 nm (in
General procedure B
The 9-(tetrahydro-2H-pyran-2-yl)-9H-purine (100 mg, 0.45 mmol) EtOH); HRMS (ES+) m/z 208.1191 [M + H]+ (calcd for C9H13ON5
and trimethyloxonium tetrafluoroborate (80 mg, 0.54 mmol) were 208.1193).
solubilised in TFE (2 mL). The resulting solution was stirred at
room temperature for 2 hours. The solvent was removed in vacuo
and the crude product was purified as indicated.
For compounds 4a–h,j,k, 6a and 10a–c see the ESI.†
Crystal data for 4f. C13H17IN4O, M = 372.21, monoclinic,
space group P21/c, a = 20.6041(14), b = 10.2213(6), c = 6.8832(5)
Å, β = 90.370(7)°, V = 1449.58(17) Å3, Z = 4, T = 150 K, 2784
reflections collected, merging of equivalent reflections pre-
General procedure C
The 9H-purine-6-carbonitrile (90 mg, 0.30 mmol) and triethyl- vented by twinning, R(F, F2 > 2s) = 0.0428, Rw(F2, all data) =
oxonium tetrafluoroborate (69 mg, 0.36 mmol) were solubil- 0.1115, goodness of fit = 1.064. CCDC 905716 contains the sup-
ised in TFE (3 mL). The resulting solution was stirred at room plementary crystallographic data for this paper.
temperature for 2 hours. The reaction was purged with nitro-
gen, sealed and heated under microwaves at 100 °C. The
solvent was removed in vacuo and the crude product was puri-
fied as indicated.
Acknowledgements
6-Ethoxy-2-iodo-7-methyl-7H-purine (4i). The title com- The authors thank Cancer Research UK for financial support
pound was synthesised following general procedure A using and the EPSRC National Mass Spectrometry Service at the
6-ethoxy-2-iodo-9-(4-methoxybenzyl)-9H-purine 3i (100 mg, University of Wales (Swansea) for mass spectrometric
0.24 mmol) and trimethyloxonium tetrafluoroborate (36 mg, determinations.
0.24 mmol). The reaction was heated for 10 min at 100 °C. The
crude product was purified by MPLC on silica (DCM : MeOH
98 : 2) to give the product 4i as a pale beige solid (55 mg,
Notes and references
0.19 mmol, 73%); mp 122–124 °C; Rf 0.84 (DCM : MeOH
1
90 : 10); H NMR (500 MHz, DMSO-d6) ppm 1.41 (3H, t, J = 7.1
Hz, CH3), 3.95 (3H, s, NCH3), 4.53 (2H, q, J = 7.1 Hz, OCH2),
8.38 (1H, s, H-8); 13C NMR (125 MHz, DMSO-d6) ppm 14.1,
33.8, 63.5, 117.4, 147.8, 155.8, 162.3; IR (cm−1) 2980, 1610,
1484, 1331, 1128; λmax 266 nm (in EtOH); HRMS (ES+) m/z
304.9899 [M + H]+ (calcd for C8H9ON4I 304.9894).
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