Synthesis and utility of 2-halo-O6-(benzotriazol-1-yl)- functionalized purine nucleosides

Article abstract of DOI:10.1002/ejoc.201001395

An efficient synthesis of 2-halo-O⁶-(benzotriazol-1-yl)- substituted purine nucleosides has been accomplished via (benzotriazol-1-yloxy) tris(dimethylamino)phosphonium hexafluorophosphate (BOP)-mediated coupling and subsequent halogenation via diazotization of the 2-amino group of various protected guanosines and directly from guanosine itself. These products are amenable to substitution and coupling reactions in the 2- and 6-positions and, accordingly, provide efficient access to highly functionalized purine nucleosides.

Full text of DOI:10.1002/ejoc.201001395

FULL PAPER
DOI: 10.1002/ejoc.201001395
Synthesis and Utility of 2-Halo-O6-(benzotriazol-1-yl)-Functionalized Purine
Nucleosides
Shane M. Devine[a] and Peter J. Scammells*[a]
Keywords: Nitrogen heterocycles / Nucleosides / Halogenation / Purines / Guanosines
An efficient synthesis of 2-halo-O6-(benzotriazol-1-yl)-substi-
tuted purine nucleosides has been accomplished via (benzo-
triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluoro-
tected guanosines and directly from guanosine itself. These
products are amenable to substitution and coupling reactions
in the 2- and 6-positions and, accordingly, provide efficient
phosphate (BOP)-mediated coupling and subsequent haloge- access to highly functionalized purine nucleosides.
nation via diazotization of the 2-amino group of various pro-
reactions. To this end, we strived towards a more stream-
lined approach to achieve these highly substituted adeno-
Introduction
Nitrogen-containing heterocycles are ubiquitous in na-
sine analogs.
ture, exhibit a wide and varied role in biological systems
For a number of years, the versatility and efficiency of
and are of great pharmaceutical importance, including pur-
phosphonium-mediated coupling of tautomerizable hetero-
ine nucleosides such as adenosines and guanosines. How-
cycles,[6] in particular nucleosides, has generated widespread
ever, syntheses of these compounds can be challenging and
attention.[7–12] Previous work by Lakshman et al.[11] as well
classically require multiple steps, often in a linear fashion,
as our group[3] has shown that it is possible to convert cer-
which reduces efficiency and does not lend itself to a con-
tain protected guanosine derivatives to the corresponding
vergent approach to drug discovery. Typically, these steps
include protection of functional groups, activation, func-
tionalization (via SNAr) and deprotection.
O6-(benzotriazol-1-yl)guanosines using BOP and DBU.
More specifically, TBS-protected guanosine was found to
undergo this conversion in 65% yield, while 2Ј,3Ј-isopro-
Previous work in our group has focused on the synthesis
pylidene-protected guanosine-5Ј-N-ethylcarboxamide gave
of highly substituted 2-, 6- and/or 5Ј-substituted adeno-
a 95% yield of the corresponding O6-(benzotriazol-1-yl) de-
sines, aimed at generating adenosine receptor (AR) agonists
rivative. However, this has not been achieved for unprotec-
more selective and/or potent at the four distinct receptor
ted guanosine until now. In a related study, Bae et al.[8] also
subtypes, A1, A2A, A2B and A3 receptors. This generally re-
showed that it was possible to generate O6-(benzotriazol-1-
quires numerous steps with incorporation of the 2-halo
yl)inosine without protection of the 2Ј-, 3Ј- and 5Ј-hydroxy
group occurring via stannylation[1] before nucleophilic sub-
groups in a yield of 53%. In all cases, these O6-(benzotri-
stitution can take place at the 6-position from either
azol-1-yl)purine nucleosides were demonstrated to be highly
versatile synthetic intermediates that readily underwent
substitution in the 6-position with a range of nucleophiles
and could also be elaborated further in the 2-position. In
chloro[2] or O6-(benzotriazol-1-yl)[3] moieties. However, pro-
tection of the hydroxy groups, as well as modifications to
the 5Ј-position of the ribose also needed to be undertaken
thereby increasing the sequence as well. Alternatively, we
this current study, our aim was to further explore the scope
have recently reported a more convergent approach utilising
and limitations of this chemistry. The requirement for ri-
a Vorbrüggen coupling strategy, whereby purine and sugar
bose protection and the efficiency of a range of protecting
moieties are independently functionalised before under-
groups were evaluated in the formation of the O6-(benzotri-
going glycosylation.[4,5] However, this method necessitated
azol-1-yl)guanosines 2a–f. The conversion of 2a–f to the
corresponding 2-halo derivatives 3–5 was also explored.
the presence of the 2-halo group in the starting purine and
greater degree of functionality resulted in often capricious
Results and Discussion
Our initial attempt to synthesize O6-(benzotriazol-1-yl)-
guanosine (2a) with BOP and DBU in MeCN was success-
ful, but proceeded in low yield (28%). This was due to poor
solubility and the majority of recovered material was unre-
[a] Medicinal Chemistry and Drug Action, Monash Institute of
Pharmaceutical Sciences, Monash University,
Parkville, 3052, Victoria, Australia
Fax: +61-3-9903-9582
E-mail: peter.scammells@monash.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001395.
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2-Halo-O6-(benzotriazol-1-yl)-Substituted Purine Nucleosides
acted guanosine. In a previous study on the conversion of atives were prepared as described previously,[3,13,14] except
Biginelli 3,4-dihydropyrimidin-2(1H)-one to pyrimidines in the case of 1e which was synthesized in an analogous
via PyBroP-mediated coupling, the choice of solvent was fashion to 1f.[3] Although, these reactions succeeded in
shown to have significant effect on the isolated yield.[6] Ac- NMP, higher yields were obtained when MeCN was used
cordingly, we explored the reaction of guanosine with BOP as the reaction solvent. The difference was particularly sig-
and DBU in a range of solvents and the results are reported nificant in the case of 2b (74% in NMP and 90% in MeCN)
in Table 1. This reaction proceeded in low yield in a number and 2e (55% in NMP and 92% in MeCN). Furthermore,
of the solvents and guanosine’s poor solubility was thought the use of MeCN facilitated the reaction work-up as it
to be a major factor in these outcomes. However, a modest could be easily evaporated under reduced pressure prior to
yield of 42% was obtained in DMF and a respectable yield a typical extractive work-up. Compounds 2b–2f were read-
of 59% was obtained when NMP was used as the solvent. ily taken up in an organic phase and were not observed in
Although the O6-(benzotriazol-1-yl)-substituted guanosine the aqueous phase, presumably due to the absence of the 2Ј-
(2a) was difficult to extract from NMP due to the water and 3Ј-hydroxy groups, therefore enhancing yields. Another
solubility of both species, this problem was largely over- attractive feature when using MeCN was evident in the pu-
come by submitting the crude reaction mixture directly to rification in that chromatography was not typically required
a silica column and eluting with a CH2Cl2/MeOH gradient (unlike the NMP method), and trituration with H2O (for
(1:0Ǟ9:1). This observation of aqueous uptake and poor 2b and 2d–2f) or Et2O (for 2a) routinely gave pure solids.
solubility of inosine was also noted by Bae et al.[8] This
A comparison of the commonly used ribose protecting
outcome is comparable to the previously reported reaction groups (acetyl, TBS and 2Ј,3Ј-isopropylidene), revealed that
between TBS-protected guanosine and BOP in the presence acetyl-protected guanosine 1b performed best. This sub-
of DBU (59% vs. 65% yield).[11]
strate gave a 90% yield of the desired product 2b, in com-
parison to yields of 75% and 78% for the TBS and 2Ј,3Ј-
isopropylidene guanosines, respectively. The 2Ј,3Ј-iso-
propylidene-protected guanosine-5Ј-N-alkylcarboxamides
1e and 1f also afforded the desired products in excellent
yield (92% and 95%, respectively).
Table 1. Results of the solvent effect for the BOP-mediated reaction
on 1.
With a series of 2-amino,O6-(benzotriazol-1-yl) com-
pounds 2a–2f prepared, a range of diazotization/halogena-
tion reactions were undertaken (Table 2).
Fluorination of the nucleosides 2 was achieved using a
HF in pyridine complex and tBuONO.[15] In the case of 1a,
the reaction was quite capricious and the best result was a
yield of 35% of 3a. This was most likely due to the presence
of the free hydroxy groups which invariably reduced the
yield. The 5Ј-hydroxy-containing 3d also resulted in a poor
yield (36%). Deprotection of TBS groups with the fluoride
ion is well known and subsequently reaction of 2c with HF
resulted in cleavage of the TBS groups as well as fluorina-
tion. However, 3b, 3e and 3f were all fluorinated in good to
high yields (59–88%).
Entry
R1
R2
Solvent
% Yield[a]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
H
H
H
H
H
H
H
H
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OAc
CH2OAc
CH2OTBS
CH2OTBS
CH2OH
CH2OH
CONHMe
CONHMe
CONHEt
MeCN
NMP
DBU
DMF
CH2Cl2
DCE
THF
dioxane
NMP
MeCN
NMP
MeCN
NMP
28
59
–
42
18
24
6
45
74
90
69
75
76
78
55
92
95[3]
The chlorination reaction to produce 4 using TMS-Cl[16]
worked well for the hydroxy protected guanosines 2b, 2c
and 2e, but failed for 2a and 2d. The yields were moderate
to high (72–96%), with the 5Ј-modified methylcarboxamide
(4e) giving the best result (96%). Changing the solvent from
CH2Cl2 to MeCN or using NaNO2 in aqueous HCl also
failed to produce the 2-chloro analogs, 2a and 2d. The pres-
ence of unprotected hydroxy groups (2a and 2d) was clearly
incompatible with this chlorination reaction. The iodinated
compounds 5 were produced using CH2I2 and tBuONO in
MeCN heated by microwave irradiation. All the protecting
groups were applicable to this reaction with yields ranging
from 56% (5a)–96% (5b). From the results observed, it was
possible to halogenate the unprotected guanosine 2a, how-
ever yields were greatly diminished in comparison to acetyl
9
1b Ac
10
11
12
13
14
15
16
17
1b Ac
1c TBS
1c TBS
1d 2Ј,3Ј-IP[b]
1d 2Ј,3Ј-IP
1e 2Ј,3Ј-IP
1e 2Ј,3Ј-IP
1f 2Ј,3Ј-IP
MeCN
NMP
MeCN
MeCN
[a] Isolated yield after chromatography. [b] IP = isopropylidene.
We proceeded to investigate the reaction of a number of (2b), TBS (2c) or amide (2e–2f) protection and only repro-
protected/modified guanosines (1b–1f) with BOP and DBU ducible in the case of 5a. Once again, acetyl protecting
in both NMP and MeCN (Table 1). These guanosine deriv- groups gave the best results, affording yields of 88%, 94%
Eur. J. Org. Chem. 2011, 1092–1098
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. M. Devine, P. J. Scammells
FULL PAPER
Table 2. Halogenation reactions of 2a–2f.
Scheme 1. Formation of CCPA (6).
iodination and TBS removal. 6-Chloropurine riboside was,
in turn, prepared from inosine[19] in three steps and 90%
yield (eight steps and 20.4% overall). Applying our method
from the inexpensive guanosine 1a achieves an overall yield
of 31.4% in 3 steps, eliminating the toxic by-products of
tin, amongst other things.
Entry
R1
R2
Method[a]
% Yield[b]
35
1
2
3
4
5
6
7
8
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
2e
2e
2e
2f
H
H
H
CH2OH
CH2OH
CH2OH
CH2OAc
CH2OAc
CH2OAc
CH2OTBS
CH2OTBS
CH2OTBS
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
C
[c]
–
56
88
94
96
Ac
Ac
Ac
TBS
TBS
TBS
[c]
–
72
68
36
9
10
11
12
13
14
15
16
17
2Ј,3Ј-IP[d] CH2OH
[c]
2Ј,3Ј-IP
2Ј,3Ј-IP
2Ј,3Ј-IP
2Ј,3Ј-IP
2Ј,3Ј-IP
2Ј,3Ј-IP
2Ј,3Ј-IP
CH2OH
CH2OH
CONHMe
CONHMe
CONHMe
CONHEt
CONHEt
–
Scheme 2. Synthesis of 2-iodo-N6-(endo-norborn-2-yl)adenosine
(7).
72
74
96
77
59[3]
76[3]
2f
Conclusions
[a] Method A: HF/pyridine, tBuONO; Method B: TMS-Cl,
tBuONO; Method C: CH2I2, tBuONO. [b] Purified yield after col-
umn chromatography. [c] Resulted in decomposition. [d] IP = iso-
propylidene.
In conclusion, we have synthesised the first reported syn-
thesis of unprotected O6-(benzotriazol-1-yl)guanosine (2a)
via a BOP/DBU-mediated reaction and have shown the util-
ity of this on protected versions 2b–2e of guanosine. In ge-
and 96% of the 2-fluoro, 2-chloro and 2-iodo derivatives neral, the protected O6-(benzotriazol-1-yl)guanosines 2b–2e
3b, 4b and 5b.
gave higher yields of halogenated products in comparison
To illustrate the applicability of these intermediates to the unprotected guanosine 2a. The O6-(benzotriazol-1-
towards our ultimate goal of forming selective and effi- yl)-substituted guanosines 2 are versatile synthetic interme-
cacious adenosine analogs we chose to synthesise 2-chloro- diates that can be readily elaborated into highly function-
N6-cyclopentyladenosine (CCPA)[17] (6) (Scheme 1) and 2- alized purine ribosides. A range of nucleophiles can substi-
iodo-N6-(endo-norborn-2-yl)adenosine[1] (7). The only re- tute at the 6-position to generate a considerable library of
ported synthesis by Jagtap et al. of CCPA was from 2Ј,3Ј,5Ј- compounds. Further derivatization of the 2-amino group to
triacetoxy-2,6-dichloropurine riboside using excess cyclo- corresponding fluoro (3), chloro (4) or iodo (5) moieties has
pentylamine to give CCPA (6) in 76% yield. Typically the been demonstrated by diazotization and nucleophilic attack
2,6-dichloro analogue is obtained in
3 steps from of the halide, typically in good yield. The use of various
guanosine, via acetylation and chlorination reactions with protecting groups on the ribose moiety demonstrates the
[18]
POCl3, 3-methyl-1-nitro-1-butene and CCl4
or by ability to incorporate 5Ј-modified analogs. The 2-fluoro
Vorbrüggen attachment of 2,6-dichloropurine and 1,2,3,5- group is amenable to SNAr processes, the 2-iodo to a wide
tetra-O-acetyl-β-d-ribofuranose.[5] In our hands, CCPA (6) range of coupling reactions. Therefore, there is wide scope
was obtained in 84% yield from the 2Ј,3Ј,5Ј-tri-O-acetyl- for derivatization of these synthetically useful intermediates
O6-(benzotriazol-1-yl)-2-chloroinosine (4b) by reaction with to generate a large variety of analogs. These various 2-
cyclopentylamine and subsequent treatment with NH3.
halo,O6-(benzotriazol-1-yl)-substituted purine nucleosides
Hutchinson, et al.[1] previously required 5 steps to produce 3–5 are now in the process of being elaborated to generate
2-iodo-N6-(endo-norborn-2-yl)adenosine (7) (Scheme 2) from novel adenosine analogs with anticipated greater selectivity
6-chloropurine riboside in a yield of 22.6%, This sequence and efficacy over the different adenosine receptors (AR),
included TBS protection, stannylation, N6-substitution, with reduced synthetic steps and greater overall yields.
1094
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Eur. J. Org. Chem. 2011, 1092–1098

2-Halo-O6-(benzotriazol-1-yl)-Substituted Purine Nucleosides
+
156.8, 158.8, 159.4 ppm. HR-ESMS calcd. for C16H17N8O5 [M +
H] 401.1316, found 401.1329.
Experimental Section
General Methods: Melting points were determined on an Electro-
thermal melting point apparatus and are uncorrected. All micro-
wave reactions took place in a Biotage Initiator Microwave Syn-
thesiser. All NMR spectra were recorded on a Bruker Avance III
400-MHz Ultrashield Plus spectrometer and 1H and 13C NMR
spectra were recorded at 400.13 and 100.62 MHz, respectively.
Thin-layer chromatography was conducted on 0.2 mm plates using
Merck silica gel 60 F254. Column chromatography was achieved
using Merck silica gel 60 (article size 0.063–0.200 μm, 70–
230 mesh). High resolution mass spectra were obtained on a Waters
LCT Premier XE (TOF) mass spectrometer fitted with an ESI ion
source, coupled to a 2795 Alliance Separations Module. LCMS
were routinely run to verify reaction outcome using an Agilent
6100 Series Single Quad coupled to an Agilent 1200 Series HPLC.
All compounds were of Ͼ 95% purity. 2Ј,3Ј,5Ј-Tri-O-acetyl-
guanosine (1b),[13] 2Ј,3Ј,5Ј-O-(tert-butyldimethylsilyl)guanosine
(1c),[14] 2Ј,3Ј-O-isopropylideneguanosine (1d)[3] and 2Ј,3Ј-O-iso-
propylideneguanosine-5Ј-N-ethylcarboxamide (1f)[3] were synthe-
sised as previously published. Guanosine (1a) was purchased from
Sigma–Aldrich.
2Ј,3Ј,5Ј-Tri-O-acetyl-O6-(benzotriazol-1-yl)guanosine (2b): To
a
mixture of 2Ј,3Ј,5Ј-tri-O-acetyl-O6-(benzotriazol-1-yl)guanosine
(1b) (1.00 g, 2.44 mmol, 1 equiv.), BOP (1.62 g, 3.66 mmol,
1.5 equiv.) in MeCN (10 mL) was added DBU (913 μL, 6.11 mmol,
2.5 equiv.) dropwise and stirred at 25 °C for 16 h. The resultant
solution was then evaporated under reduced pressure to give an
orange gum. This was taken up in EtOAc (100 mL) and washed
with H2O (100 mL). The aqueous phase was then re-extracted with
EtOAc (100 mL). The combined organic fractions were then
washed with H2O (3ϫ50 mL) and satd. NaCl (2ϫ10 mL), dried
with MgSO4, filtered and the filtrate evaporated under pressure to
give a foam (1.35 g). H2O (500 mL) was added and the mixture was
filtered, washed with H2O to give (2b) as a colourless solid (1.16 g,
1
90%); m.p. 115–118 °C (dec.) H NMR (CDCl3): δ = 2.08 (s, 3 H,
CH3), 2.11 (s, 3 H, CH3), 2.13 (s, 3 H, CH3), 4.37 (dd, J = 13.0,
6.1 Hz, 1 H, 5Ј-H), 4.42–4.48 (m, 2 H, 4Ј-H, 5Ј-H), 4.94 (br. s, 2
H, NH2), 5.76 (t, J = 5.0 Hz, 1 H, 3Ј-H), 5.97 (t, J = 5.1 Hz, 1 H,
2Ј-H), 6.04 (d, J = 4.8 Hz, 1 H, 1Ј-H), 7.42–7.56 (m, 3 H, Ar-H),
7.87 (s, 1 H, 8-H), 8.11 (dt, J = 8.4, 0.9 Hz, 1 H, Ar-H) ppm. 13C
NMR (CDCl3): δ = 20.6, 20.7, 20.9, 63.1, 70.6, 72.9, 80.1, 86.8,
109.0, 113.9, 120.5, 124.9, 128.8, 129.0, 140.5, 143.5, 155.7, 158.9,
2Ј,3Ј-O-Isopropylideneguanosine-5Ј-N-methylcarboxamide (1e):[20]
Methyl 2Ј,3Ј-O-isopropylideneguanosine-5Ј-carboxylate[3] (1.00 g,
2.85 mmol) was suspended in a mixture of MeOH/DMF (9:1)
(10 mL) and 2.0 m MeNH2 in THF (8 mL) was added. The mixture
+
159.9, 169.5, 169.7, 170.7 ppm. HR-ESMS calcd. for C22H23N8O8
[M + H] 527.1633, found 527.1630.
O6-(Benzotriazol-1-yl)-2Ј,3Ј,5Ј-tri-O-(tert-butyldimethylsilyl)guan-
was heated in a 10–20 mL Biotage vial in the microwave at 100 °C osine (2c):[11] Same procedure as for 2b, from 1c, (petroleum ether/
for 2 h. The solution was then evaporated at reduced pressure to
give a yellow gum. To this, was added Et2O (200 mL) and a white
precipitate formed, which was filtered, washed with Et2O and dried
EtOAc, 4:1 Rf = 0.23) to give 2c as a colourless solid (856 mg,
75%); m.p. 157–160 °C (dec.) 1H NMR (CDCl3): δ = –0.11 (s, 3
H, SiCH3), 0.01 (s, 3 H, SiCH3), 0.10 (s, 3 H, SiCH3), 0.11 (s, 3 H,
to give 1e (1.00 g, 100%) as a white solid; m.p. 140–142 °C (dec.) SiCH3), 0.15 (s, 3 H, SiCH3), 0.16 (s, 3 H, SiCH3), 0.84 [s, 9 H,
1H NMR ([D6]DMSO): δ = 1.32 (s, 3 H, CH3), 1.50 (s, 3 H, CH3),
2.40 (d, J = 4.7 Hz, 3 H, NHCH3), 4.48 (d, J = 2.3 Hz, 1 H, 4Ј-
H), 5.24 (dd, J = 6.2, 1.6 Hz, 1 H, 3Ј-H), 5.37 (dd, J = 6.2, 2.4 Hz,
1 H, 2Ј-H), 6.10 (d, J = 1.7 Hz, 1 H, 1Ј-H), 6.40 (br. s, 2 H, NH2),
7.44 (q, J = 4.3 Hz, 1 H, NHCH3), 7.81 (s, 1 H, 8-H), 10.65 (br. s,
C(CH3)3], 0.93 [s, 9 H, C(CH3)3], 0.97 [s, 9 H, C(CH3)3], 3.80 (dd,
J = 11.5, 2.4 Hz, 1 H, 5Ј-H), 4.00 (dd, J = 11.5, 3.4 Hz, 1 H, 5Ј-
H), 4.13 (dd, J = 6.6, 3.4 Hz, 1 H, 4Ј-H), 4.31 (t, J = 4.3 Hz, 1 H,
3Ј-H), 4.48 (t, J = 4.4 Hz, 1 H, 2Ј-H), 4.73 (br. s, 2 H, NH2), 5.95
(d, J = 4.5 Hz, 1 H, 1Ј-H), 7.42–7.46 (m, 1 H, Ar-H), 7.48–7.55
1 H, NH) ppm. 13C NMR ([D6]DMSO): δ = 25.0, 25.4, 26.7, 83.1, (m, 2 H, Ar-H), 8.11 (dt, J = 8.4, 0.9 Hz, 1 H, Ar-H), 8.23 (s, 1 H,
83.3, 85.8, 88.8, 112.9, 116.6, 136.4, 150.7, 153.6, 156.7, 169.0 ppm.
8-H) ppm. 13C NMR (CDCl3): δ = –5.2 (ϫ2), –4.8, –4.6, –4.5, –4.2,
18.1, 18.2, 18.7, 25.8, 25.9, 26.3, 62.6, 71.9, 76.7, 85.4, 88.1, 109.0,
113.4, 120.5, 124.8, 128.6, 129.0, 140.5, 143.6, 156.1, 158.7, 159.5
+
HR-ESMS calcd. for C14H19N6O5 [M + H] 351.1411, found
351.1422.
+
ppm. HR-ESMS calcd. for C34H59N8O5Si3 [M + H] 743.3911,
O6-(Benzotriazol-1-yl)guanosine (2a): To a mixture of guanosine
(1a) (100 mg, 0.35 mmol, 1 equiv.), BOP (234 mg, 0.53 mmol,
1.5 equiv.) in NMP (2 mL) was added DBU (132 μL, 0.88 mmol,
2.5 equiv.) dropwise and stirred at 25 °C for 16 h. The resultant
solution was then worked up in one of two ways: a) added directly
to a column containing a large amount of SiO2 in DCM and
flushed with a significant quantity of DCM (to elute the NMP),
before increasing the gradient to DCM/MeOH, 9:1 (Rf = 0.17) to
give 2a (83 mg, 59%). Alternatively, b) added to EtOAc (100 mL),
washed with H2O (3ϫ15 mL), dried with MgSO4, filtered and the
filtrate evaporated under reduced pressure. The residue was puri-
fied by column chromatography (DCM/MeOH, 9:1 Rf = 0.17) to
give 2a as a colourless solid (21 mg, 15%); m.p. 156–160 °C (dec.)
1H NMR ([D6]DMSO): δ = 3.52–3.57 (m, 1 H, 5Ј-H), 3.62–3.67
(m, 1 H, 5Ј-H), 3.92 (q, J = 3.9 Hz, 1 H, 4Ј-H), 4.13 (d, J = 3.6 Hz,
found 743.3947.
O6-(Benzotriazol-1-yl)-2Ј,3Ј-O-isopropylideneguanosine (2d): Same
procedure as for 2b, from 1d, (DCM/MeOH, 9:1 Rf = 0.49) to give
2d as a colourless solid (505 mg, 78%); m.p. 187–189 °C (dec.) H
NMR (CDCl3): δ = 1.37 (s, 3 H, CH3), 1.64 (s, 3 H, CH3), 3.76 (d,
J = 10.7 Hz, 1 H, 5Ј-H), 3.94 (dd, J = 12.6, 1.5 Hz, 1 H, 5Ј-H),
4.50 (d, J = 1.4 Hz, 1 H, 4Ј-H), 4.95 (br. s, 2 H, NH2), 5.06 (dd, J
= 6.0, 1.3 Hz, 1 H, 3Ј-H), 5.15–5.18 (m, 1 H, 2Ј-H), 5.77 (d, J =
7.5 Hz, 1 H, OH), 5.83 (d, J = 4.8 Hz, 1 H, 1Ј-H), 7.42–7.56 (m, 3
H, Ar-H), 7.81 (s, 1 H, 8-H), 8.10 (d, J = 8.1 Hz, 1 H, Ar-H) ppm.
13C NMR (CDCl3): δ = 25.4, 27.7, 63.5, 81.6, 82.8, 86.0, 93.9,
108.9, 114.5, 114.7, 120.5, 125.0, 128.8, 128.9, 141.5, 143.5, 154.7,
1
+
158.3, 160.2 ppm. HR-ESMS calcd. for C19H21N8O5 [M + H]
441.1629, found 441.1644.
1 H, 3Ј-H), 4.50 (dd, J = 10.3, 5.1 Hz, 1 H, 2Ј-H), 5.07 (t, J = O6-(Benzotriazol-1-yl)-2Ј-3Ј-O-isopropylideneguanosine-5Ј-N-meth-
4.9 Hz, 1 H, 5Ј-OH), 5.20 (d, J = 4.0 Hz, 1 H, OH), 5.49 (d, J = ylcarboxamide (2e): Same procedure as for 2b, from 1e, (DCM/
5.5 Hz, 1 H, OH), 5.84 (d, J = 5.9 Hz, 1 H, 1Ј-H), 6.73 (br. s, 2 H, MeOH, 9:1 Rf = 0.50) to give 2e as a colourless solid (1.07 g, 92%);
NH2), 7.51–7.55 (m, 1 H, Ar-H), 7.62–7.67 (m, 1 H, Ar-H), 7.76
(d, J = 8.3 Hz, 1 H, Ar-H), 8.17 (d, J = 8.4 Hz, 1 H, Ar-H), 8.35
(s, 1 H, 8-H) ppm. 13C NMR ([D6]DMSO): δ = 61.4, 70.4, 73.7,
85.5, 86.8, 109.5, 111.4, 120.0, 125.4, 128.6, 129.4, 140.9, 142.9,
m.p. 195–198 °C (dec.) 1H NMR ([D6]DMSO): δ = 1.34 (s, 3 H,
CH3), 1.52 (s, 3 H, CH3), 2.35 (d, J = 4.5 Hz, 3 H, NHCH3), 4.55
(d, J = 2.1 Hz, 1 H, 4Ј-H), 5.37 (dd, J = 6.1, 1.3 Hz, 1 H, 2Ј-H),
5.44 (dd, J = 6.1, 2.2 Hz, 1 H, 3Ј-H), 6.25 (d, J = 1.4 Hz, 1 H, 1Ј-
Eur. J. Org. Chem. 2011, 1092–1098
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1095

S. M. Devine, P. J. Scammells
FULL PAPER
H), 6.67 (br. s, 2 H, NH2), 7.48–7.56 (m, 2 H, Ar-H, CONH), 7.63–
1 H, Ar-H) 8.27 (s, 1 H, 8-H) ppm. 13C NMR (CDCl3): δ = 25.3,
7.72 (m, 2 H, Ar-H), 8.18 (d, J = 8.4 Hz, 1 H, Ar-H), 8.21 (s, 1 H, 27.6, 63.2, 81.4, 83.7, 86.6, 93.3, 108.5, 114.8, 119.1 (d, J = 5.0 Hz),
8-H) ppm. 13C NMR ([D6]DMSO): δ = 25.0, 25.3, 26.6, 83.2 (ϫ2), 120.9, 125.3, 128.7, 129.3, 143.5, 144.9 (d, J = 3.0 Hz), 154.9 (d, J
86.2, 89.1, 109.2, 111.0, 112.8, 120.0, 125.2, 128.5, 129.2, 141.7,
= 16.4 Hz), 157.1 (d, J = 223.7 Hz), 161.1 (d, J = 16.4 Hz) ppm.
+
142.8, 156.1, 158.7, 159.2, 168.9 ppm. HR-ESMS calcd. for HR-ESMS calcd. for C19H19FN7O5 [M + H] 444.1426, found
+
C20H22N9O5 [M + H] 468.1738, found 468.1745.
444.1445.
O6-(Benzotriazol-1-yl)-2Ј-3Ј-O-isopropylideneguanosine-5Ј-N-ethyl- O6-(Benzotriazol-1-yl)-2-fluoro-2Ј,3Ј-O-isopropylideneinosine-5Ј-N-
carboxamide (2f):[3] Same procedure as for 2b, from 1f, to give 2f
as a yellow foam (95%); m.p. 140–141 °C. H NMR ([D6]DMSO):
methylcarboxamide (3e): Same procedure as for 3a, from 2e, (DCM/
1
MeOH, 9:1 Rf = 0.45) to give 3e (40 mg, 74%). 1H NMR (CDCl3):
δ = 0.68 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.35 (s, 3 H, CH3), 1.52 (s, δ = 1.38 (s, 3 H, CH3), 1.64 (s, 3 H, CH3), 2.72 (d, J = 4.9 Hz, 3
3 H, CH3), 2.78–2.92 (m, 2 H, CH2CH3), 4.52 (d, J = 2.1 Hz, 1 H, H, NHCH3), 4.75 (d, J = 2.0 Hz, 1 H, 4Ј-H), 5.25 (dd, J = 6.2,
4Ј-H), 5.40 (d, J = 6.0 Hz, 1 H, 3Ј-H), 5.51 (dd, J = 2.1, 6.0 Hz, 1 3.4 Hz, 1 H, 2Ј-H), 5.30 (dd, J = 6.2, 2.1 Hz, 1 H, 3Ј-H), 6.13 (d,
H, 2Ј-H), 6.28 (s, 1 H, 1Ј-H), 6.65 (s, 2 H, NH2), 7.46 (t, J = 6.0 Hz, J = 3.4 Hz, 1 H, 1Ј-H), 6.73 (d, J = 4.4 Hz, 1 H, CONH), 7.46–
1 H, CONH), 7.52–7.56 (m, 1 H, Ar-H), 7.65 (d, J = 3.9 Hz, 2 H, 7.52 (m, 2 H, Ar-H), 7.58 (ddd, J = 8.6, 6.9, 0.9 Hz, 1 H, Ar-H),
Ar-H), 8.17 (d, J = 8.4 Hz, 1 H, Ar-H), 8.21 (s, 1 H, 8-H) ppm.
8.15 (dd, J = 8.4, 0.9 Hz, 1 H, Ar-H), 8.17 (s, 1 H, 8-H) ppm. 13C
13C NMR ([D6]DMSO): δ = 14.4, 25.5, 27.0, 33.5, 83.7 (ϫ 2), 87.0, NMR (CDCl3): δ = 25.2, 25.9, 27.3, 82.5, 83.2, 85.5, 92.2, 108.4,
89.6, 109.5, 111.5, 133.1, 120.4, 125.7, 128.9, 129.6, 142.4, 143.3,
156.5, 159.1, 159.5, 168.6 ppm. HR-ESMS calcd. for C21H24N9O5
[M + H] 482.1895, found 482.1901.
115.4, 118.9 (d, J = 5.1 Hz), 120.9, 125.3, 128.7, 129.4, 143.6, 144.7
(d, J = 3.2 Hz), 155.1 (d, J = 16.5 Hz), 157.3 (d, J = 223.5 Hz),
161.3 (d, J = 16.5 Hz), 168.7 ppm. HR-ESMS calcd. for
+
+
C20H20FN8O5 [M + H] 471.1535, found 471.1535.
O6-(Benzotriazol-1-yl)-2-fluoroinosine (3a): O6-(Benzotriazol-1-yl)-
guanosine (2a) (94 mg, 0.23 mmol) was dissolved in pyridine
(1 mL) and cooled in an ice/salt bath. To this was added, 70%
HF in pyridine (2 mL) dropwise, followed by tBuONO (140 μL,
1.17 mmol) dropwise with vigorous stirring. The reaction was
stirred at this temperature for 20 min before being poured onto
ca. 100 mL of ice/water and stirred for 30 min. The resultant pre-
cipitate was filtered and thoroughly washed with water to give 3a
as a colourless solid (33 mg, 35%); m.p. 189–192 °C (dec.) 1H
O6-(Benzotriazol-1-yl)-2-fluoro-2Ј,3Ј-O-isopropylideneinosine-5Ј-N-
ethylcarboxamide (3f):[3] Same procedure as for 3a, from 2f, to give
3f (59 %); m.p. 140–145 °C (dec.) 1H NMR (300 MHz, [D6]-
DMSO): δ = 1.11 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.35 (s, 3 H, CH3),
1.52 (s, 3 H, CH3), 2.70–2.95 (m, 2 H, CH2CH3), 4.61 (s, 1 H, 4Ј-
H), 5.38 (d, J = 4.8 Hz, 1 H, 3Ј-H), 5.44 (d, J = 4.8 Hz, 1 H, 2Ј-
H), 6.45 (s, 1 H, 1Ј-H), 7.59 (t, J = 6.3 Hz, 1 H, CONH), 7.65–
7.80 (m, 3 H, Ar-H), 8.22 (d, J = 9.5 Hz, 1 H, Ar-H), 8.76 (s, 1 H,
NMR ([D6]DMSO): δ = 3.56–3.62 (m, 1 H, 5Ј-H), 3.68–3.73 (m, 1 8-H) ppm. 13C NMR (300 MHz, CD3OD): δ = 14.2, 25.0, 27.0,
H, 5Ј-H), 3.99 (q, J = 3.9 Hz, 1 H, 4Ј-H), 4.18 (dd, J = 9.4, 4.8 Hz, 34.0, 82.7, 83.2, 85.8, 91.8, 108.3, 115.0, 118.6, 120.7, 125.3, 128.5,
1 H, 3Ј-H), 4.53 (dd, J = 10.5, 5.2 Hz, 1 H, 2Ј-H), 5.08 (t, J = 129.3, 143.4, 144.9, 155.1 (J = 16.4 Hz), 157.1 (J = 221.8 Hz), 160.0
5.4 Hz, 1 H, OH), 5.28 (d, J = 5.4 Hz, 1 H, OH), 5.61 (d, J = (J = 16.4 Hz), 167.9 ppm. HR-ESMS calcd. for C21H22N8O5F+ [M
5.9 Hz, 1 H, 5Ј-OH), 5.96 (d, J = 5.1 Hz, 1 H, 1Ј-H), 7.56–7.60 (m,
1 H, Ar-H), 7.67–7.71 (m, 1 H, Ar-H), 7.86 (d, J = 8.3 Hz, 1 H,
+ H] 485.1692, found 485.1699.
2Ј,3Ј,5Ј-Tri-O-acetyl-O6-(benzotriazol-1-yl)-2-chloroinosine (4b): A
solution of tBuONO (689 μL, 5.79 mmol) in DCM (30 mL) was
added TMS-Cl (368 μL, 2.90 mmol) at 0 °C. To this was added
drop wise 2b (305 mg, 0.58 mmol), dissolved in DCM (30 mL),
then stirred at 0 °C for 1 h. The solution was then diluted with
more DCM (40 mL), washed with H2O (20 mL), saturated
NaHCO3 (20 mL), dried with MgSO4 and evaporated at reduced
Ar-H), 8.23 (d, J = 8.4 Hz, 1 H, Ar-H), 8.91 (s, 1 H, 8-H) ppm. 13
C
NMR ([D6]DMSO): δ = 60.9, 69.9, 74.0, 85.7, 88.3, 109.5, 117.8 (d,
J = 5.0 Hz), 120.0, 125.6, 128.3, 129.6, 142.7, 145.7 (d, J = 3.0 Hz),
155.8 (d, J = 17.6 Hz), 156.0 (d, J = 214.2 Hz), 159.6 (d, J =
+
17.0 Hz) ppm. HR-ESMS calcd. for C16H15FN7O5 [M + H]
404.1113, found 404.1109.
2Ј,3Ј,5Ј-Tri-O-acetyl-O6-(benzotriazol-1-yl)-2-fluoroinosine
(3b): pressure. The residue was purified by column chromatography
1
Same procedure as for 3a, from 2b, (DCM/MeOH, 9:1 Rf = 0.75) to
(DCM/MeOH, 9:1 Rf = 0.66) to give 4e (297 mg, 94%). H NMR
(CDCl3): δ = 2.06 (s, 3 H, CH3), 2.11 (s, 3 H, CH3), 2.13 (s, 3 H,
give 3b (440 mg, 88%); m.p. 132–133 °C (dec.) 1H NMR (CDCl3): δ
= 2.10 (s, 3 H, CH3), 2.16 (s, 3 H, CH3), 2.17 (s, 3 H, CH3), 4.35– CH3), 4.39 (d, J = 3.7 Hz, 2 H, 5Ј-H, 5Ј-H), 4.46 (dd, J = 7.9,
4.46 (m, 2 H, 5Ј-H, 5Ј-H), 4.48 (dd, J = 7.2, 4.0 Hz, 1 H, 4Ј-H), 3.8 Hz, 1 H, 4Ј-H), 5.56 (dd, J = 5.5, 4.4 Hz, 1 H, 3Ј-H), 5.80 (t, J
5.56 (dd, J = 5.6, 4.3 Hz, 1 H, 3Ј-H), 5.83 (t, J = 5.6 Hz, 1 H, 2Ј- = 5.6 Hz, 1 H, 2Ј-H), 6.23 (d, J = 5.6 Hz, 1 H, 1Ј-H), 7.43–7.50
H), 6.19 (d, J = 5.6 Hz, 1 H, 1Ј-H), 7.46–7.53 (m, 2 H, Ar-H),
7.56–7.60 (m, 1 H, Ar-H), 8.15 (dt, J = 8.4, 0.9 Hz, 1 H, Ar-H),
8.23 (s, 1 H, 8-H) ppm. 13C NMR (CDCl3): δ = 20.5, 20.6, 20.9,
70.6, 73.2, 81.0, 86.8, 108.5, 118.6 (d, J = 5.1 Hz), 120.8, 125.2,
128.7, 129.3, 143.5, 143.7 (d, J = 3.2 Hz), 155.6 (d, J = 16.8 Hz),
157.4 (d, J = 222.3 Hz), 161.1 (d, J = 16.4 Hz), 169.5, 169.7, 170.4
(m, 2 H, Ar-H), 7.53–7.57 (m, 1 H, Ar-H), 8.11 (dt, J = 8.4, 0.8 Hz,
1 H, Ar-H), 8.25 (s, 1 H, 8-H) ppm. 13C NMR (CDCl3): δ 20.4,
20.6, 20.9, 63.0, 70.6, 73.3, 80.9, 86.7, 108.6, 119.2, 120.7, 125.1,
128.7, 129.1, 143.5, 143.6, 153.2, 155.1, 159.4, 169.5, 169.6, 170.3.
HR-ESMS calcd. for C22H21ClN7O5 [M + H] 546.1135, found
546.1160.
+
+
ppm. HR-ESMS calcd. for C22H21FN7O8 [M + H] 530.1430,
found 530.1440.
O6-(Benzotriazol-1-yl)-2Ј,3Ј,5Ј-tri-O-(tert-butyldimethylsilyl)-2-chlo-
roinosine (4c): Same procedure as for 4b, from 2c, (petroleum ether/
O6-(Benzotriazol-1-yl)-2-fluoro-2Ј,3Ј-O-isopropylideneinosine (3d): EtOAc, 4:1 Rf = 0.45) to give 4c as a colourless foam (50 mg, 72%).
Same procedure as for 3a, from 2d, (DCM/MeOH, 9:1 Rf = 0.57) 1H NMR (CDCl3): δ = –0.12 (s, 3 H, SiCH3), 0.02 (s, 3 H, SiCH3),
to give 3d as a colourless solid (35 mg, 36%); m.p. 195–199 °C
(dec.) 1H NMR (CDCl3): δ = 1.38 (s, 3 H, CH3), 1.64 (s, 3 H, 0.16 (s, 3 H, SiCH3), 0.85 [s, 9 H, C(CH3)3], 0.93 [s, 9 H, C(CH3)
CH3), 3.82 (m, 2 H, 5Ј-H, OH), 3.97 (d, J = 11.1 Hz, 1 H, 5Ј-H), 3], 0.96 [s, 9 H, C(CH3)3], 3.81 (dd, J = 11.6, 2.4 Hz, 1 H, 5Ј-H),
0.09 (s, 3 H, SiCH3), 0.10 (s, 3 H, SiCH3), 0.15 (s, 3 H, SiCH3),
4.51 (s, 1 H, 4Ј-H), 5.08 (dd, J = 6.1, 1.8 Hz, 1 H, 3Ј-H), 5.17 (dd, 4.06 (dd, J = 11.6, 3.8 Hz, 1 H, 5Ј-H), 4.17 (dt, J = 4.1, 2.6 Hz, 1
J = 6.0, 4.3 Hz, 1 H, 2Ј-H), 6.02 (d, J = 4.2 Hz, 1 H, 1Ј-H), 7.46– H, 4Ј-H), 4.32 (t, J = 4.4 Hz, 1 H, 3Ј-H), 4.55 (t, J = 4.2 Hz, 1 H,
7.50 (m, 2 H, Ar-H), 7.55–7.59 (m, 1 H, Ar-H), 8.14 (d, J = 8.4 Hz,
2Ј-H), 6.05 (d, J = 4.1 Hz, 1 H, 1Ј-H), 7.43–7.50 (m, 2 H, Ar-H),
1096
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1092–1098

2-Halo-O6-(benzotriazol-1-yl)-Substituted Purine Nucleosides
7.55 (ddd, J = 8.3, 6.7, 0.9 Hz, 1 H, Ar-H), 8.13 (dt, J = 8.4, 0.9 Hz, 1 H, 5Ј-H), 4.15–4.18 (m, 1 H, 4Ј-H), 4.31 (t, J = 4.6 Hz, 1 H, 3Ј-
1 H, Ar-H), 8.58 (s, 1 H, 8-H) ppm. 13C NMR (CDCl3): δ = –5.3,
–5.2, –4.8, –4.7, –4.6, –4.2, 18.0, 18.2, 18.7, 25.8, 26.0, 26.2, 62.1,
71.4, 76.4, 85.5, 89.5, 108.7, 119.2, 120.8, 125.1, 128.9, 129.1, 143.6,
144. 6, 152. 8, 155.0, 159.2 ppm. HR-ESMS calcd. for
H), 4.53 (t, J = 4.0 Hz, 1 H, 2Ј-H), 6.03 (d, J = 3.8 Hz, 1 H, 1Ј-
H), 7.44–7.49 (m, 2 H, Ar-H), 7.53–7.57 (m, 1 H, Ar-H), 8.13 (d,
J = 8.3 Hz, 1 H, Ar-H), 8.50 (s, 1 H, 8-H) ppm. 1H NMR (CDCl3):
δ = –5.3, –5.1, –4.7, –4.6, –4.5, 4.1, 18.1, 18.2, 18.7, 25.9, 26.0, 26.3,
61.9, 71.1, 76.2, 85.2, 89.7, 108.7, 115.5, 120.1, 120.7, 125.0, 128.9,
129.0, 143.6, 144.0, 154.4, 157.4 ppm. HR-ESMS calcd. for
+
C34H57ClN7O5Si3 [M + H] 762.3412, found 762.3424.
O6-(Benzotriazol-1-yl)-2-chloro-2Ј,3Ј-O-isopropylideneinosine-5Ј-N-
methylcarboxamide (4e): Same procedure as for 4b, from 2e, (DCM/
MeOH, 9:1 Rf = 0.65) to give 4e as a colourless solid (757 mg,
+
C34H57IN7O5Si3 [M + H] 854.2768, found 854.2780.
O6-(Benzotriazol-1-yl)-2-iodo-2Ј,3Ј-O-isopropylideneinosine
Same procedure as for 5a, from 2d, (DCM/MeOH, 9:1 Rf = 0.54)
(5d):
1
96%); m.p. 188–191 °C (dec.) H NMR ([D6]DMSO): δ = 1.35 (s,
3 H, CH3), 1.54 (s, 3 H, CH3), 2.32 (d, J = 4.6 Hz, 3 H, NHCH3), to give 5d (44 mg, 72%). 1H NMR (CDCl3): δ = 1.38 (s, 3 H, CH3),
4.66 (d, J = 1.9 Hz, 1 H, 4Ј-H), 5.36 (d, J = 6.1, 2.1 Hz, 1 H, 3Ј-
H), 5.42 (dd, J = 6.1, 1.2 Hz, 1 H, 2Ј-H), 6.46 (d, J = 1.3 Hz, 1 H,
1.64 (s, 3 H, CH3), 3.83 (t, J = 10.4 Hz, 1 H, 5Ј-OH), 3.98 (d, J =
12.6 Hz, 1 H, 5Ј-H), 4.16 (d, J = 9.3 Hz, 1 H, 5Ј-H), 4.52 (d, J =
1Ј-H), 7.56–7.60 (m, 2 H, Ar-H, CONH), 7.67–7.72 (m, 1 H, Ar- 1.8 Hz, 1 H, 4Ј-H), 5.10 (dd, J = 6.0, 1.6 Hz, 1 H, 3Ј-H), 5.16–5.19
H), 7.75–7.78 (m, 1 H, Ar-H), 8.23 (d, J = 8.5 Hz, 1 H, Ar-H),
8.78 (s, 1 H, 8-H) ppm. 13C NMR ([D6]DMSO): δ = 25.0, 25.3,
26.6, 83.3 (ϫ 2), 86.6, 90.1, 109.2, 113.0, 118.4, 120.1, 125.6, 128.2,
129.6, 142.7, 146.8, 150.4, 155.4, 158.3, 168.6 ppm. HR-ESMS
(m, 1 H, 2Ј-H), 5.95 (d, J = 4.7 Hz, 1 H, 1Ј-H), 7.45–7.51 (m, 2 H,
Ar-H), 7.55–7.59 (m, 1 H, Ar-H), 8.10 (s, 1 H, 8-H), 8.14 (d, J =
8.6 Hz, 1 H, Ar-H) ppm. 13C NMR (CDCl3): δ = 25.4, 27.7, 63.3,
81.5, 83.2, 86.4, 93.8, 108.6, 114.8, 116.0, 120.8, 121.1, 125.2, 128.8,
129.2, 143.6, 144.5, 154.1, 158.0 ppm. HR-ESMS calcd. for
+
calcd. for C20H20ClN8O5 [M + H] 487.1240, found 487.1254.
+
C19H19IN7O5 [M + H] 552.0487, found 552.0493.
O6-(Benzotriazol-1-yl)-2-iodoinosine (5a): O6-(Benzotriazol-1-yl)-
guanosine (2a) (50.6 mg, 0.107 mmol) was suspended in MeCN
O6-(Benzotriazol-1-yl)-2-iodo-2Ј,3Ј-O-isopropylideneinosine-5Ј-N-
(2 mL) in a 2–5 mL Biotage microwave vial. Diiodomethane methylcarboxamide (5e): Same procedure as for 5a, from 2e, (DCM/
(250 μL) and isopentylnitrite (68 μL, 0.506 mmol) were added and
the microwave vial capped. The mixture was heated in the micro-
wave at 90 °C for 1h. The solution was then added to EtOAc
(30 mL) and washed with satd. NaHCO3 (25 mL). The aqueous
phase was re-extracted with EtOAc (15 mL), the combined organic
extracts combined and washed subsequently with satd. NaHCO3
(15 mL), H2O (15 mL) and satd. NaCl (10 mL). The organic phase
was dried with MgSO4, filtered and the filtrate evaporated under
reduced pressure. The residue was purified by column chromatog-
raphy (DCM/MeOH, 9:1 Rf = 0.23) to give 5a as a pale yellow
solid (36 mg, 56%); m.p. 179–182 °C (dec.) 1H NMR ([D6]DMSO):
δ = 3.52–3.62 (m, 1 H, 5Ј-H), 3.64–3.72 (m, 1 H, 5Ј-H), 3.98 (q, J
= 4.0 Hz, 1 H, 4Ј-H), 4.17 (dd, J = 8.6, 4.6 Hz, 1 H, 3Ј-H), 4.54
(q, J = 5.4 Hz, 1 H, 2Ј-H), 5.06 (t, J = 5.2 Hz, 1 H, 5Ј-OH), 5.29
(d, J = 5.1 Hz, 1 H, OH), 5.59 (d, J = 5.8 Hz, 1 H, OH), 5.99 (d,
J = 5.4 Hz, 1 H, 1Ј-H), 7.55–7.60 (m, 1 H, Ar-H), 7.66–7.70 (m, 1
H, Ar-H), 7.83 (d, J = 8.3 Hz, 1 H, Ar-H), 8.22 (d, J = 8.4 Hz, 1
H, Ar-H), 8.81 (s, 1 H, 8-H) ppm. 13C NMR ([D6]DMSO): δ =
61.0, 70.1, 74.0, 85.9, 88.0, 109.5, 117.3, 119.0, 120.0, 125.5, 128.4,
129.5, 142.7, 145.0, 155.1, 156.8 ppm. HR-ESMS calcd. for
MeOH, 9:1 Rf = 0.49) to give 5e (48 mg, 77%). 1H NMR ([D6]-
DMSO): δ = 1.35 (s, 3 H, CH3), 1.54 (s, 3 H, CH3), 2.32 (d, J =
4.6 Hz, 3 H, NHCH3), 4.63 (d, J = 1.9 Hz, 1 H, 4Ј-H), 5.36 (dd, J
= 6.1, 2.1 Hz, 1 H, 3Ј-H), 5.39 (dd, J = 6.2, 0.8 Hz, 1 H, 2Ј-H),
6.45 (d, J = 0.7 Hz, 1 H, 1Ј-H), 7.51 (q, J = 4.2 Hz, 1 H, CONH),
7.55–7.60 (m, 1 H, Ar-H), 7.66–7.76 (m, 2 H, Ar-H), 8.23 (d, J =
8.4 Hz, 1 H, Ar-H), 8.66 (s, 1 H, 8-H) ppm. 13C NMR ([D6]-
DMSO): δ = 25.0, 25.4, 26.6, 83.3, 83.4, 86.8, 89.9, 109.2, 113.0,
117.0, 118.9, 120.1, 125.5, 128.3, 129.5, 142.7, 146.1, 154.9, 156.7,
168.6 ppm. HR-ESMS calcd. for C20H20IN8O5+ [M + H] 579.0596,
found 579.0607.
2-Iodo-N6-(endo-norborn-2-yl)adenosine (7):[1] O6-(Benzotriazol-1-
yl)-2-iodoinosine (5a) (69.6 mg, 0.14 mmol) was suspended in
tBuOH (3 mL) in a 2–5 mL Biotage microwave vial. DIPEA
(119 μL, 0.68 mmol) and (Ϯ)-endo-2-norbornylamine hydrochlo-
ride (30 mg, 0.20 mmol) were added and the microwave vial
capped. The mixture was heated in the microwave at 80 °C for 3 h.
The yellow solution was evaporated and purified by column
chromatography (DCM/MeOH, 9:1 Rf = 0.31) to give 7 (63 mg,
1
95%). H NMR (MeOD): δ = 0.97–1.05 (m, 1 H, CH), 1.32–1.44
+
C16H15IN7O5 [M + H] 512.0174, found 512.0178.
(m, 3 H, CH, CH2), 1.52–1.72 (m, 3 H, CH, CH2), 2.08–2.18 (m,
2 H, CH2), 2.25 (br. s, 1 H, CH), 2.59 (br. s, 1 H, CH), 3.74 (dd, J
2Ј,3Ј,5Ј-Tri-O-acetyl-O6-(benzotriazol-1-yl)-2-iodoinosine
(5b):
Same procedure as for 5a, from 2b, (DCM/MeOH, 19:1 Rf = 0.45) = 12.5, 2.9 Hz, 1 H, 5Ј-H), 3.88 (dd, J = 12.5, 2.6 Hz, 1 H, 5Ј-H),
to give 5b (61 mg, 96%). 1H NMR (CDCl3): δ = 2.09 (s, 3 H, CH3),
4.15 (q, J = 2.5 Hz, 1 H, 4Ј-H), 4.31 (dd, J = 5.0, 3.0 Hz, 1 H, 3Ј-
2.12 (s, 3 H, CH3), 2.15 (s, 3 H, CH3), 4.39 (dd, J = 3.8, 1.9 Hz, 2 H), 4.35 (br. s, 1 H, NHCH), 4.67 (t, J = 5.6 Hz, 1 H, 2Ј-H), 5.89
H, 5Ј-H, 5Ј-H), 4.47 (dd, J = 7.8, 4.3 Hz, 1 H, 4Ј-H), 5.58 (dd, J =
5.5, 4.5 Hz, 1 H, 3Ј-H), 5.79 (dd, J = 5.5 Hz, 1 H, 2Ј-H), 6.22 (d,
J = 5.4 Hz, 1 H, 1Ј-H), 7.44–7.50 (m, 2 H, Ar-H), 7.56 (ddd, J =
8.2, 6.8, 0.9 Hz, 1 H, Ar-H), 8.12 (dd, J = 7.6, 0.8 Hz, 1 H, Ar-H),
8.16 (s, 1 H, 8-H) ppm. 13C NMR (CDCl3): δ = 20.5, 20.6, 21.0,
63.0, 70.7, 73.4, 80.9, 86.8, 108.7, 116.3, 120.0, 120.7, 125.1, 128.7,
129.1, 143.0, 143.5, 154.6, 157.7, 169.5, 169.7, 170.4 ppm. HR-
ESMS calcd. for C22H21IN7O8+ [M + H] 638.0491, found 638.0504.
(d, J = 6.1 Hz, 1 H, 1Ј-H), 8.15 (s, 1 H, 8-H) ppm. 13C NMR
(MeOD): δ = 22.4, 30.7, 37.9, 38.1, 39.1, 41.5, 53.7, 63.3, 72.4, 75.4,
87.9, 91.1, 120.9, 121.0, 141.0, 149.5, 155.4 ppm. HR-ESMS calcd.
+
for C17H23IN5O4 [M + H] 488.0789, found 488.0804.
2-Chloro-N6-cyclopentyladenosine (6):[17] 2Ј,3Ј,5Ј-Tri-O-acetyl-O6-
(benzotriazol-1-yl)-2-chloroinosine (4b) (91 mg, 0.17 mmol) was
dissolved in MeCN (3 mL) in a 2–5 mL Biotage microwave vial. To
this was added cyclopentylamine (82 μL, 0.83 mmol) and stirred at
O6-(Benzotriazol-1-yl)-2Ј,3Ј,5Ј-tri-O-(tert-butyldimethylsilyl)-2-iodo- 25 °C for 2 h, at which time all starting material was completely
inosine (5c): Same procedure as for 5a, from 2c, (petroleum ether/
consumed by LCMS. To this solution was added NH4OH (500 μL),
EtOAc, 4:1 Rf = 0.46) to give 5c (44 mg, 68%). 1H NMR (CDCl3): the microwave vial capped and heated in the microwave at 80 °C
δ = –0.07 (s, 3 H, SiCH3), 0.03 (s, 3 H, SiCH3), 0.09 (s, 3 H, SiCH3), for 2h. The solution was evaporated at reduced pressure and the
0.10 (s, 3 H, SiCH3), 0.15 (s, 3 H, SiCH3), 0.16 (s, 3 H, SiCH3),
0.86 [s, 9 H, C(CH3)3], 0.92 [s, 9 H, C(CH3)3], 0.95 [s, 9 H, C(CH3)
residue purified by column chromatography (DCM/MeOH, 9:1 Rf
= 0.30) to give 6 (52 mg, 84%). H NMR (MeOD): δ = 1.61–1.74
1
3], 3.81 (dd, J = 11.6, 2.4 Hz, 1 H, 5Ј-H), 4.06 (dd, J = 11.5, 3.9 Hz, (m, 4 H, CH2, CH2), 1.79–1.86 (m, 2 H, CH2), 2.08–2.14 (m, 2 H,
Eur. J. Org. Chem. 2011, 1092–1098
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1097

S. M. Devine, P. J. Scammells
FULL PAPER
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Received: October 11, 2010
Published Online: December 27, 2010
1098
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1092–1098