Linear and convergent approaches to 2-substituted adenosine-5′-N-alkylcarboxamides

Article abstract of DOI:10.1016/j.tet.2009.08.057

Herein we report both linear and convergent pathways for the preparation of 2-alkynyl substituted adenosine-5′-N-ethylcarboxamides via the versatile synthetic intermediate, 2-iodoadenosine-5′-N-ethylcarboxamide (13). The linear approach afforded 13 in an overall yield of 30% from guanosine over eight synthetic steps. The convergent approach was shorter, but proceeded in lower yield (five steps, 20% yield). Both approaches compare favourably with previously reported syntheses of 13, which has been prepared in 15% yield from guanosine over nine steps. 2-Iodoadenosine-5′-N-ethylcarboxamide (13) was subsequently converted to HENECA (2) and PHPNECA (3) to exemplify the utility of this approach for the preparation of?potent A_2A adenosine receptor agonists. The linear approach was also amenable to the synthesis of 2-fluoropurine ribosides, which were subsequently elaborated into 2-alkylaminoadenosine-5′-N-ethylcarboxamides. Furthermore, both of these synthetic approaches are readily amenable to the synthesis of adenosine analogues with varied 2-, 6- and 5′-substitution patterns.

Full text of DOI:10.1016/j.tet.2009.08.057

Tetrahedron 65 (2009) 8851–8857
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Linear and convergent approaches to 2-substituted adenosine-50-N-
alkylcarboxamides
*
Richard C. Foitzik, Shane M. Devine, Nicholas E. Hausler, Peter J. Scammells
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, Victoria 3052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 May 2009
Received in revised form 3 August 2009
Accepted 20 August 2009
Available online 26 August 2009
Herein we report both linear and convergent pathways for the preparation of 2-alkynyl substituted
adenosine-50-N-ethylcarboxamides via the versatile synthetic intermediate, 2-iodoadenosine-50-N-ethyl-
carboxamide (13). The linear approach afforded 13 in an overall yield of 30% from guanosine over eight
synthetic steps. The convergent approach was shorter, but proceeded in lower yield (five steps, 20% yield).
Both approaches compare favourably with previously reported syntheses of 13, which has been prepared in
15% yield from guanosine over nine steps. 2-Iodoadenosine-50-N-ethylcarboxamide (13) was subsequently
converted to HENECA (2) and PHPNECA (3) to exemplify the utility of this approach for the preparation
of potent A2A adenosine receptor agonists. The linear approach was also amenable to the synthesis of
2-fluoropurine ribosides, which were subsequently elaborated into 2-alkylaminoadenosine-50-N-ethyl-
carboxamides. Furthermore, both of these synthetic approaches are readily amenable to the synthesis of
adenosine analogues with varied 2-, 6- and 50-substitution patterns.
Keywords:
Adenosine-50-N-alkylcarboxamides
Adenosine A2A receptor agonists
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2-Substituted adenosine-50-N-alkylcarboxamides are an im-
portant class of compound, many of which are agonists at the A2A
adenosine receptor (A2AAR).1 The synthesis and cardiovascular
activity of 50-N-ethylcarboxamidoadenosine (NECA) was reported
in 1980.2 Further substitution of the 2-position lead to the discov-
ery of 2-[4-(2-carboxyethyl)phenylethyl]amino-50-N-ethylcarbox-
amide (CGS 21680, 1),3 which is selective for the rat A2AAR, and has
seen widespread use as a pharmacological tool for the study of this
receptor. 2-Alkynyl substituted adenosine-50-N-carboxamides such
as 2-(hexyn-1-yl)adenosine-50-N-ethylcarboxamide (HENECA, 2)
and 2-(R,S)-phenylhydroxypropynyladenosine-50-N-ethylcarbox-
amide ((R,S)-PHPNECA, 3) have also proven to be potent A2AAR ag-
onists.4,5 More recently, another 2-alkynyl substituted derivative,
Apadenoson (ATL-146e, 4),6 entered phase III clinical trials as
a pharmacologic stress agent for use in myocardialperfusion imaging.
2-Alkynyl adenosine-50-N-ethylcarboxamides such as HENECA
(2), (R,S)-PHPNECA (3) and ATL-146e (4) are typically prepared
from 2-iodoadenosine-50-N-ethylcarboxamide (2-iodoNECA) via
Sonogashira coupling with the appropriate terminal alkyne.4–6
2-IodoNECA was originally synthesised from 2-iodoadenosine in
five steps in 26% yield,4 which was in turn prepared from guanosine
in four steps in yields ranging from 45 to 58% yield (i.e.,12–15% over
nine steps).7,8 Herein we report two different and higher yielding
synthetic pathways to 2-iodoNECA and the 2-alkynyl derivatives, 2
and 3. The first of these is a more convergent approach, which
features a microwave-assisted Vorbru¨ggen coupling step to form
the purine riboside core. The second synthesis is a linear sequence
from guanosine, which employs a new methodology for the ami-
nation of the 6-position. Both approaches afforded 2-iodoNECA in
fewer synthetic steps and higher overall yield than previously
reported methods.
2. Results and discussion
2,6-Dihalopurines, such as 6-chloro-2-iodopurine (6), are com-
mon intermediates for the synthesis of a range of 2,6-disubstituted
* Corresponding author. Tel.: þ61 3 9903 9542; fax: þ61 3 9903 9582.
E-mail address: peter.scammells@pharm.monash.edu.au (P.J. Scammells).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.057

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R.C. Foitzik et al. / Tetrahedron 65 (2009) 8851–8857
adenosines and purine ribosides. The presence of a 2-iodo moiety is
particularly advantageous for the synthesis of 2-alkynyl purines via
Sonogashira coupling reactions. The synthesis of 6-chloro-2-iodo-
purine (6) was achieved from commercially available 2-amino-6-
chloropurine (5) in one high yielding step (73% isolated yield)
(Scheme 1). This diazotisation–iodination sequence employed
standard reagents (iso-amylnitrite, CuI, CH2I2, DMF) and microwave
irradiation. Preparation of 6-chloro-2-iodopurine (6) previously
required a multiple step synthesis, such as the five-step process
outlined by Taddei et al.9 In addition to the longer synthetic se-
quence needed, this approach also required relatively expensive
reagents such as 2,2,6,6-tetramethylpiperidine, which were es-
sential for the selective substitution of the 2-position.10
approach afforded 2-iodoadenine (9) in an overall yield of 46% in
four steps from 2-amino-6-chloropurine (5).
We subsequently found that 6-chloro-2-iodopurine (6) could be
converted to 2-iodoadenine (9) directly without the need for N-9
protection using a microwave reactor. The reaction of 6-chloro-2-
iodopurine (6) with 3.5 equiv of NH4Cl and a base at 150 ꢀC for 2 h
afforded 2-iodoadenine (9) in 91% yield. This was the preferred
method for the synthesis of 2-iodoadenine (9), which was obtained
in an overall yield of 66% over two steps from commercially avail-
able 2-amino-6-chloropurine (5).
2-Iodoadenine (9) was subsequently evaluated as a coupling
partner for the synthesis of the corresponding adenosines via a Vor-
bru¨ggen coupling approach. We recently reported a high yielding
synthesis of highly functionalised adenosines, which utilised micro-
wave irradiation in the key Vorbru¨ggen coupling step.11 The other
coupling partner, methyl 1,2,3-tri-O-acetyl-
was prepared from commercially available 1,2,3,5-tetra-O-acetyl-
-ribofuranoside (10) using the conditions described in this report
(Scheme 2). However, the coupling of 2-iodoadenine (9) with methyl
1,2,3-tri-O-acetyl- -ribofuronate (11) afforded a moderate 55%
b-D-ribofuronate (11),
b-
D
b-D
yield of the desired 2-iodoadenosine (12). 2-Iodoadenosine-20,30-O-
diacetyl-50-methylcarboxylate (12) was subsequently converted to
2-iodoNECA (13) in one step in 61% yield. A Sonogashira coupling
reaction of 2-iodoNECA (9) with 1-hexyne afforded HENECA (2) in six
steps in an overall yield of 15%.
A
linear approach from guanosine was also investigated
resulting in an eight-step process (Scheme 3) to the common in-
termediate 2-iodoNECA (13) with a superior overall yield of 30%.
This process was initiated with the protection of guanosine with an
isopropylidene group, followed by oxidation of the 50-alcohol (15)
to the corresponding carboxylic acid (16) using a BAIB–TEMPO
oxidation reaction.12 Unlike other traditional oxidations, which
employ toxic transition metal reagents such as CrO3, the BAIB–
TEMPO oxidation offers mild conditions and produces less toxic by-
products.12
The introduction of the 50-N-ethylcarboxamide proved to be
more challenging than expected. The reaction of the carboxylic acid
(16) with ethylamine and the carbodiimide activating agent, EDCI,
proceeded in low yield. This transformation was ultimately ach-
ieved by first forming the corresponding methylcarboxylate (17),
which was subsequently treated with ethylamine in a reaction
bomb for several days to form the carboxamide (18). These steps
proceeded in yields of 61% and 98%, respectively.
Scheme 1. Synthesis of 2-iodo-6-aminopurine. Method A: (i) iso-amylnitrite, CuI,
CH2I2, DMF, MW, 120 ꢀC, 2 h, 73%; (ii) dihydropyran, THF, TsOH, 66 ꢀC, 16 h, 78%; (iii)
MeOH/NH3, 25 ꢀC, 7 days, 90%; (iv) CuCl2, EtOH/H2O (95:5), 25 ꢀC, 16 h, 89%. Method B:
(i) iso-amylnitrite, CuI, CH2I2, DMF, MW, 120 ꢀC, 2 h, 73%; (v) NH4Cl, DIPEA, i-PrOH,
MW, 150 ꢀC, 2 h, 91%.
The conversion of 6-chloro-2-iodopurine (6) to 2-iodoadenine
(9) was subsequently investigated. Amination of 6-halogenated
purines generally requires either a protecting group or a sugar at
the N-9-position due to their poor solubility in most organic
solvents.9 Accordingly, 6-chloro-2-iodopurine (6) was protected
as the tetrahydropyran-2-yl derivative (7) and reacted with
methanolic ammonia at 60 ꢀC. This procedure resulted in the
formation of substantial amounts of the corresponding 2,6-di-
aminopurine. Maximum yields (90%) of 2-iodo-9-(tetra-
hydropyran-2-yl)adenine (7) were achieved by the stirring of the
starting materials at 25 ꢀC for 7 days. Deprotection using copper
(II) chloride afforded 2-iodoadenine (9) in 89% yield. This
Activation of the 6-position was initially attempted via halo-
genation. However, the reaction of 18 with POCl3 in the presence of
N,N-dimethylaniline proved to be capricious and low yielding. Bae
Scheme 2. (i) Candida rugosa lipase, 0.1 M sodium phosphate buffer (pH 7.0), 1,4-dioxane, rt 16 h, 91%11; (ii) TEMPO, BAIB, MeCN/H2O (1:1), 25 ꢀC, 16 h, 72%11; (iii) EDCI, DMAP,
MeOH, 25 ꢀC, 4 h, 92%11; (iv) 9, HMDS, MeCN, (NH4)2SO4, MW, 110 ꢀC, 3 h, 55% (v) EtNH2, THF, MW, 110 ꢀC, 3 h, 61%; (vi) THF, Et3N, CuI, PdCl2(PPh3)2, alkyne, 25 ꢀC, 4 days, 76%.

R.C. Foitzik et al. / Tetrahedron 65 (2009) 8851–8857
8853
Scheme 3. (i) Acetone, TsOH, (CH3)2C(OCH3)2, 25 ꢀC, 16 h, 94%; (ii) TEMPO, BAIB, MeCN/H2O (1:1), 25 ꢀC, 16 h, 72%; (iii) SOCl2, MeOH, 0 ꢀC/25 ꢀC, 16 h, 61%; (iv) EtNH2, MeOH/DMF
(9:1), 70–75 ꢀC, 3 days, 98%; (v) for X¼Cl: POCl3, DMA, Et4NCl, MeCN, reflux, 1 h, 36%; for X¼OBt: BOP, DBU, MeCN, 25 ꢀC, 16 h, 95%; (vi) t-BuONO, CH2I2, 85 ꢀC, 1 h, 88%; (vii) NH4OH,
MeCN, 25 ꢀC, 3 days, 96%; (viii) TFA, H2O, 50 ꢀC, 3 h, 93%; (ix) PdCl2(PPh3)2, alkyne, Et3N, CuI, THF, 25 ꢀC, 4 days, 76% for 2, 56% for 3.
and Lakshman recently reported that inosine could be converted
to the corresponding O6-(benzotriazol-1-yl) derivative using
1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexa-
fluorophosphate (BOP).13 These researchers also found that
O6-(benzotriazol-1-yl)inosine reacted cleanly with a variety of nu-
cleophiles, including amines to give the corresponding
6-substituted products. Accordingly, we prepared the O6-(benzo-
triazol-1-yl) derivative of 20,30-O-isopropylideneguanosine-50-N-
ethylcarboxamide (18) in excellent (95%) yield using the BOP
This synthetic approach is also amenable to the incorporation of
other substituents in the 2-position. One example, shown in
Scheme 4, is the preparation of 2-alkylamino adenosines. In this
case, the key 2-amino intermediate 19b is diazotised and fluori-
nated prior to the introduction of the 6-amino and 2-phenethyl-
amino groups via nucleophilic aromatic substitution reactions.
Cleavage of the isopropylidene protecting group afforded the
known A2AAR agonist, 2-phenethylaminoadenosine-50-N-ethyl-
carboxamide (24).
Scheme 4. (i) Pyridine-HF, t-BuONO, ꢁ20 ꢀC, 20 min, 59%; (ii) NH4OH, MeCN, 0 ꢀC/25 ꢀC, 2 h, 88%; (iii) phenethylamine, DIPEA, EtOH,110 ꢀC, 3 days, 47%; (iv) 1 M HCl, 60 ꢀC, 5 h, 80%.
reagent. Diazotisation and iodination of the 2-position produced the
versatile synthetic intermediate (20), which was well poised for
selective substitution of the 2- and 6-positions. A 6-amino sub-
stituent was introduced prior to the cleavage of the isopropylidene
protecting group to afford 2-iodoadenosine-50-N-ethylcarboxamide
(13) in high yield. This compound was used to prepare the known
A2A agonists, HENECA (2) and (R,S)-PHPNECA (3), following Sono-
gashira coupling with the appropriate alkyne (Scheme 3).
3. Conclusions
In conclusion, we have optimised convergent and linear routes
to 2-alkynyladenosine-50-N-alkylcarboxamides. Both routes pro-
ceeded via the common synthetic intermediate, 2-iodoNECA (13),
which was coupled with the appropriately substituted terminal
alkyne in the final step. The convergent approach afforded 13 in
20% yield over five-synthetic steps. The linear approach required
a longer sequence of reactions, but gave a higher overall yield (30%

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R.C. Foitzik et al. / Tetrahedron 65 (2009) 8851–8857
yield over eight steps). Both approaches compare favourably with
previously reported methods in which 13 has been prepared from
guanosine in 12–15% yield over nine steps. 2-IodoNECA (13) was
subsequently coupled with hexyne and (R,S)-1-phenyl-2-propyn-
1-ol under standard Sonogashira coupling conditions to give
HENECA (2) and (R,S)-PHPNECA (3), respectively, to exemplify the
utility of this chemistry for the preparation of potent A2AAR
agonists.
4.3. Synthesis of (R,S)-2-(3-phenyl-3-hydroxy-1-propyn-1-
yl)adenosine-50-N-ethylcarboxamide ((R,S)-PHPNECA) (3)5
Compound 13 (32 mg, 0.074 mmol) was dissolved in THF
(10 mL) under an atmosphere of N2. Et3N (1 mL) and CuI (10 mg,
0.053 mmol) were added to the solution forming a suspension, the
mixture was de-gassed by bubbling N2 through the reaction mix-
ture for 30 min. Addition of PdCl2(PPh3)2 (13 mg, 0.019 mmol),
The linear approach featured an improved procedure for func-
tionalising the 6-position of the purine, which involved activation
using 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate and subsequent nucleophilic displacement of
the resultant 6-benzotriazol-1-yloxy moiety. The 6-OBt group was
introduced in 95% yield, which compares favourably with the
modest 35% yield obtained for the phosphorous oxychloride me-
diated chlorination of this position. This approach was also readily
amenable to the introduction of alkylamino functionality in the 2-
position via the substitution of 22.
followed promptly by (R,S)-1-phenyl-2-propyn-1-ol (19 mL, 0.15
mmol) caused the mixture to change from yellow to black, this was
stirred at 25 ꢀC for 16 h before more PdCl2(PPh3)2 (13 mg,
0.019 mmol) and (R,S)-1-phenyl-2-propyn-1-ol (19 mL, 0.15 mmol)
were added and stirred for a further 4 days. The crude mixture was
loaded onto silica gel and purified via column chromatography
using gradient elution from DCM to DCM/MeOH (4:1) to yield
a grey solid (18 mg, 56%), mp: 146–147 ꢀC, (lit.5 mp 135–137 ꢀC
dec); 1H NMR (300 MHz, CD3OD)
d
: 0.95 (t, 3H, J¼7.2 Hz), 2.95–3.06
(m, 2H), 4.16 (s, 1H), 4.33 (s, 1H), 4.60 (s, 1H), 5.53 (s, 1H), 5.69 (s,
Both of the synthetic approaches described herein are readily
amenable to the preparation of a range of adenosine-50-N-alkyl-
carboxamides, which are functionalised in the 2- and N6-positions.
1H), 5.97 (s, 1H), 7.39–7.45 (m, 5H), 8.44 (s, 1H); 13C NMR (75 MHz,
CD3OD) d: 14.8, 34.1, 64.3, 83.6, 84.2, 85.9, 86.6, 91.9, 112.4, 116.6,
126.5,127.9,128.4,137.1,139.8,152.2,153.0,156.3,169.0; HRMS (ESI)
m/z calcd for C21H23N6Oþ5 [MþH] 439.1724, found: 437.1731.
4. Experimental
4.4. Synthesis of 2-iodo-6-chloropurine (6)9
4.1. General experimental
In a 10–20 mL microwave tube, 2-amino-6-chloropurine (5)
Starting materials were purchased from either Sigma–Aldrich or
Advanced Molecular Technologies and had a purity of 96% or
greater. Microwave reactions were performed using a Biotage Ini-
tiator 2.0. Melting points were determined on an Electrothermal
melting point apparatus and are uncorrected. NMR spectra were
recorded on a Bruker Avance DPX 300 spectrometer or a Varian
Unity Inova 600 MHz spectrometer. Optical rotations were mea-
sured on a Jasco P-2000 Polarimeter. Infrared spectra were recor-
ded with a Scimitar Series Varian 800 FT-IR Spectrometer fitted
with a PIKE Technologies MIRacle ATR and neat samples were used.
Low resolution electrospray mass spectra (LRMS) using electro-
spray ionisation (ESI) were obtained on a Micromass Platform II
spectrometer. Unless otherwise stated, cone voltage was 20 eV.
High resolution mass spectra (HRMS) were obtained on a Waters
LCT Premier XE (TOF) spectrometer fitted with an electrospray ion
source.
(200 mg, 1.20 mmol) was dissolved in DMF (8 mL). CuI (23 mg,
0.12 mmol), CH2I2 (1.5 mL) and iso-amylnitrite (800 mL, 6.00 mmol)
were added and the reaction mixture was heated to 120 ꢀC for 2 h
in the microwave. The solvents were evaporated under reduced
pressure and the resultant oil loaded onto a silica gel plug (w100 g),
the impurities were removed by eluting with 500 mL of hexane/
EtOAc (4:1), elution of the product was achieved using EtOAc
(500 mL) leaving a brown oil, which was triturated with hexane/
EtOAc (4:1) and a few drops of conc. HCl to yield a cream powder
(242 mg, 73%), mp: 210 ꢀC dec, (lit.9 mp 200 ꢀC dec); 1H NMR
(300 MHz, DMSO-d6)
d
: 8.63 (s, 1H), 13.87 (s, 1H); 13C NMR
(75 MHz, DMSO-d6) d: 117.7,129.7,147.1,147.4,156.1; HRMS (ESI) m/z
calcd for C5H3ClINþ4 [MþH] 280.9085, found: 280.9094.
4.5. Synthesis of 2-iodo-6-chloro-9-(tetrahydropyran-2-yl)-
purine (7)9
4.2. Synthesis of 2-(hexyn-1-yl)adenosine-50-N-
The purine 6 (1.00 g, 3.57 mmol) was dissolved in THF (10 mL)
under an atmosphere of N2. 3,4-Dihydro-2H-pyran (1.30 mL,
14.30 mmol) and p-toluenesulfonic acid (68 mg, 0.36 mmol) were
added and the reaction mixture heated to reflux overnight. Upon
cooling, H2O (100 mL) was added and the product extracted using
EtOAc (3ꢂ100 mL). The organic fractions were combined, washed
with H2O (100 mL), brine (100 mL), then dried using Na2SO4. The
solvents were removed under reduced pressure to yield an oil.
Trituration with hexane afforded a yellow solid (1.03 g, 78%), mp:
ethylcarboxamide (2)4,14
Compound 13 (32 mg, 0.074 mmol) was dissolved in THF
(10 mL) under an atmosphere of N2. Et3N (1 mL) and CuI (10 mg,
0.053 mmol) were added to the solution forming a suspension. The
mixture was de-gassed by bubbling N2 through the reaction mix-
ture for 30 min. Addition of PdCl2(PPh3)2 (13 mg, 0.019 mmol),
followed promptly by hexyne (17 mL, 0.15 mmol) caused the mix-
ture to change from yellow to black, this was stirred at 25 ꢀC for
16 h before additional PdCl2(PPh3)2 (13 mg, 0.019 mmol) and hex-
112–114 ꢀC, (lit.9 mp 112–113 ꢀC dec); 1H NMR (300 MHz, CDCl3)
d:
1.41–1.45 (m, 3H), 1.65–1.88 (m, 2H), 1.94–2.00 (m, 1H), 3.79 (t, 1H,
yne (17
m
L, 0.15 mmol) were added and stirred for a further 3 days.
J¼9.6 Hz), 4.19 (d, 1H, J¼12.3 Hz), 5.77 (d, 1H, J¼10.5 Hz), 8.25 (s,
The crude mixture was loaded onto silica gel and purified via col-
umn chromatography using gradient elution from DCM to DCM/
MeOH (9:1) to yield a tan solid 22 mg (76%), mp: 145–146 ꢀC, (lit.14
1H); 13C NMR (75 MHz, CDCl3)
d: 22.1, 24.7, 31.9, 68.9, 82.4, 116.6,
131.5, 143.4, 150.0, 151.6; HRMS (ESI) m/z calcd for C10H11ClIN4Oþ
[MþH] 364.9661, found: 364.9675.
mp 147–150 ꢀC); 1H NMR (300 MHz, acetone-d6)
d: 0.93 (t, 3H,
J¼7.2 Hz), 1.13 (t, 3H, J¼6.9 Hz), 1.50–1.55 (m, 2H), 1.60–1.66 (m,
2H), 2.43 (t, 2H, J¼6.9 Hz), 3.35–3.47 (m, 2H), 4.32 (br s, 1H), 4.39
(br s, 1H), 4.64 (br s, 1H), 4.82 (br s, 2H), 5.97 (d, 1H, J¼8.4 Hz), 6.81
(br s, 2H), 8.21 (s, 1H), 8.72 (br s, 1H); 13C NMR (151 MHz, DMSO-d6)
4.6. Synthesis of 2-iodo-9-(tetrahydropyran-2-yl)adenine (8)
A solution of 7 (500 mg, 1.37 mmol) in MeOH (10 mL) was
cooled to 0 ꢀC in a pressure tube. Gaseous NH3 was slowly bubbled
through this solution for 30 min before the tube was sealed and
stirred at room temperature for 7 days. The solvents were removed
under reduced pressure and the resultant solid was purified on
d: 13.9, 15.4, 18.3, 21.9, 30.3, 49.0, 73.6, 76.6, 86.2, 88.2, 108.3, 109.5,
117.1, 140.1, 145.9, 156.4, 158.8, 169.7; HRMS (ESI) m/z calcd for
C18H25N6Oþ4 [MþH] 389.1932, found: 389.1945.

R.C. Foitzik et al. / Tetrahedron 65 (2009) 8851–8857
8855
a silica gel column using EtOAc as the eluent (Rf¼0.57) to yield the
desired product as a white powder (427 mg, 90%), mp: 209–210 ꢀC;
1H NMR (300 MHz, DMSO-d6)
: 1.45–1.48 (m, 2H), 1.76–1.80 (m,
2H), 1.97–2.03 (m, 2H), 3.68–3.72 (m, 2H), 5.55 (d, 1H, J¼10.8 Hz),
7.67 (s, 2H), 8.28 (s, 1H); 13C NMR (75 MHz, DMSO-d6)
: 22.8, 25.0,
5.97 (d, 1H, J¼7.1 Hz), 8.22 (s, 1H); 13C NMR (151 MHz, DMSO-d6)
d:
15.3, 34.0, 73.1, 73.4, 84.7, 87.5, 119.6, 121.6, 140.4, 150.3, 156.4,
169.6; HRMS (ESI) m/z calcd for C12H16IN6Oþ4 [MþH] 435.0272,
found: 435.0284.
d
d
30.8, 68.2, 81.2, 119.0, 121.5, 139.3, 149.8, 156.4; HRMS (ESI) m/z
calcd for C10H13IN5Oþ [MþH] 346.0159, found: 346.0163.
4.9.2. Method B. A solution of 20 (300 mg, 0.51 mmol), NH4OH
(28%) in MeCN (20 mL) was stirred at 25 ꢀC for 3 days. The reaction
mixture was evaporated to dryness, then dissolved in EtOAc
(100 mL), washed with H2O (5ꢂ100 mL) and dried over MgSO4.
Evaporation of the filtrate afforded a yellow foam as the pure
protected product (231 mg, 96%). This compound was subsequently
dissolved in TFA (3 mL) and H2O (0.5 mL) and stirred at 50 ꢀC for
3 h. This reaction mixture was partitioned between EtOAc (100 mL)
and H2O (100 mL) and then basified with solid NaHCO3. The organic
layer was separated and washed with H2O (3ꢂ100 mL), brine
(50 mL), dried over MgSO4 and the filtrate was evaporated to afford
a white solid (207 mg, 93%).
4.7. Synthesis of 2-iodoadenine (9)
4.7.1. Method A. To a solution of 8 (173 mg, 0.48 mmol) in 95:5
EtOH/H2O (25 mL), CuCl2 (13 mg, 0.10 mmol) was added and the
reaction mixture stirred at reflux overnight. Upon cooling, the re-
action mixture was evaporated to dryness to afford a green solid.
This solid was suspended in a 1 M HCl solution (50 mL) then fil-
tered, resulting in 115 mg (89%) of a tan solid as the product, mp:
258–260 ꢀC dec; 1H NMR (300 MHz, DMSO-d6)
d
: 7.56 (br s, 2H),
8.04 (s, 1H), 12.98 (br s, 1H); 13C NMR (75 MHz, DMSO-d6)
d: 117.2,
121.0, 139.9, 152.6, 155.9; HRMS (ESI) m/z calcd for C5H5INþ5 [MþH]
4.10. Synthesis of 20,30-O-isopropylideneguanosine (15)15
261.9584, found: 261.9585.
Guanosine (14) (15.00 g, 53.0 mmol) was stirred in acetone
(600 mL). p-Toluenesulfonic acid (9.15 g, 53.0 mmol) and 2,2-
dimethoxypropane (150 mL) were added and the reaction mixture
was stirred overnight at 25 ꢀC. The reaction mixture was evapo-
rated to dryness and then dissolved in H2O (100 mL). Solid NaHCO3
(4.45 g, 53.0 mmol) was added cautiously portion wise and the
solution was stirred for 2 h. Saturated NaHCO3 (100 mL) was added
and the solution was stirred for a further 2 h. The suspension was
filtered and the product washed with cold H2O (2ꢂ50 mL) to yield
4.7.2. Method B. Purine (6) (150 mg, 0.53 mmol), NH4Cl (100 mg,
1.87 mmol), DIPEA (1.5 mL) and i-PrOH (3.5 mL) were added to
2–5 mL microwave vial and heated at 150 ꢀC for 2 h. The mixture
was cooled to room temperature, filtered and the filtrate evapo-
rated under reduced pressure. To this oil, H2O (100 mL) was added
and the precipitate that formed was collected by filtration and
washed with H2O to give a yellow solid (9) (127 mg, 91%).
4.8. Synthesis of 2-iodoadenosine-20,30-O-diacetyl-50-
methylcarboxylate (12)
a white solid (16.05 g, 94%), mp: 260–262 ꢀC dec, (lit.15 mp 292 ꢀC
24
dec); [
a
]
ꢁ30.5 (c 0.93, DMSO) (lit.15
[a
]
D ꢁ36.3 (c 4.98, DMF)). IR
n
D
3427, 3322, 3206, 2729, 1717, 1629, 1375, 1213, 1071, 861; 1H NMR
2-Iodo-6-aminopurine (9) (50 mg, 0.19 mmol), (NH4)2SO4
(6 mg, 0.05 mmol) and hexamethyldisilazane (5 mL) in anhydrous
MeCN (2 mL) were heated under reflux for 2 h under an atmos-
phere of N2. After evaporation at reduced pressure, the residue was
taken up in anhydrous 1,2-dichloroethane (DCE) (2 mL) and added
(300 MHz, DMSO-d6) d: 1.33 (s, 3H), 1.53 (s, 3H), 3.49–3.59 (m, 2H),
4.11–4.15 (m, 1H), 4.97 (dd, 1H, J¼3.0, 6.2 Hz), 5.02 (br s, 1H), 5.20
(dd, 1H, J¼2.5, 6.2 Hz), 5.94 (d, 1H, J¼2.5 Hz), 6.49 (br s, 2H), 7.92 (s,
1H), 10.66 (br s, 1H); 13C NMR (75 MHz, DMSO-d6)
d: 25.7, 27.5, 62.1,
81.7, 84.0, 87.1, 88.9, 113.5, 117.2, 136.4, 151.2, 154.2, 157.3; HRMS
to a stirred solution of methyl 1,2,3-tri-O-acetyl-
b-
D-ribofuronate
(ESI) m/z calcd for C13H18N5O5þ [MþH] 324.1302, found: 324.1303.
(11) (73 mg, 0.24 mmol) in anhydrous DCE (3 mL) in a 2–5 mL
microwave vial and capped under N2. After 5 min stirring, TMS
4.11. Synthesis of 20,30-O-isopropylideneguanosine-50-
triflate (45
mL, 0.25 mmol) was added dropwise and the mixture
carboxylic acid (16)
was heated in the microwave at 90 ꢀC for 20 min. This was then
added to a mixture of a saturated solution of NaHCO3 (50 mL) and
DCM (50 mL) and extracted into the organic phase. The aqueous
layer was then extracted with DCM (2ꢂ20 mL), washed with brine
(50 mL), dried over MgSO4, filtered and the filtrate evaporated
under reduced pressure to afford a yellow oil (89 mg). Purification
was achieved using a silica gel column using gradient elution from
1:1 hexane/EtOAc to neat EtOAc to give a colourless oil (12) (53 mg,
20,30-O-Isopropylideneguanosine (15) (2.5 g, 7.73 mmol), TEMPO
(302 mg, 1.93 mmol) and bis(acetoxy)iodobenzene (BAIB) (5.48 g,
17.0 mmol) were combined in MeCN/H2O (1:1, 100 mL) and stirred
overnight at 25 ꢀC. Acetone (50 mL) was added followed by Et2O
(250 mL) and the mixture stirred for a further 2 h. The mixture was
filtered and the solid washed with a further 100 mL of Et2O
resulting in an orange solid (1.88 g, 72%), mp: 210–212 ꢀC dec. IR
n
55%); 1H NMR (300 MHz, CDCl3)
d: 2.06 (s, 3H), 2.22 (s, 3H), 3.87 (s,
3340, 1634, 1383, 1056, 865, 772; 1H NMR (300 MHz, DMSO-d6)
d
:
3H), 4.74 (d, 1H, J¼1.5 Hz), 5.70–5.75 (m, 2H), 6.09 (br s, 2H), 6.36–
6.40 (m, 1H), 8.34 (s, 1H). ESMS calcd for C15H17IN5Oþ7 [MþH] 506.0,
found: 505.8.
1.45 (s, 3H), 1.51 (s, 3H), 4.63 (s, 1H), 5.33 (d, 1H, J¼6.0 Hz), 5.59 (d,
1H, J¼6.0 Hz), 6.12 (s, 1H), 6.40 (s, 2H), 7.78 (s, 1H), 10.60 (s, 1H); 13C
NMR (151 MHz, DMSO-d6) d: 25.4, 27.1, 84.3, 84.4, 86.5, 89.6, 112.9,
116.8, 137.0, 151.4, 154.1, 157.4, 172.4; MS (ESI) m/z calcd for
4.9. Synthesis of 2-iodoadenosine-50-N-ethyl-
C13H16N5Oþ6 [MþH] 338.1, found: 338.1.
carboxylamide (13)4
4.12. Synthesis of 20,30-O-isopropylideneguanosine-50-
4.9.1. Method A. Compound 12 (53 mg, 0.11 mmol) and ethylamine
(1 mL, 2.0 M solution in THF) were combined in THF (2 mL) and
heated (microwave) at 110 ꢀC for 3 h. The solvents were removed
under reduced pressure leaving a dark oil. Purification was ach-
ieved using a silica gel column using gradient elution from EtOAc to
89:10:1 EtOAc/acetone/NH4OH to yield a tan solid (13) (28 mg,
61%), mp: 214–216 ꢀC dec, (lit.4 mp 232–234 ꢀC dec); 1H NMR (300
methylcarboxylate (17)
A suspension of the carboxylic acid (16) (3.00 g, 8.89 mmol) in
MeOH (400 mL) was stirred at 0 ꢀC for 30 min. SOCl2 (3.22 mL,
44.50 mmol) was slowly added and the reaction mixture left to
warm to room temperature overnight. A solution of saturated
NaHCO3 (20 mL) was cautiously added, followed by solid NaHCO3
portion wise over several hours until the solid NaHCO3 was sus-
pended in the mixture. Silica gel was added to the reaction mixture
MHz, CD3OD)
d: 1.27 (t, 3H, J¼7.2 Hz), 3.40–3.55 (m, 2H), 4.36 (dd,
1H, J¼2.0, 5.0 Hz), 4.44 (d, 1H, J¼2.0 Hz), 4.75 (dd, 1H, J¼5.0, 7.1 Hz),

8856
R.C. Foitzik et al. / Tetrahedron 65 (2009) 8851–8857
and the mixture evaporated to dryness, this was loaded onto a plug
1H NMR (300 MHz, DMSO-d6)
d
: 0.68 (t, 3H, J¼7.2 Hz), 1.35 (s, 3H),
of silica and the product extracted using 800 mL of DCM/MeOH
1.52 (s, 3H), 2.78–2.92 (m, 2H), 4.52 (d, 1H, J¼2.1 Hz), 5.40 (d, 1H,
J¼6.0 Hz), 5.51 (dd, 1H, J¼2.1, 6.0 Hz), 6.28 (s, 1H), 6.65 (br s, 2H),
7.46 (t, 1H, J¼6.0 Hz), 7.52–7.56 (m, 1H), 7.65 (m, 2H), 8.17 (d, 1H,
24
(9:1) to yield a white solid (1.90 g, 61%), mp: 203–205 ꢀC dec; [
a]
D
þ24.5 (c 0.73, DMSO). IR
n
3441, 3158, 2990, 2717, 1702, 1637, 1603,
: 1.25 (s,
1385, 1212, 1101, 865, 781; 1H NMR (300 MHz, DMSO-d6)
d
J¼8.4 Hz), 8.21 (s, 1H); 13C NMR (151 MHz, DMSO-d6)
d: 14.4, 25.5,
3H),1.46 (s, 3H), 3.38 (s, 3H), 4.73 (d,1H, J¼1.5 Hz), 5.25 (d,1H, J¼6.0
27.0, 33.5, 2ꢂ83.7, 87.0, 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; HRMS (ESI) m/z calcd
for C21H24N9Oþ5 [MþH] 482.1895, found: 482.1901.
Hz), 5.69 (dd, 1H, J¼1.5, 6.0 Hz), 6.15 (s, 1H), 6.37 (br s, 2H), 7.75 (s,
1H),10.60 (br s,1H); 13C NMR (75 MHz, DMSO-d6)
d: 25.3, 26.8, 52.1,
84.0, 84.8, 86.4, 90.0, 112.8, 117.2, 137.7, 151.1, 153.7, 157.2, 170.2;
HRMS (ESI) m/z calcd for C14H18N5Oþ6 [MþH] 352.1252, found:
352.1262.
4.16. Synthesis of 2-fluoro-O6-(benzotriazol-1-yl)-20,30-O-
isopropylideneinosine-50-N-ethylcarboxamide (20)
4.13. Synthesis of 20,30-O-isopropylideneguanosine-50-N-
Compound 19 (200 mg, 0.42 mmol) was dissolved in dry MeCN
ethylcarboxamide (18)
(3 mL). CH2I2 (1 mL) and t-BuONO (200 mL, 1.66 mmol) were added
and the reaction mixture was heated to 65–70 ꢀC for 4 h. The re-
action mixture was diluted with EtOAc (200 mL) and washed with
H2O (3ꢂ100 mL). The crude reaction mixture was purified on a sil-
20,30-O-Isopropylideneguanosine-50-methylcarboxylate (17)
(3.00 g, 8.54 mmol), ethylamine (2.0 M in THF, 25 mL) and
MeOH/DMF (9:1, 20 mL) were combined in a 150 mL bomb
reactor and heated to 70–75 ꢀC for 3 days. Upon cooling the
solvents were evaporated and the crude reaction mixture pu-
rified on a silica gel column using gradient elution from DCM to
ica gel column using gradient elution from DCM to DCM/MeOH
24
(9:1) to yield a tan solid 190 mg (76%), mp: 195–196 ꢀC dec; [
a]
D
þ23.7 (c 0.92, DMSO). IR
n 3293, 3098, 2991, 1655, 1557, 1384, 1205,
1084, 747; 1H NMR (300 MHz, DMSO-d6)
d
: 0.61 (t, 3H, J¼7.2 Hz),
DCM/MeOH (9:1) to yield a tan solid (3.05 g, 98%), mp: 199–
1.35 (s, 3H), 1.53 (s, 3H), 2.78–2.92 (m, 2H), 4.60 (d, 1H, J¼1.5 Hz),
24
200 ꢀC dec; [
a
]
ꢁ4.30 (c 0.93, DMSO). IR
n
3316, 3157, 2934,
5.31–5.39 (m, 2H), 6.45 (s,1H), 7.55–7.59 (m, 2H), 7.67–7.69 (m, 2H),
D
2755, 1694, 1659, 1598, 1531, 1381, 1084, 865, 781; 1H NMR
(300 MHz, CD3OD)
8.21 (d, 1H, J¼8.4 Hz), 8.65 (s, 1H); 13C NMR (151 MHz, DMSO-d6)
d:
d: 0.79 (t, 3H, J¼7.2 Hz), 1.36 (s, 3H), 1.58 (s,
14.6, 25.5, 27.0, 33.5, 83.8, 83.9, 87.5, 90.3, 109.5, 113.3, 117.5, 119.3,
120.5, 125.9, 128.7, 130.0, 143.2, 146.8, 155.3, 157.1, 168.3; HRMS
(ESI) m/z calcd for C21H22IN8O5þ [MþH] 593.0752, found: 593.0750.
3H), 2.85–3.10 (m, 2H), 4.63 (d, 1H, J¼1.8 Hz), 5.41 (d, 1H,
J¼6.0 Hz), 5.72 (dd, 1H, J¼1.8, 6.0 Hz), 6.23 (s, 1H), 7.86 (s, 1H);
13C NMR (75 MHz, CD3OD)
d: 14.4, 25.5, 27.0, 33.6, 83.6, 83.9,
86.6, 89.4, 113.1, 117.0, 137.1, 151.1, 154.0, 157.3, 168.7; HRMS
4.17. Synthesis of 2-fluoro-O6-(benzotriazol-1-yl)-20,30-O-
isopropylideneinosine-50-N-ethylcarboxamide (21)
(ESI) m/z calcd for C15H21N6O5þ [MþH] 365.1568, found: 365.1581.
4.14. Synthesis of 2-amino-6-chloropurin-9-yl-20,30-O-
isopropylidene-50-N-ethylcarboxamide (19a)16
Pyridine (520
m
L) was cooled to ꢁ30 ꢀC, and 70% HF in pyridine
(2.7 mL) added with stirring. Compound 19b (500 mg, 1.04 mmol)
was added and stirred until dissolution occurred. The temperature
Under inert conditions Et4NCl (200 mg, 1.21 mmol) and guano-
sine-20,30-O-isopropylidene-50-N-ethylcarboxamide (18) (200 mg,
0.55 mmol) were dried under vacuum for 16 h. To this, freshly
was allowed to rise to ꢁ20 ꢀC and t-BuONO (520
mL, 5.82 mmol)
added slowly dropwise. The reaction mixture was maintained at
ꢁ20 ꢀC with stirring for 20 min, and then poured over ice. The
resulting precipitate was collected via vacuum filtration, rinsed
with H2O and dried in vacuo to yield a beige solid (298 mg, 59%),
distilled DMA (100
m
L, 0.86 mmol) and MeCN (20 mL) were added
and the reaction mixture was cooled to 0 ꢀC, distilled POCl3 (500
mL,
2.0 mmol) was added and the reaction mixture heated to reflux for
1 h. The reaction mixture was evaporated to dryness under reduced
pressure. The resultant oil was diluted with CHCl3 (100 mL) and to
this was added ice water (100 mL) cautiously followed by a satd
soln of NaHCO3 (100 mL). The organic fraction was separated and
the aqueous phase washed with CHCl3 (2ꢂ100 mL). The organic
fractions were combined and dried over MgSO4, evaporated and
adsorbed on a silica gel column. The product was purified using
gradient elution (DCM to 9:1 DCM/methanol) to yield a brown oil as
the product (75 mg, 36%). Rf¼0.50 DCM/MeOH (9:1); 1H NMR (300
mp: 140–145 ꢀC dec. IR
n 3401, 3098, 2986, 1628, 1588, 1378, 1199,
1085, 743; 1H NMR (300 MHz, DMSO-d6)
d: 1.11 (t, 3H, J¼7.2 Hz),
1.35 (s, 3H), 1.52 (s, 3H), 2.70–2.95 (m, 2H), 4.61 (d, 1H, J¼1.8 Hz),
5.38 (dd, 1H, J¼1.8, 6.0 Hz), 5.44 (d, 1H, J¼6.0 Hz), 6.45 (s, 1H), 7.59
(t, 1H, J¼6.3 Hz), 7.65–7.80 (m, 3H), 8.22 (d, 1H, J¼9.5 Hz), 8.76 (s,
1H);13C NMR (300 MHz, CD3OD)
d: 14.2, 25.0, 27.0, 34.0, 82.7, 83.2,
85.8, 91.8, 108.3, 115.0, 118.6, 120.7, 125.3, 128.5, 129.3, 143.4, 144.9,
155.1 (J¼16.4 Hz), 157.1 (J¼221.8 Hz), 160.0 (J¼16.4 Hz), 167.9; ESMS
calcd for C21H22N8O5Fþ [MþH] 485.2, found: 485.4.
MHz, CDCl3)
d
: 0.76 (t, 3H, J¼7.2 Hz), 1.41 (s, 3H), 1.60 (s, 3H), 2.86–
4.18. 2-Fluoroadenosine-20,30-O-isopropylidene-50-N-
ethylcarboxamide (22)
3.11 (m, 2H), 4.72 (d, 1H, J¼1.8 Hz), 5.31 (d, 1H, J¼6.0 Hz), 5.69 (dd,
1H, J¼1.8, 6.0 Hz), 5.97 (s, 1H), 6.10 (t, 1H, J¼5.5 Hz), 6.49 (br s, 2H),
7.93 (s, 1H); 13C NMR (151 MHz, CDCl3)
d: 14.0, 25.3, 27.0, 34.7, 85.3,
To a stirred solution of 21 (600 mg, 1.24 mmol) in MeCN (6 mL)
at 0 ꢀC was added 28% ammonia solution (500
mL). The solution was
89.7, 92.4, 114.6, 124.9, 144.5, 151.8, 154.3, 161.3, 171.7; HRMS (ESI)
m/z calcd for C15H20ClN6Oþ4 383.1229, found 383.1231.
allowed to rise to room temperature and stirring was continued for
2 h. The solvent was removed in vacuo, and the residue partitioned
between H2O and EtOAc. The aqueous phase was extracted into
EtOAc (ꢂ3) and the combined organic phase was washed with H2O
and brine, dried over MgSO4 and evaporated to afford the crude
product. Purification was achieved via column chromatography
4.15. Synthesis of O6-(benzotriazol-1-yl)-20,30-O-
isopropylideneguanosine-50-N-ethylcarboxamide (19b)
Compound 18 (500 mg, 1.37 mmol) was suspended in MeCN
(30 mL). BOP (911 mg, 2.06 mmol) and DBU (308
m
L, 2.06 mmol)
(silica gel) using EtOAc as the eluent to yield a pale yellow solid
23
were added and the reaction mixture was stirred at room tem-
perature for 16 h. The mixture was diluted with EtOAc (200 mL)
and washed with H2O (5ꢂ100 mL), brine (50 mL), dried over MgSO4
and evaporated to yield a yellow foam as the product (629 mg,
(399 mg, 88%), mp: 182–185 ꢀC dec; [
a
]
ꢁ31.6 (c 0.67, CHCl3). IR
n
D
3290, 3141, 1672, 1373, 1205, 1089, 1053, 858; 1H NMR (300 MHz,
DMSO-d6)
d
: 0.67 (t, 3H, J¼7.2 Hz), 1.34 (s, 3H), 1.52 (s, 3H), 2.70–
2.97 (m, 2H), 4.54 (s, 1H), 5.37 (br s, 2H), 6.29 (s, 1H), 7.52
95%), mp: 140–141 ꢀC. IR
n
3398, 1641, 1572, 1376, 1205, 1093, 835;
(t, J¼5.4 Hz, 1H), 7.87 (br s, 2H), 8.21 (s, 1H); 13C NMR (300 MHz,

R.C. Foitzik et al. / Tetrahedron 65 (2009) 8851–8857
8857
CD3OD)
d
: 14.3, 25.4, 27.2, 33.5, 83.5, 83.6, 86.5, 89.8, 113.4, 117.8,
74.9, 85.7, 90.3, 115.0, 127.4, 129.7, 130.1, 139.4, 141.3, 153.3, 157.7,
161.3, 172.2; HRMS (ESI) m/z calcd for C20H26N7Oþ4 [MþH]þ
428.2041, found: 428.2037.
141.0,150.7 (J¼20.1 Hz),158.1 (J¼21.1 Hz),158.8 (J¼203.2 Hz),168.5;
MS (ESI) m/z calcd for C15H20N6O4Fþ [MþH] 367.2, found: 367.6.
4.19. 2-(Phenethyl-2-amino)adenosine-20,30-O-
isopropylidene-50-N-ethylcarboxamide (23)17
Acknowledgements
The authors wish to thank the ARC Centre of Excellence for Free
Radical Chemistry and Biotechnology for financial support.
A solution of 22 (50 mg, 0.137 mmol), phenylethyl-2-amine
(33 mg, 0.273 mmol) and DIPEA (200 mL) in EtOH (2 mL) was stirred
in a sealed reaction vessel at 110 ꢀC for 3 days. The crude mixture
was evaporated onto silica gel and purified by column chroma-
tography using EtOAc as the eluent (30 mg, 47%), mp: 185–187 ꢀC;
References and notes
1. Cristalli, G.; Cacciari, B.; Dal Ben, D.; Lambertucci, C.; Moro, S.; Spalluto, G.;
Volpini, R. ChemMedChem 2007, 2, 260–281.
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Egan, R. J. Med. Chem. 1980, 23, 313–319.
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1H NMR (300 MHz, CD3OD)
d
: 0.61 (t, 3H, J¼7.2 Hz),1.38 (s, 3H),1.59
(s, 3H), 2.70–2.85 (m, 2H), 2.85–2.95 (m, 2H), 3.44–3.54 (m, 1H),
3.69–3.80 (m, 1H), 4.61 (s, 1H), 5.58 (d, 1H, J¼6.0 Hz), 5.63 (d, 1H,
J¼6.0 Hz), 6.22 (s, 1H), 7.15–7.32 (m, 5H), 7.88 (s, 1H); 13C NMR
(300 MHz, MeOD) d: 12.3, 23.8, 25.2, 33.1, 35.1, 42.3, 83.6, 84.1, 87.9,
91.1, 112.8, 113.0, 125.7, 128.0, 128.5, 138.1, 139.8, 151.0, 156.1, 159.3,
170.1; MS (ESI) m/z calcd for C23H30N7Oþ4 [MþH] 468.2, found:
468.4.
5. Cristalli, G.; Volpini, R.; Vittori, S.; Camaioni, E.; Monopoli, A.; Conti, A.;
Dionisotti, S.; Zocchi, C.; Ongini, E. J. Med. Chem. 1994, 37, 1720–1726.
6. Rieger, J. M.; Brown, M. L.; Sullivan, G. W.; Linden, J.; Macdonald, T. L. J. Med.
Chem. 2001, 44, 531–539.
7. Nair, V.; Young, D. A. J. Org. Chem. 1985, 50, 406–408.
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Med. Chem. 2008, 16, 19–26.
9. Taddei, D.; Kilian, P.; Slawin, A. M. Z.; Woollins, J. D. Org. Biomol. Chem. 2004, 2,
665–670.
4.20. 2-(Phenethyl-2-amino)adenosine-50-N-
}
ethylcarboxamide (24)17
10. Kato, K.; Hayakawa, H.; Tanaka, H.; Kumamoto, H.; Shindoh, S.; Miyasaka, T.
J. Org. Chem. 1997, 62, 6833–6841.
A solution of 23 (30 mg, 0.064 mmol) in 1 M HCl (10 mL) was
stirred for 5 h at 60 ꢀC. The solution was cooled, basified with
NaHCO3, and extracted with EtOAc (ꢂ4). The organic phase washed
with brine, dried over MgSO4 and evaporated to yield pure 24
(22 mg, 80%), mp: 104–106 ꢀC, (lit.17 mp 115–118 ꢀC dec); 1H NMR
11. Devine, S. M.; Scammells, P. J. Tetrahedron 2008, 64, 1772–1777.
12. Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293–295.
13. Bae, S.; Lakshman, M. K. J. Am. Chem. Soc. 2007, 129, 782–789.
14. Homma, H.; Watanabe, Y.; Abiru, T.; Murayama, T.; Nomura, Y.; Matsuda, A.
J. Med. Chem. 1992, 35, 2881–2890.
15. Hampton, A. J. Am. Chem. Soc. 1961, 83, 3640–3645.
16. Adachi, H.; Palaniappan, K. K.; Ivanov, A. A.; Bergman, N.; Gao, Z.-G.; Jacobson,
K. A. J. Med. Chem. 2007, 50, 1810–1827.
(300 MHz, CD3OD)
d
: 1.06 (t, 3H, J¼7.2 Hz), 2.90 (t, 2H, J¼7.2 Hz),
3.07–3.20 (m, 1H), 3.21–3.33 (m, 1H), 3.48–3.60 (m, 1H), 3.60–3.71
(m, 1H), 4.40 (d, 1H, J¼2.7 Hz), 4.51 (dd, 1H, J¼2.7, 4.8 Hz), 5.02 (dd,
1H, J¼4.8, 6.3 Hz), 5.93 (d, 1H, J¼6.3 Hz), 7.15–7.34 (m, 5H), 7.99
17. Hutchison, A. J.; Williams, M.; de Jesus, R.; Yokoyama, R.; Oei, H. H.; Ghai, G. R.;
Webb, R. L.; Zoganas, H. C.; Stone, G. A.; Jarvis, M. F. J. Med. Chem. 1990, 33, 1919–
1924.
(s, 1H); 13C NMR (600 MHz, MeOD)
d: 14.9, 35.4, 37.1, 44.5, 73.5,