Synthesis of (purin-6-yl)acetates and their transformations to 6-(2-hydroxyethyl)-and 6-(carbamoylmethyl)purines

Article abstract of DOI:10.1135/cccc2009042

A novel approach to the synthesis of (purin-6-yl)acetates was developed based on Pdcatalyzed cross-coupling reactions of 6-chloropurines with a Reformatsky reagent. Their reduction with NaBH₄ and treatment with MnO₂ gave 6-(2-hydroxyethyl)purines, while reactions with amines in presence of NaCN afforded 6-(carbamoylmethyl)purines. Mesylation of the 6-(2-hydroxyethyl)purines followed by nucleophilic substitutions gave rise to several 6-(2-substituted ethyl)purines. This methodology was successfully applied to the synthesis of substituted purine bases and nucleosides for cytostatic and antiviral activity screening. None of the compounds exerted significant activity.

Full text of DOI:10.1135/cccc2009042

Synthesis of (Purin-6-yl)acetates
1035
SYNTHESIS OF (PURIN-6-YL)ACETATES AND THEIR
TRANSFORMATIONS TO 6-(2-HYDROXYETHYL)-
AND 6-(CARBAMOYLMETHYL)PURINES
1,
Zbyněk HASNÍK, Radek POHL, Blanka KLEPETÁŘOVÁ and Michal HOCEK *
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i.,
Gilead Sciences & IOCB Research Center, Flemingovo nám. 2, CZ-166 10 Prague 6,
1
Czech Republic; e-mail: hocek@uochb.cas.cz
Received March 20, 2009
Accepted April 30, 2009
Publish ed on lin e July 7, 2009
Dedicated to Dr. Alfred Bader for his generous support of chemical research and education.
A n ovel approach to th e syn th esis of (purin -6-yl)acetates was developed based on Pd-
catalyzed cross-couplin g reaction s of 6-ch loropurin es with a Reform atsky reagen t. Th eir
reduction with NaBH4 an d treatm en t with Mn O2 gave 6-(2-h ydroxyeth yl)purin es, wh ile re-
action s with am in es in presen ce of NaCN afforded 6-(carbam oylm eth yl)purin es. Mesylation
of th e 6-(2-h ydroxyeth yl)purin es followed by n ucleoph ilic substitution s gave rise to several
6-(2-substituted eth yl)purin es. Th is m eth odology was successfully applied to th e syn th esis of
substituted purin e bases an d n ucleosides for cytostatic an d an tiviral activity screen in g. Non e
of th e com poun ds exerted sign ifican t activity.
Keyw ord s: Purin es; Nucleosides; Organ ozin c reagen ts; Cross-couplin g; Reform atsky reagen t;
Fun ction alized organ om etallics.
Purin e bases an d n ucleosides bearin g diverse C-substituen ts in position 6
are an im portan t class of com poun ds possessin g a broad spectrum of bio-
logical effects. 6-Arylpurin e bases an d n ucleosides exert cytostatic1, an ti-
viral2 an d an tim icrobial3 activity or receptor m odulation 4. 6-Meth ylpurin e
an d its ribon ucleoside are h igh ly cytotoxic5 an d its liberation by purin e
n ucleoside ph osph orylases from its n on -toxic deoxyribon ucleoside was
proposed as a n ovel prin ciple in th e gen e th erapy of can cer6. We h ave been
in terested in th e syn th esis of purin es bearin g fun ction alized alkyl substitu-
en ts, an d reported syn th eses an d cytostatic activities of 6-(h ydroxym eth yl)-7,
6-(fluorom eth yl)-8 an d 6-(difluorom eth yl)purin e9 bases an d n ucleosides as
well as syn th eses of in active (purin -6-yl)alan in es10 an d -ph en ylalan in es11.
Very recen tly, we h ave fin ish ed syn th eses of a large series of 6-[(dialkyl-
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059
© 2009 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2009042

1036
Hasník, Pohl, Klepetářová, Hocek:
am in o)m eth yl]-, 6-(alkoxym eth yl)- an d 6-[(alkylsulfan yl)m eth yl]purin e
derivatives12, as well as h om ologous 6-[2-(dialkylam in o)eth yl]-, 6-[2-
(dialkylam in o)vin yl]-, 6-(2-alkoxyeth yl)- an d 6-[2-(alkylsulfan yl)eth yl]-
purin es13 wh ich also exerted sign ifican t cytostatic effects an d m oderate
n on -selective an ti-HCV activities. Several types of 6-(1,2-disubstituted
eth yl)purin es were prepared14 by oxiran e rin g-open in g reaction s of
6-oxiran ylpurin es with n ucleoph iles an d several substituted 6-cyclo-
propylpurin es by cyclopropan ation 15 of 6-vin ylpurin es with eth yl diazo-
acetate but th ese com poun ds were in active. 6-(2-Hydroxyeth yl)purin es
are of in terest as h om ologues of th e h igh ly cytostatic 6-(h ydroxym eth yl)-
purin es. Recen tly we h ave publish ed a prelim in ary com m un ication 16 on
th eir syn th esis via purin e-6-acetates prepared by cross-couplin g of 6-h alo-
purin es with th e Reform atsky reagen t. Here we give a full report on th is
m eth odology an d exten d th e study by furth er tran sform ation s to 6-(carb-
am oylm eth yl)purin es an d β-substituted 6-eth ylpurin es.
RESULTS AND DISCUSSION
(Purin -6-yl)acetates were prepared previously in m oderate yields by h etero-
cyclization of pyrim idin es17 an d by arylation of m alon ates18 or eth yl aceto-
acetate19 with 6-h alo- or 6-tosyloxypurin es followed by decarboxylation or
cleavage of acetoacetate. Th e form er m eth od is laborious17, wh ile th e latter
approach es18,19 were n ot reliably reproducible in our h an ds due to side re-
action s. Sin ce th ese com poun ds are apparen tly useful in term ediates for fur-
th er fun ction alization , we h ave tried to develop a practical n ew approach
to th eir syn th esis based on Pd-catalyzed cross-couplin g reaction s of h alo-
purin es with a Reform atsky reagen t un der m ild con dition s. Alth ough th e
first Pd-catalyzed arylation of aryl h alides was reported20 in 1979, on ly th e
developm en t of a n ew gen eration of sterically h in dered ph osph in e ligan ds
en abled application of th is reaction to a wide ran ge of aryl h alides un der
m ild con dition s21.
In order to fin d th e best catalytic system for th e preparation of (purin -
6-yl)acetates, reaction s of BrZn CH2COOEt with m odel 9-ben zyl-6-ch loro-
purin e (1a) to give (purin -6-yl)acetate 2a were perform ed usin g several
types of Pd catalysts an d ph osph in e ligan ds with varyin g Pd/ligan d ratios
an d reagen t am oun ts (Sch em e 1, Table I). Th e Reform atsky reagen t was
gen erated from eth yl brom oacetate an d zin c dust in an alogy with th e pro-
cedure publish ed22 for oth er organ ozin cs usin g preactivation of zin c by tri-
m eth ylsilyl ch loride an d 1,2-dibrom oeth an e. Th e first reaction perform ed
in th e presen ce of com m on Pd(PPh 3)4 catalyst gave th e desired (purin -6-yl)-
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

Synthesis of (Purin-6-yl)acetates
1037
acetate 2a in a low yield of 15% (en try 1). Th erefore we h ave tried differen t
catalytic system s based on Pd2dba3 in com bin ation with various ph osph in e
ligan ds. Th e use of P(o-Tol)3 or P(t-Bu)3·HBF4 ligan ds did n ot give an y reac-
tion (en tries 2, 3), wh ereas th e use of Joh n Ph os23 ((2-biph en yl)di-tert-butyl-
ph osph in e) with on ly 1 m ole % of Pd2dba3 loadin g resulted in a bit m ore
prom isin g 16% yield of 2a (en try 4) an d th is catalytic system was furth er
optim ized. Th e reaction con version stron gly depen ded on th e catalyst load-
in g, Pd/ligan d ratio an d on th e am oun t of th e Reform atsky reagen t (en tries
5–9). Ch an gin g th e Pd2dba3/ligan d ratio from in itial 1:2 to 1:4 in creased
th e yield to 31% (en try 5) an d in crease in Pd loadin g (2 m ole %) gave 48%
yield (en try 6). Sin ce furth er in crease in th e ratio or catalyst loadin g did n ot
brin g an y im provem en t (en tries 7, 8), th e excess of th e organ ozin c reagen t
was varied. Wh en usin g 4 equiv. of BrZn CH2COOEt in presen ce of 2 m ole %
R
N
COOEt
N
R
Cl
N
N
BrZn
COOEt
N
N
Bn
catalyst
solvent
N
N
Bn
2a,3a,4a
R= H, Me, Ph
1a
SCHEME 1
TABLE I
Optim ization of th e cross-couplin g of 1a with th e Reform atsky reagen t
Pd catalyst
m ole %
Ligan d
m ole %
Equivalen ts
of ester
Yield
%
En try
1
R
Product
H
H
Pd(PPh 3)4 (5)
Pd2dba3 (1)
Pd2dba3 (1)
Pd2dba3 (1)
Pd2dba3 (1)
Pd2dba3 (2)
Pd2dba3 (2)
Pd2dba3 (3)
Pd2dba3 (2)
Pd2dba3 (2)
Pd2dba3 (2)
3
2
2
2
2
2
2
2
4
4
4
2a
2a
2a
2a
2a
2a
2a
2a
2a
3a
4a
15
0
P(o-Tol)3 (4)
P(t-Bu)3·HBF4 (2)
Joh n Ph os (2)
Joh n Ph os (4)
Joh n Ph os (8)
Joh n Ph os (12)
Joh n Ph os (12)
Joh n Ph os (8)
Joh n Ph os (8)
Joh n Ph os (8)
3
4
H
0
H
16
31
48
43
47
91
0
5
H
6
H
7
H
8
H
9
H
10
11
Me
Ph
0
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

1038
Hasník, Pohl, Klepetářová, Hocek:
of Pd2dba3 an d 8 m ole % of Joh n Ph os ligan d, th e reaction proceeded very
sm ooth ly to afford th e desired ester 2a in an excellen t yield of 91% (en try 9).
We h ave also tried to apply th is optim ized procedure to th e reaction s of
bran ch ed Reform atsky reagen ts in order to prepare α-substituted (purin -6-yl)-
acetates 3a an d 4a. However, th ese reagen ts were en tirely un reactive un der
th ese con dition s an d on ly th e startin g com poun d was recovered after sepa-
ration (en tries 10, 11).
COOEt
Cl
N
N
N
N
BrZnCH2COOEt
N
N
Pd2dba3
JohnPhos
THF
N
N
R
R
1a-f
2a-f
In compounds 1-14:
TolO
TolO
O
O
R =
Bn
TolO OTol
TolO
a
c
e
TBSO
HO
TBSO
O
O
THP
TBSO OTBS
TBSO
b
d
O
f
O
HO
H
OH
i
HO OH
g
h
SCHEME 2
TABLE II
Cross-couplin gs of diverse h alopurin es with th e Reform atsky reagen t
En try
Halopurin e
Product
Yield, %
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
91
76
75
97
67
96
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

Synthesis of (Purin-6-yl)acetates
1039
Th e optim ized con dition s were th en applied to th e syn th esis of oth er de-
rivatives usin g a set of protected purin e bases an d n ucleosides with various
substituen ts in position 9 of th e purin e rin g (Sch em e 2, Table II). THP-
protected 6-ch loropurin e base 1b an d both toluoyl an d silyl protected ribo-
an d 2′-deoxyribon ucleosides 1c–1f reacted with [(eth oxycarbon yl)m eth yl]-
zin c brom ide gen erally very well givin g con version s to correspon din g
(purin -6-yl)acetates 3b–3f. Th e isolated yields of th e THP-protected base 2b
an d Tol-protected n ucleosides 2c an d 2e were som ewh at lower (67–76%)
com pared to alm ost quan titative yields of th e silylated n ucleosides 2d
an d 2f probably due to th e lim ited stability of th e THP- an d Tol-protectin g
groups durin g th e aqueous work-up. Th erefore, th e TBS groups were furth er
used for protection of n ucleosides in th e follow-up ch em istry.
Havin g developed an efficien t an d practical m eth odology for th e syn -
th esis of (purin -6-yl)acetates, we n ext explored th e possibility of furth er
fun ction al group tran sform ation s. Th e first reaction un der study was th e
h ydrolysis of th e ester in order to prepare (purin -6-yl)acetic acid (as a n ovel
in terestin g h etarylacetic acid). A m odel alkalin e h ydrolysis of 2a was per-
form ed un der m ild con dition s with aqueous NaOH in eth an ol (Sch em e 3).
Th e startin g com poun d quickly disappeared from th e reaction m ixture but,
after n eutralization with dilute HCl, th e on ly product obtain ed was
6-m eth ylpurin e 5a as a product of decarboxylation of th e un stable free
acetic acid form ed in situ. Wh en we tried a m ilder n eutralization with
Am berlite 67 followed by ch rom atograph y, th e sam e decarboxylation oc-
curred. Apparen tly, th e desired (purin -6-yl)acetic acid is too un stable to be
isolated.
COOEt
CH3
N
N
N
N
1.NaOH/EtOH/water
2. HCl or Amberlite 67
N
N
N
N
Bn
Bn
2a
5a
SCHEME 3
Th e m ost desirable tran sform ation of esters 2 is th e reduction to th e cor-
respon din g 6-(2-h ydroxyeth yl)purin es 6 (h om ologues of biologically active
6-(h ydroxym eth yl)purin es7). Th e reduction s were studied an d optim ized
with m odel ester 2a (Sch em e 4, Table III). Due to possible side reaction s in
protic m edia, we h ave tested several m etal h ydrides an d boran es in various
aprotic solven ts. Wh en usin g stron g m etal h ydrides such as LiAlH4, LiBEt3H
or L-Selectride, th e reaction did n ot proceed even after 2 days of h eatin g
an d th e startin g com poun d was recovered (en try 1). Th e use of sm all excess
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

1040
Hasník, Pohl, Klepetářová, Hocek:
of NaBH4 in DMF or th e use of boran e·Me2S in THF resulted on ly in decom -
position of th e startin g m aterial (en tries 2, 3). Usin g excess of NaBH4 in
refluxin g THF already gave traces of th e desired 6-(2-h ydroxyeth yl)purin e
6a (en try 4), wh ile th e use of 1 equiv. of DIBAH in toluen e gave a m ore
prom isin g 15% yield of 6a (en try 5). Furth er im provem en t was ach ieved by
usin g excess of DIBAH in toluen e (26% yield, en try 6) or AlH3 (prepared in
situ from LiAlH4 an d AlCl3) in THF (39% yield, en try 7). Due to in com pati-
bility of TBS-protected n ucleosides 2d , 2f, wtih DIBAH 24, we focused on
th e use of excess NaBH4 in oth er solven ts. Th e use of ten -fold excess of
NaBH4 in dioxan e gave 40% yield (en try 8), wh ile th e use of protic EtOH
furth er im proved th e yield of th e desired purin e 6a to 54% (en try 11).
COOEt
OH
OH
N
N
N
H
hydrides
N
N
+
N
HN
N
conditions
N
N
Bn
Bn
N
Bn
N
2a
6a
6aH
SCHEME 4
TABLE III
Optim ization of reduction of (purin -6-yl)acetate 2a
En try Hydride (equiv.)
Solven t
Tem perature, °C Tim e, h
Yield of 6a, %
1
2
Oth er h ydridesa
NaBH4 (4)
THF
0–60
40
6–48
0
dec.
dec.
5
DMF
6
3
BH3·Me2S (6)
NaBH4 (3)
THF
reflux
reflux
0
6
4
THF
6
5
DIBAH (1)
toluen e
THF
1
15
26
39
40
43
52
54
82
6
LiAlH4/AlCl3 (3:1)
DIBAH (3)
0
3
7
THF/toluen e
dioxan e
THF/MeOH
dioxan e
EtOH
0
6
8
NaBH4 (10)
80
overn igh t
9
NaBH4 (6)
70
1
10
11
12
NaBH4/DIBAH (10:2)
NaBH4 (10)
60
48
50
3
NaBH4 (10)
EtOH
rt
overn igh t
a
b
LiAlH4, LiBEt3H an d L-Selectride. Followed by Mn O2.
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

Synthesis of (Purin-6-yl)acetates
1041
Durin g careful ch rom atograph y of th e reaction m ixture, an un stable side
product was iden tified by NMR as 9-ben zyl-6-(2-h ydroxyeth yl)-1,6-dih ydro-
9H-purin e (6aH), a product of over-reduction of th e purin e rin g. Th is un sta-
ble com poun d could n ot h ave been fully ch aracterized due to spon tan eous
re-oxidation an d its 1H NMR spectrum was m easured on ly in a m ixture
with 6a. However, its iden tification h as h elped us in furth er optim ization
of th e reduction protocol wh ich apparen tly n eeded an addition al m ild an d
efficien t re-oxidation step. Th e optim um procedure th en in volved th e re-
duction of 2a with 10 equiv. of NaBH4 in EtOH followed by work-up, evap-
oration , dissolvin g in CH2Cl2 an d treatm en t of th e reaction m ixture with
Mn O2 un der son ication (in order to re-oxidize th e dih ydropurin e). Th is
procedure fin ally gave th e desired 6-(2-h ydroxyeth yl)purin e 6a in a good
overall yield of 82% (en try 12).
Th ese optim ized con dition s were th en used for th e reduction of th e
wh ole series of (purin -6-yl)acetates 2a–2d , 2f (Sch em e 5, Table IV). Toluoyl
groups in com poun d 2c were n ot stable in th e reduction in alkalin e eth an ol
an d on ly degradation of th e startin g m aterial occurred (en try 3). On th e
oth er h an d, reduction s of THP-protected n ucleobase 2b an d TBS-protected
n ucleosides 2d , 2f gave th e correspon din g 2-(h ydroxyeth yl)purin e bases
an d n ucleosides 6b, 6d , 6f in good yields of ca. 70% (en tries 2, 4, 5).
COOEt
OH
N
N
N
1. NaBH4, EtOH
2. MnO2, CH2Cl2
N
N
N
N
N
R
R
2a-d,f
6a,b,d,f
SCHEME 5
TABLE IV
Preparative reduction s of esters 2 to alcoh ols 6
En try
Ester
Product
Yield, %
1
2
3
4
5
2a
2b
2c
2d
2f
6a
6b
6c
6d
6f
82
65
0
74
71
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

1042
Hasník, Pohl, Klepetářová, Hocek:
Con version of th e (purin -6-yl)acetates to diverse am ides was an oth er
attractive tran sform ation wh ich we decided to pursue. Am idation s of m odel
ester 2a with prim ary an d secon dary secon dary am in es were attem pted un -
der several con dition s (Sch em e 6, Table V). Dim eth ylam m on ium dim eth yl-
carbam ate is a con ven ien t reagen t releasin g dim eth ylam in e upon h eatin g25.
Its reaction with 2a in aceton itrile un der reflux (m eth od A, en try 1) was
very slow an d after 7 days th e yield of th e desired am ide 8a was on ly 20%.
Heatin g of 2a with eth an olic Me2NH in a sealed tube (m eth od B, en try 2)
gave a som ewh at better yield (50%) of 8a but on ly after a prolon ged reac-
O
COOEt
R1
R2
H
NR1R2
N
N
N
7
8
CH3
A, B or C
N
N
CH3 CH3
N
R
N
N
R
(CH2CH2)2CH2
9
7 a,b,d
8 a,b,d
9 a,b,d
2a,b,d
cPr
H
10
SCHEME 6
TABLE V
10 a,b,d
Am idation s of (purin -6-yl)acetates
En try
Ester
Meth oda
Am in e
Product
Yield, %
+
1
2
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2d
2d
2d
2d
A
B
C
C
C
C
C
C
C
C
C
C
C
C
Me2NCOO–Me2NH2
Me2NH
8a
8a
20
50
55
67
60
51
95
49
41
66
66
39
49
0
3
Me2NH
8a
4
MeNH2
7a
5
piperidin e
cyclopropylNH2
MeNH2
9a
6
10a
7b
7
8
Me2NH
8b
9
piperidin e
cyclopropylNH2
MeNH2
9b
10
11
12
13
14
10b
7d
Me2NH
8d
piperidin e
cyclopropylNH2
9d
10d
a
+
A: Me2NCOO–Me2NH2 (5 equiv.), MeCN, reflux, 7 days; B: 5.6
M Me2NH in EtOH
(10 equiv.), 80 °C, 7 days; C: 5.6 M Me2NH in EtOH (10 equiv.), 10% NaCN, 60 °C, 2 days.
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

Synthesis of (Purin-6-yl)acetates
1043
tion tim e of 7 days. Th e use of a catalytic am oun t of NaCN 26 sign ifican tly
sh orten ed th e reaction tim e to 2 days givin g 8a in acceptable 55% yield
(m eth od C, en try 3). Usin g th ese optim ized con dition s (m eth od C), we were
able to prepare a sm all set of am ides startin g from m eth yl-, dim eth yl- an d
cyclopropylam in e as well as piperidin e. In all cases we observed h igh er
reactivity of prim ary am in es com pared to secon dary an d th e yields varied
from m oderate to excellen t (Table V, en tries 4–13). Th e on ly un successful
reaction was am idation of TBS-protected purin e 2d with cyclopropylam in e,
wh ere on ly degradation of th e startin g m aterial occurred (en try 14).
A large series of 6-(β-substituted eth yl)purin es was previously pre-
pared13,27 by con jugate addition s to 6-vin ylpurin es an d m an y of th em dis-
played cytostatic an d an tiviral effect. Th erefore, we wan ted to explore an
altern ative approach to th e syn th esis of th is class of com poun ds startin g
from 6-(2-h ydroxyeth yl)purin es via n ucleoph ilic substitution s of reactive
m esylates. Treatm en t of 6-(2-h ydroxyeth yl)purin es 6a, 6d with m eth an e-
sulfon ic an h ydride in presen ce of trieth ylam in e an d DMAP in dich loro-
m eth an e gave un stable m esylates wh ich were directly (with out ch aracter-
ization ) used in th e reaction with n ucleoph iles (Sch em e 7, Table VI). Th e
OH
N
OMs
N
Nu
N
Ms2O
Et3N
N
N
Nu- or NuH
Nu
N
N
N
N
or
N
R
N
R
N
R
N
DMAP
CH2Cl2
N
N
N
R
14d
6a,d
11-13 a,d
OCH3
11
12
N(CH3)2
13 SCH3
SCHEME 7
TABLE VI
Mesylation s of alcoh ols 6 followed by n ucleoph ilic substitution s
En try
Startin g alcoh ol
Nucleoph ile
Product
Yield, %
1
2
3
4
5
6
6a
6a
6a
6d
6d
6d
MeONa/MeOH
Me2NH/MeCN
MeSNa/EtOH
MeONa/MeOH
Me2NH/MeCN
MeSNa/EtOH
11a
12a
13a
11d
14d
14d
76
88
60
63
78
85
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

1044
Hasník, Pohl, Klepetářová, Hocek:
reaction s of th e m esylates with MeONa, Me2NH an d MeSNa were at-
tem pted. Th e ben zylpurin e m esylate gave th e desired products of n ucleo-
ph ilic substitution : 6-(2-m eth oxyeth yl)- (11a), 6-[2-(dim eth ylam in o)eth yl]-
(12a) an d 6-[2-(m eth ylsulfan yl)eth yl]purin e (13a) in good yields. On th e
oth er h an d, in an alogous reaction of n ucleoside 6d th e m esylate was very
un stable an d th e startin g m aterial spon tan eously elim in ated in th e reaction
with dim eth ylam in e or sodium m eth an th iolate to give 6-vin ylpurin e 14d .
On ly th e reaction with sodium m eth oxide gave th e desired (2-m eth oxy-
eth yl)purin e n ucleoside 11d . Th is four-step reaction sequen ce (cross-
couplin g, reduction , m esylation an d n ucleoph ilic substitution ) to com -
poun ds 11–13 is certain ly lon ger, less efficien t an d of m ore lim ited scope
X
X
N
N
N
N
A or B
X= COOEt (2)
CH2OH (6)
N
N
N
N
CONR1R2 (7-10)
R
R'
2g,h,i, 6g,h,i
7g,h, 8g,h, 9g,h, 10g
2b,d,f, 6b,d,f
7b,d, 8b,d, 9b,d, 10b
SCHEME 8
TABLE VII
Deprotection s of purin e bases an d n ucleosides
Protected
com poun d
En try
Reagen t
Product
Yield, %
1
2
2b
6b
7b
8b
9b
10b
2d
6d
7d
8d
9d
2f
Dowex 50 (H+), EtOH
Dowex 50 (H+), EtOH
Dowex 50 (H+), EtOH
Dowex 50 (H+), EtOH
Dowex 50 (H+), EtOH
Dowex 50 (H+), EtOH
Et3N·3HF, THF
2g
6g
7g
8g
9g
10g
2h
6h
7h
8h
9h
2i
93
75
64
58
75
67
96
92
88
91
98
69
69
3
4
5
6
7
8
Et3N·3HF, THF
9
Et3N·3HF, THF
10
11
12
13
Et3N·3HF, THF
Et3N·3HF, THF
Et3N·3HF, THF
6f
Et3N·3HF, THF
6i
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

Synthesis of (Purin-6-yl)acetates
1045
th an th e altern ative con jugate addition s13,27 to 6-vin ylpurin es. However,
th is sequen ce avoids th e use of toxic stan n an e reagen ts used for prepara-
tion of 6-vin ylpurin es.
Fin ally, protectin g groups were rem oved by stardard m eth ods to produce
free purin e bases an d n ucleosides. THP groups in protected bases 2b, 6b, 7b,
8b, 9b, 10b were cleaved using catalytic am ount of Dowex 50 (H+ form )28
in eth an ol at elevated tem perature for 3 h (Sch em e 8, Table VII) to give th e
correspon din g free 9H-purin e bases 2g, 6g, 7g, 8g, 9g, 10g (en tries 1–6).
Th e TBS-protected purin e n ucleosides 2d , 2f, 6d , 6f an d 7d , 8d , 9d were
deprotected by Et3N·3HF 11 (1.5 equiv. for each TBS group) in THF. Free pu-
rin e n ucleosides 2h , 2i, 6h , 6i an d 7h , 8h , 9h were obtain ed at room tem -
perature after 18 h in good to excellen t yields (en tries 7–13).
All com poun ds were fully ch aracterized by an alytical an d spectral m eth -
ods. In addition , crystal structures of 2a, 6a an d 9a were determ in ed by
X-ray diffraction (Fig. 1). In com poun d 6a, an in term olecular H-bon d to N7
of th e n eigh borin g m olecule is presen t in stead of expected in tram olecular
H-bon d of OH to N1 or N7.
In con clusion , an efficien t m eth odology for th e cross-couplin g of
6-ch loropurin e bases an d n ucleosides with th e Reform atsky reagen t was
developed givin g an access to (purin -6-yl)acetates. Th ese com poun ds are
versatile in term ediates useful for th e syn th esis of 6-(2-h ydroxyeth yl)purin es
by reduction an d 6-(carbam oylm eth yl)purin es by am idation s. Th e 6-(2-
h ydroxyeth yl)purin es can be furth er tran sform ed to reactive m esylates
FIG. 1
Crystal structures of 2a (a), 6a (b) an d 9a (c). Th erm al ellipsoids at th e 50% probability level
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

1046
Hasník, Pohl, Klepetářová, Hocek:
con vertible to eth ers, am in es an d th ioeth ers. All th e fin al deprotected
com poun ds un derwen t screen in g for cytostatic an d an ti-HCV activities.
Un fortun ately, n on e of th em sh owed an y con siderable activity.
EXPERIMENTAL
NMR spectra were recorded on a Bruker Avan ce 400 spectrom eter (1H at 400 MHz, 13C at
100.6 MHz), a Bruker Avan ce 500 (1H at 500 MHz, 13C at 125.8 MHz) an d a Bruker Avan ce
600 (1H at 600 MHz, 13C at 151 MHz). Ch em ical sh ifts (in ppm , δ-scale) were referen ced to
TMS as in tern al stan dard. Couplin g con stan ts (J) are given in Hz. Th e assign m en t of carbon s
was based on C,H-HSQC an d C,H-HMBC experim en ts. IR spectra (waven um bers in cm –1
)
were recorded on a Bruker IFS 88 spectrom eter. Meltin g poin ts were determ in ed on a Kofler
block an d are un corrected. Optical rotation s were m easured at 25 °C on a Autopol IV
(Rudolph Research An alytical) polarim eter, [α]D values are given in 10–1 deg cm 2 g–1. Mass
spectra were m easured on a ZAB-EQ (VG An alytical) spectrom eter.
Preparation of [(Eth oxycarbon yl)m eth yl]zin c Brom ide an d Its Cross-Couplin g Reaction s
with 6-Ch loropurin es 1a–1f. Gen eral Procedure
A solution of eth yl brom oacetate (417.5 m g, 278.33 µl, 2.5 m m ol) in THF (3 m l) prepared
un der argon was added at room tem perature to an argon -purged flask con tain in g suspen sion
of zin c dust (327.4 m g, 5 m m ol) in THF (2 m l), wh ich was preactivated with trim eth ylsilyl
ch loride (15 µl). Th e suspen sion was stirred for 1 h , zin c was allowed to settle an d 4 m l of
supern atan t was tran sferred th rough a septum to a m ixture of 6-ch loropurin e 1a (122 m g,
0.5 m m ol), Pd2dba3 (8 m g, 0.01 m m ol) an d Joh n Ph os (12 m g, 0.04 m m ol) in THF (1 m l)
prepared un der argon . Th e reaction m ixture was stirred for 12 h an d th en quen ch ed with
1 M NH4Cl (40 m l) an d extracted with ch loroform (3 × 30 m l). Collected organ ic layers were
dried over an h ydrous MgSO4, filtered an d th e solven t was evaporated. Th e residue was
ch rom atograph ed on silica gel colum n (eth yl acetate/h exan e) to give pure 9-ben zyl-
6-[(2-eth oxycarbon yl)m eth yl]-9H-purin e (2a). Yellowish crystals (91%) were obtain ed by
crystallization from CH2Cl2/h eptan e.
9-Benzyl 6-[2-(ethoxycarbonyl)methyl]-9H-purine (2a). Yellowish crystals, m .p. 90–96 °C. MS
(FAB): 297 (100, M + 1). HRMS (FAB): for C16H17N4O2 calculated 297.1351, foun d 297.1356.
1H NMR (400 MHz, CDCl3): 1.27 (t, 3 H, J = 7.1, CH3); 4.22 (q, 2 H, J = 7.1, CH2O); 4.26 (s,
2 H, CH2-6); 5.45 (s, 2 H, CH2-9); 7.29–7.41 (m , 5 H, Ph ); 8.04 (s, 1 H, H-8); 8.97 (s, 1 H,
H-2). 13C NMR (100.6 MHz, CDCl3):14.11 (CH3); 39.03 (CH2-6); 47.37 (CH2-9); 61.36
(CH2O); 127.92 (CH-o-Ph ); 128.66 (CH-p-Ph ); 129.16 (CH-m-Ph ); 133.00 (C-5); 134.93
(C-i-Ph ); 144.33 (CH-8); 151.32 (C-4); 152.62 (CH-2); 154.55 (C-6); 169.21 (CO). MS (FAB):
297 (100, M + 1). IR: 2983, 1744, 1599, 1500, 1407, 1333, 1178. For C16H16N4O2 (296.1) cal-
culated: C 64.85%, H 5.44%, N 18.91%; foun d: C 64.46%, H 5.37%, N 18.50%.
6-[2-(Ethoxycarbonyl)methyl]-9-(tetrahydropyran-2-yl)-9H-purine (2b). Yellowish crystals. MS
(FAB): 291 (25, M + 1), 207 (100). HRMS (FAB): for C14H18N4O3 calculated 291.1457, foun d
291.1463. 1H NMR (400 MHz, CDCl3): 1.26 (t, 3 H, J = 7.1, CH3CH2); 1.63–1.88 an d
2.00–2.20 (2 × m , 6 H, CH2-THP); 3.80 (dt, 1 H, J = 11.7, 2.6, bCH2O-THP); 4.19 (ddt, 1 H,
J = 11.7, 4.1, 1.9, aCH2O-THP); 4.22 (q, 2 H, J = 7.1, CH2CH3); 4.23 an d 4.28 (2 × d, 2 H,
Jgem = 15.9, CH2-6); 5.80 (dd, 1 H, J = 10.2, 2.7, CHO-THP); 8.28 (s, 1 H, H-8); 8.93 (s, 1 H,
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

Synthesis of (Purin-6-yl)acetates
1047
H-2). 13C NMR (100.6 MHz, CDCl3): 14.12 (CH3CH2); 22.73, 24.83 an d 31.82 (CH2-THP);
39.09 (CH2-6); 61.37 (CH2CH3); 68.85 (CH2O-THP); 82.06 (CHO-THP); 133.20 (C-5); 142.35
(CH-8); 150.49 (C-4); 152.43 (CH-2); 154.57 (C-6); 169.17 (CO). IR (CCl4): 2980, 2948, 2856,
1743, 1600, 1494, 1411, 1334, 1087, 1046.
6-[2-(Ethoxycarbonyl)methyl]-9-(2,3,5-tri-O-4-methylbenzoyl-β-D-ribofuranosyl)-9H-purine (2c).
Yellowish foam . MS (FAB): 693 (4, M + 1), 487 (10), 215 (10), 119 (100), 91 (17). HRMS
(FAB): for C38H37N4O9 calculated 693.2560, foun d 693.2543. 1H NMR (400 MHz, CDCl3):
1.25 (t, 3 H, J = 7.2, CH3CH2); 2.38 an d 2.42 (2 × s, 9 H, CH3-Tol); 4.20 (q, 2 H, J = 7.2,
CH2CH3); 4.21 an d 4.24 (2 × d, 2 H, Jgem = 15.8, CH2CO); 4.67 (dd, 1 H, Jgem = 12.2, J5′b,4′
4.1, H-5′b); 4.82 (td, 1 H, J4′,3′ = 4.5, J4′,5′ = 4.1, 3.1, H-4′); 4.89 (dd, 1 H, Jgem = 12.2, J5′a,4′
=
=
3.1, H-5′a); 6.22 (dd, 1 H, J3′,2′ = 5.7, J3′,4′ = 4.5, H-3′); 6.38 (t, 1 H, J2′,3′ = 5.7, J2′,1′ = 5.5,
H-2′); 6.43 (d, 1 H, J1′,2′ = 5.5, H-1′); 7.16, 7.22 an d 7.26 (3 × m , 3 × 2 H, H-m-Tol); 7.82,
7.90 an d 8.00 (3 × m , 3 × 2 H, H-o-Tol); 8.21 (s, 1 H, H-8); 8.83 (s, 1 H, H-2). 13C NMR
(100.6 MHz, CDCl3): 14.12 (CH3CH2); 21.70 an d 21.73 (CH3-Tol); 39.12 (CH2CO); 61.41
(CH2CH3); 63.47 (CH2-5′); 71.41 (CH-3′); 73.69 (CH-2′); 81.06 (CH-4′); 86.83 (CH-1′); 125.64,
126.02 an d 126.58 (C-i-Tol); 129.22, 129.26 an d 129.35 (CH-m-Tol); 129.79, 129.88 an d
129.90 (CH-o-Tol); 133.76 (C-5); 143.16 (CH-8); 144.23, 144.58 an d 144.69 (C-p-Tol); 150.96
(C-4); 152.73 (CH-2); 155.00 (C-6); 165.17, 165.38 an d 166.20 (CO-Tol); 168.32 (COOEt).
IR (CCl4): 2983, 1733, 1613, 1600, 1266, 1179, 1093, 1021.
6-[2-(Ethoxycarbonyl)methyl]-9-[2,3,5-tri-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-9H-
purine (2d ). Yellow oil. MS (FAB): 681 (10, M + 1), 72 (100). HRMS (FAB): for C32H61N4O6Si3
calculated 681.3899, foun d 681.3885. 1H NMR (400 MHz, CDCl3): –0.25, –0.04, –0.10, 0.11,
0.14 an d 0.15 (6 × s, 6 × 3 H, CH3Si); 0.79, 0.94 an d 0.96 (3 × s, 3 × 9 H, (CH3)3C); 1.25 (t,
3 H, Jvic = 7.1, CH3CH2); 3.80 (dd, 1 H, Jgem = 11.5, J5′b,4′ = 2.8, H-5′b); 4.03 (dd, 1 H, Jgem
11.5, J5′a,4′ = 3.9, H-5′a); 4.15 (td, 1 H, J4′,5′ = 3.9, 2.8, J4′,3′ = 3.7, H-4′); 4.21 (q, 2 H, Jvic
=
=
7.1, CH2CH3); 4.24 an d 4.28 (2 × d, Jgem = 15.9, CH2-pur); 4.33 (t, 1 H, J3′,2′ = 4.4, J3′,4′ = 3.7,
H-3′); 4.68 (dd, 1 H, J2′,1′ = 5.1, J2′,3′ = 4.4, H-2′); 6.12 (d, 1 H, J1′,2′ = 5.1, H-1′); 8.42 (s, 1 H,
H-8); 8.91 (s, 1 H, H-2). 13C NMR (100.6 MHz, CDCl3): –5.36, –5.08, –5.08, –4.72 an d –4.69
(CH3Si); 14.11 (CH3CH2); 17.83, 18.08 an d 18.54 (C(CH3)3); 25.63, 25.84 an d 26.09
((CH3)3C); 39.10 (CH2-pur); 61.31 (CH2CH3); 62.47 (CH2-5′); 71.87 (CH-3′); 75.91 (CH-2′);
85.55 (CH-4′); 88.36 (CH-1′); 133.68 (C-5); 143.48 (CH-8); 151.04 (C-4); 152.34 (CH-2);
154.54 (C-6); 169.17 (CO). IR (CCl4): 2956, 2931, 2859, 1746, 1599, 1472, 1255, 1166, 1072.
For C32H60N4O6Si3 (680.3) calculated: C 56.43%, H 8.88%, N 8.23%; foun d: C 56.47%,
H 8.98%, N 7.96%.
9-(2-Deoxy-3,5-di-O-4-methylbenzoyl-β-D-erythro-pentofuranosyl)-6-[2-(ethoxycarbonyl)methyl]-
9H-purine (2e). Yellowish foam . MS (FAB): 559 (5, M + 1), 207 (55), 161 (15), 119 (100), 91
(20), 81 (87). HRMS (FAB): for C30H31N4O7 calculated 559.2192, foun d 559.2173. 1H NMR
(500 MHz, CDCl3): 1.26 (t, 3 H, J = 7.1, CH3CH2); 2.41 an d 2.45 (2 × s, 2 × 3 H, CH3-Tol);
2.85 (ddd, 1 H, Jgem = 14.2, J2′b,1′ = 5.8, J2′b,3′ = 2.1, H-2′b); 3.19 (ddd, 1 H, Jgem = 14.2,
J2′a,1′ = 8.4, J2′a,3′ = 6.3, H-2′a); 4.22 (q, 2 H, J = 7.1, CH2CH3); 4.24 (s, 2 H, CH2CO);
4.62–4.70 (m , 2 H, H-5′b an d H-4′); 4.78 (m , 1 H, H-5′a); 5.84 (dt, 1 H, J3′,2′ = 6.3, 2.1, J3′,4′
=
2.1, H-3′); 6.60 (dd, 1 H, J1′2′ = 8.4, 5.8, H-1′); 7.23 an d 7.29 (2 × m , 2 × 2 H, H-m-Tol);
7.91 an d 7.98 (2 × m , 2 × 2 H, H-o-Tol); 8.24 (s, 1 H, H-8); 8.87 (s, 1 H, H-2). 13C NMR
(125.8 MHz, CDCl3): 14.11 (CH3CH2); 21.67 an d 21.73 (CH3-Tol); 37.77 (CH2-2′); 39.07
(CH2CO); 61.41 (CH2CH3); 63.94 (CH2-5′); 75.07 (CH-3′); 83.12 (CH-4′); 84.89 (CH-1′);
126.34 an d 126.62 (C-i-Tol); 129.29 (CH-m-Tol); 129.63 an d 129.81 (CH-o-Tol); 133.77 (C-5);
142.77 (CH-8); 144.18 an d 144.56 (C-p-Tol); 150.74 (C-4); 152.47 (CH-2); 154.85 (C-6);
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

1048
Hasník, Pohl, Klepetářová, Hocek:
165.93 an d 166.14 (CO-Tol); 169.10 (COOEt). IR (CCl4): 2983, 1728, 1613, 1599, 1266,
1178, 1100, 1021.
9-[3,5-Di-O-(tert-butyldimethylsilyl)-2-deoxy-β-D-erythro-pentofuranosyl)-6-[2-(ethoxycarbonyl)-
methyl]-9H-purine (2f). Yellow oil. MS (FAB): 551 (10, M + 1), 207 (80), 72 (100). HRMS
(FAB): for C26H47N4O5Si2 calculated 551.3085, foun d 551.3106. 1H NMR (500 MHz, CDCl3):
0.085, 0.09 an d 0.12 (3 × s, 12 H, CH3Si); 0.91 an d 0.92 (2 × s, 2 × 9 H, (CH3)3C); 1.27 (t,
3 H, J = 7.1, CH3CH2); 2.46 (ddd, 1 H, Jgem = 13.1, J2′b,1′ = 6.1, J2′b,3′ = 3.7, H-2′b); 2.69 (ddd,
1 H, Jgem = 13.1, J2′a,1′ = 6.9, J2′a,3′ = 5.8, H-2′a); 3.78 (dd, 1 H, Jgem = 11.2, J5′b,4′ = 3.2, H-5′b);
3.88 (dd, 1 H, Jgem = 11.2, J5′a,4′ = 4.2, H-5′a); 4.04 (dt, 1 H, J4′,5′ = 4.2, 3.2, J4′,3′ = 3.1, H-4′);
4.22 (q, 2 H, J = 7.1, CH2CH3); 4.23 an d 4.27 (2 × d, 2 H, Jgem = 15.8, CH2CO); 4.64 (m , 1 H,
J3′,2′ = 5.8, 3.7, J3′,4′ = 3.1, H-3′); 6.52 (t, 1 H, J1′,2′ = 6.9, 6.1, H-1′); 8.38 (s, 1 H, H-8); 8.91 (s,
1 H, H-2). 13C NMR (125.8 MHz, CDCl3): –5.49, –5.39, –4.81 an d –4.67 (CH3Si); 14.13
(CH3CH2); 17.99 an d 18.41 (C(CH3)3); 25.74 an d 25.94 ((CH3)3C); 39.05 (CH2CO); 41.21
(CH2-2′); 61.35 (CH2CH3); 62.78 (CH2-5′); 71.97 (CH-3′); 84.50 (CH-1′); 88.05 (CH-4′);
133.68 (C-5); 143.12 (CH-8); 150.72 (C-4); 152.28 (CH-2); 154.47 (C-6); 169.23 (CO).
IR (CCl4): 2956, 2859, 1745, 1599, 1463, 1472, 1258, 1108, 1034. For C26H46N4O5Si2 (680.3)
calculated: C 56.69%, H 8.42%, N 10.17%; foun d: C 56.87%, H 8.49%, N 9.67%.
Alkalin e Hydrolysis of Ester 2a
NaOH (60 m g, 1.5 m m ol) was added to a solution of ester 2a (148 m g, 0.5 m m ol) in aque-
ous eth an ol (1:1, 5 m l) an d th e reaction was stirred at room tem perature for 3 h . Th e reac-
tion m ixture was dilluted with water (15 m l) an d ch rom atograph ed on Am berlite 67
(distilled water/0.1 M AcOH) to give 110 m g (98%) of 9-ben zyl-6-m eth yl-9H-purin e (5a) as a
wh ite solid. 1H NMR spectra were in accord with previously publish ed data29
.
Reduction of 6-[2-(Eth oxycarbon yl)m eth yl]purin es 2a, 2b, 2d , 2f to
(2-Hydroxyeth yl)purin es 6a, 6b, 6d , 6f. Gen eral Procedure
To a stirred solution of purin e 2a (296 m g, 1 m m ol) in EtOH (8 m l) was added excess of
NaBH4 (380 m g, 10 m m ol), th e reaction m ixture was stirred at room tem perature overn igh t
an d th en quen ch ed by addition of MeOH (8 m l) an d 1 M NH4Cl (10 m l). Alcoh ols were
evaporated an d th e residue extracted with ch loroform (3 × 30 m l). Collected organ ic layers
were dried over an h ydrous MgSO4, filtered an d th e solven t was evaporated. Th e residue was
dissolved in CH2Cl2 (10 m l), Mn O2 (174 m g, 2 m m ol) was added an d th e m ixture was
son icated at am bien t tem perature for 1 h . Th en th e m ixture was filtered th rough Celite an d
th e solven t evaporated. Th e residue was ch rom atograph ed on silica gel colum n (ch loroform /
m eth an ol) to give yellowish oil. Alcoh ol 6a was obtain ed by crystallization from CH2Cl2/
h eptan e as wh ite crystals (208 m g, 82%).
9-Benzyl-6-(2-hydroxyethyl)-9H-purine (6a). Wh ite crystals, m .p. 72–73 °C. MS (FAB): 255
(100, M + 1), 91 (55). HRMS (FAB): for C14H15N4O calculated 255.1246, foun d 255.1242.
1H NMR (400 MHz, CDCl3): 3.45 (t, 2 H, J = 5.4, CH2-pur); 4.16 (bt, 2 H, J = 5.4, CH2-O);
4.89 (bs, 1 H, OH); 5.45 (s, 2 H, CH2-N); 7.28–7.40 (m , 5 H, Ph ); 8.04 (s, 1 H, H-8); 8.90 (s,
1 H, H-2). 13C NMR (100.6 MHz, CDCl3): 36.04 (CH2-pur); 47.25 (CH2-N); 60.19 (CH2-O);
127.81 (CH-o-Ph ); 128.58 (CH-p-Ph ); 129.08 (CH-m-Ph ); 132.15 (C-5); 134.85 (C-i-Ph );
143.71 (CH-8); 150.70 (C-4); 152.23 (CH-2); 161.14 (C-6). IR: 2931, 1596, 1500, 1407, 1331,
1196, 1063. For C14H14N4O (254.1) calculated: C 66.13%, H 5.55%, N 22.03%; found: C 65.87%,
H 5.47%, N 21.90%.
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

Synthesis of (Purin-6-yl)acetates
1049
9-Benzyl-6-(2-hydroxyethyl)-1,6-dihydro-9H-purine (6aH). Un stable com poun d isolated by
ch rom atograph y after reduction of 2a with NaBH4 in EtOH with out re-oxidation . It was n ot
isolated as a pure compound, and identified by NMR only in mixture with 3a. 1H NMR (600 MHz,
DMSO-d6): 1.76 (dq, 1 H, Jgem = 12.4, Jvic = 6.8, 6.2, CHaHb-pur); 1.88 (dtd, 1 H, Jgem = 12.4,
Jvic = 6.8, 5.5, CHaHb-pur); 3.54 an d 3.62 (2 × dt, 2 H, Jgem = 10.8, Jvic = 6.8, CH2O); 4.92 (bt,
1 H, Jvic = 6.2, 5.5, H-6); 5.03 (s, 2 H, CH2Ph ); 6.91 (s, 1 H, J2,NH = 3.8, H-2); 7.23 (m , 2 H,
H-o-Ph ); 7.32 (m , 2 H, H-m-Ph ); 7.34 (m , 1 H, H-p-Ph ); 7.53 (bd, 1 H, JNH,2 = 3.8, NH); 8.32
(s, 1 H, H-8). 13C NMR (600 MHz, DMSO-d6): 42.60 (CH2-pur); 45.82 (CH2Ph ); 51.10 (CH-6);
57.56 (CH2O); 119.96 (C-5); 127.61 (CH-o-Ph ); 127.88 (CH-p-Ph ); 128.73 (CH-m-Ph ); 132.58
(CH-8); 134.17 (C-4); 138.32 (C-i-Ph ); 147.00 (CH-2).
6-(2-Hydroxyethyl)-9-tetrahydropyran-2-yl-9H-purine (6b). Yellowish oil. MS (FAB): 249 (10,
M + 1), 165 (100, M – THP), 85 (40, THP). HRMS (FAB): for C12H17N4O2 calculated 249.1351,
foun d 249.1342. 1H NMR (500 MHz, CDCl3): 1.65–1.87 an d 2.02–2.20 (2 × m , 6 H,
CH2-THP); 3.45 (m , 2 H, CH2-pur); 3.80 (dt, 1 H, J = 11.8, 2.6, CHaHbO-THP); 4.16 (t, 2 H,
Jvic = 5.3, CH2O); 4.19 (ddt, 1 H, J = 11.8, 4.3, 1.9, CHaHbO-THP); 4.71 (bs, 1 H, OH);
5.80 (dd, 1 H, J = 10.5, 2.5, CHO-THP); 8.28 (s, 1 H, H-8); 8.88 (s, 1 H, H-2). 13C NMR
(125.7 MHz, CDCl3): 22.70, 24.80 an d 31.82 (CH2-THP); 36.01 (CH2-pur); 60.29 (CH2O);
68.86 (CH2O-THP); 82.00 (CHO-THP); 132.34 (C-5); 141.76 (CH-8); 149.95 (C-4); 152.12
(CH-2); 161.35 (C-6). IR (CCl4): 3392, 2949, 2931, 2858, 1598, 1410, 1333, 1210, 1047.
6-(2-Hydroxyethyl)-9-[2,3,5-tri-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-9H-purine (6d ).
Wh ite foam . MS (FAB): 639 (100, M + 1), 343 (30), 288 (35). HRMS (FAB): for C30H59N4O5Si3
calculated 639.3793, foun d 639.3776. 1H NMR (400 MHz, CDCl3): –0.22, –0.03, 0.10, 0.11,
0.14 an d 0.15 (6 × s, 6 × 3 H, CH3Si); 0.80, 0.94 an d 0.96 (3 × s, 3 × 9 H, (CH3)3C); 3.45 (m ,
2 H, CH2-pur); 3.81 (dd, 1 H, Jgem = 11.5, J5′b,4′ = 2.6, H-5′b); 4.04 (dd, 1 H, Jgem = 11.5,
J5′a,4′ = 3.8, H-5′a); 4.13–4.18 (m , 3 H, H-4′ an d CH2-O); 4.33 (t, 1 H, J3′,2′ = 4.3, J3′,4′ = 3.9,
H-3′); 4.65 (t, 1 H, J2′,1′ = 4.9, J2′,3′ = 4.3, H-2′); 6.13 (d, 1 H, J1′,2′ = 4.9, H-1′); 8.47 (s, 1 H,
H-8); 8.86 (s, 1 H, H-2). 13C NMR (100.6 MHz, CDCl3): –5.37, –5.06, –4.73, –4.69 an d –4.39
(CH3Si); 17.84, 18.07 an d 18.52 (C(CH3)3); 25.62, 25.82 an d 26.07 ((CH3)3C); 36.08
(CH2-pur); 60.31 (CH2-O); 62.36 (CH2-5′); 71.75 (CH-3′); 76.04 (CH-2′); 85.48 (CH-4′); 88.36
(CH-1′); 132.76 (C-5); 142.94 (CH-8); 150.53 (C-4); 152.02 (CH-2); 161.32 (C-6). IR (CCl4):
3409, 2956, 2931, 2859, 1597, 1472, 1255, 1071, 839. For C30H58N4O5Si3 (639.0) calculated:
C 56.38%, H 9.15%, N 8.77%; foun d: C 56.38%, H 9.25%, N 8.30%.
9-[3,5-Di-O-(tert-butyldimethylsilyl)-2-deoxy-β-D-erythro-pentofuranosyl)-6-(2-hydroxyethyl)-9H-
purine (6f). Yellow oil. MS (FAB): 509 (20, M + 1), 165 (60), 73 (100). HRMS (FAB): for
C
24H45N4O4Si2 calculated 509.2979, foun d 509.2971. 1H NMR (500 MHz, CDCl3): 0.08, 0.09
an d 0.11 (3 × s, 12 H, CH3Si); 0.90 an d 0.92 (2 × s, 2 × 9 H, (CH3)3C); 2.48 (ddd, 1 H, Jgem
=
13.1, J2′b,1′ = 6.2, J2′b,3′ = 4.0, H-2′b); 2.66 (ddd, 1 H, Jgem = 13.1, J2′a,1′ = 7.4, J2′a,3′ = 5.7,
H-2′a); 3.44 (t, 2 H, J = 5.3, CH2-pur); 3.78 (dd, 1 H, Jgem = 11.3, J5′b,4′ = 3.0, H-5′b); 3.88 (dd,
1 H, Jgem = 11.3, J5′a,4′ = 3.9, H-5′a); 4.04 (dt, 1 H, J4′,5′ = 3.9, 3.0, J4′,3′ = 3.7, H-4′); 4.16 (bt,
2 H, J = 6.4, CH2-O); 4.76 (m , 1 H, J3′,2′ = 5.7, 4.0, J3′,4′ = 3.7, H-3′); 4.90 (bs, 1 H, OH); 6.53
(t, 1 H, J1′,2′ = 7.4, 6.2, H-1′); 8.40 (s, 1 H, H-8); 8.85 (s, 1 H, H-2). 13C NMR (125.8 MHz,
CDCl3): –5.49, –5.40, –4.81 an d –4.66 (CH3Si); 18.00 an d 18.41 (C(CH3)3); 25.74 an d 25.93
((CH3)3C); 36.16 (CH2-pur); 41.37 (CH2-2′); 60.35 (CH2OH); 62.69 (CH2-5′); 71.81 (CH-3′);
84.52 (CH-1′); 88.06 (CH-4′); 132.81 (C-5); 142.54 (CH-8); 150.18 (C-4); 151.98 (CH-2);
161.28 (C-6). IR (CCl4): 3401, 2956, 2931, 2859, 1598, 1472, 1258, 1109, 839. For
C
24H44N4O4Si2 (508.8) calculated: C 56.65%, H 8.72%, N 11.01%; foun d: C 56.87%, H 9.09%,
N 10.38%.
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

1050
Hasník, Pohl, Klepetářová, Hocek:
Am idation of Esters 2a, 2b, 2d . Gen eral Procedure
Mixture of ester 2a (296 m g, 1 m m ol) an d NaCN (5 m g, 0.1 m m ol) was dissolved in 5.6
M
solution of dim eth ylam in e in EtOH (1.78 m l, 10 m m ol) an d addition al eth an ol (2 m l) was
added. Th e reaction m ixture was stirred at 60 °C for 48 h , th en evaporated an d extracted
with ch loroform (3 × 50 m l). Collected organ ic layers were dried over an h ydrous MgSO4,
filtered an d th e solven t was evaporated. Th e residue was ch rom atograph ed on silica gel
colum n (eth yl acetate/m eth an ol) to give 9-ben zyl-6-[(dim eth ylcarbam oyl)m eth yl]-9H-purin e
(8a) in 55% yield. Yellow crystals were obtain ed after crystallization from CH2Cl2/h eptan e.
9-Benzyl-6-[(methylcarbamoyl)methyl]-9H-purine (7a). Prepared from ester 2a (148 m g, 0.5 m m ol)
an d 33% solution of m eth ylam in e in EtOH (582 µl, 5 m m ol) an d addition al eth an ol (1.5 m l).
Yield 67%, yellowish crystals were obtain ed after crystallization from CH2Cl2/h eptan e, m .p.
119–122 °C. MS (FAB): 282 (100, M + 1), 251 (10), 91 (50). HRMS (FAB): for C15H16N5O cal-
culated 282.1354, foun d 282.1365. 1H NMR (400 MHz, CDCl3): 2.84 (d, 3 H, J = 4.8, CH3);
4.20 (s, 2 H, CH2-6); 5.45 (s, 2 H, CH2-9); 7.28–7.45 (m , 6 H, NH an d Ph ); 8.05 (s, 1 H, H-8);
8.95 (s, 1 H, H-2). 13C NMR (100.6 MHz, CDCl3): 26.41 (CH3); 39.94 (CH2-6); 47.43 (CH2-9);
127.92 (CH-o-Ph ); 128.72 (CH-p-Ph ); 129.20 (CH-m-Ph ); 132.67 (C-5); 134.84 (C-i-Ph );
144.42 (CH-8); 151.24 (C-4); 152.31 (CH-2); 155.73 (C-6); 168.01 (CO). IR (CCl4): 2928,
2360, 1687, 1597, 1499, 1333. For C15H15N5O·3/5H2O (292.0) calculated: C 61.67%, H 5.59%,
N 23.97%; foun d: C 61.72%, H 5.30%, N 23.38%.
9-Benzyl-6-[(dimethylcarbamoyl)methyl]-9H-purine (8a). Yield 55%, yellow crystals, m .p.
115–121 °C. MS (FAB): 296 (100, M + 1), 251 (10), 91 (40). HRMS (FAB): for C16H18N5O cal-
culated 296.1511, foun d 296.1515. 1H NMR (500.0 MHz, CDCl3): 3.00 an d 3.15 (2 × s, 2 ×
3 H, (CH3)2N); 4.32 (s, 2 H, CH2-6); 5.44 (s, 2 H, CH2-9); 7.32 (m , 2 H, H-o-Ph ); 7.36 (m ,
2 H, H-m-Ph ); 7.37 (m , 1 H, H-p-Ph ); 8.03 (s, 1 H, H-8); 8.96 (s, 1 H, H-2). 13C NMR
(125.7 MHz, CDCl3): 35.58 an d 37.72 ((CH3)2N); 38.47 (CH2-6); 47.30 (CH2-9); 127.92
(CH-o-Ph ); 128.60 (CH-p-Ph ); 129.12 (CH-m-Ph ); 133.06 (C-5); 134.95 (C-i-Ph ); 144.13
(CH-8); 151.08 (C-4); 152.60 (CH-2); 156.06 (C-6); 168.32 (CO). IR (CCl4): 3035, 2932, 1662,
1591, 1499, 1395, 1333, 773.
9-Benzyl-6-[(piperidine-1-carbonyl)methyl]-9H-purine (9a). Prepared from ester 2a (0.5 m m ol)
an d piperidin e (494 µl, 5 m m ol) as yellowish crystals, yield 60%, m .p. 123–125 °C.
MS (FAB): 693 (100, 2 M + Na), 358 (20, M + Na), 336 (20, M + H). HRMS (FAB): for
C
19H21N5NaO calculated 358.1638, foun d 358.1641. IR (CCl4): 2941, 2858, 1648, 1592,
1443, 1333, 1214. For C19H21N5O·1/6H2O (338.4) calculated: C 67.43%, H 6.35%, N 20.70%;
foun d: C 67.63%, H 6.31%, N 20.70%.
9-Benzyl-6-[(cyclopropylcarbamoyl)methyl]-9H-purine (10a). Prepared from ester 2a (290 m g,
1 m m ol) an d eth an ol (1.5 m l), an d cyclopropylam in e (571 m g, 692 µl, 10 m m ol). Yield 51%,
wh ite crystals were obtain ed after crystallization from CH2Cl2/h eptan e, m .p. 114–122 °C.
MS (FAB): 308 (55, M + 1), 251 (20), 91 (100). HRMS (FAB): for C17H17N5O calculated
308.1511, foun d 308.1522. 1H NMR (500.0 MHz, CDCl3): 0.51 an d 0.75 (2 × m , 2 × 2 H,
CH2-cyclopropyl); 2.73 (tt, 1 H, J = 7.2, 3.9, CH-cyclopropyl); 4.16 (s, 2 H, CH2-6); 5.45 (s,
2 H, CH2-9); 7.32 (m , 2 H, H-o-Ph ); 7.36 (m , 2 H, H-m-Ph ); 7.38 (m , 1 H, H-p-Ph ); 7.64 (bs,
1 H, NH); 8.05 (s, 1 H, H-8); 8.94 (s, 1 H, H-2). 13C NMR (125.7 MHz, CDCl3): 6.44
(CH2-cyclopropyl); 22.67 (CH-cyclopropyl); 39.95 (CH2-6); 47.41 (CH2-9); 127.89 (CH-o-Ph );
128.72 (CH-p-Ph ); 129.19 (CH-m-Ph ); 132.64 (C-5); 134.80 (C-i-Ph ); 144.38 (CH-8); 151.20
(C-4); 152.22 (CH-2); 155.59 (C-6); 168.70 (CO). IR (CCl4): 3328, 3034, 1690, 1596, 1499,
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

Synthesis of (Purin-6-yl)acetates
1051
1333, 1196, 726. For C17H15N5O·1/4H2O (311.8) calculated: C 65.47%, H 5.66%, N 22.46%;
foun d: C 65.31%, H 5.60%, N 22.24%.
6-[(Methylcarbamoyl)methyl]-9-tetrahydropyran-2-yl-9H-purine (7b). Prepared from ester 2b
(0.5 m m ol) an d 33% solution of m eth ylam in e in EtOH (5 m m ol) as wh ite crystals, yield
95%, m .p. 119–121 °C. MS (FAB): 572 (100, 2 M + Na), 298 (35, M + Na), 276 (10, M + H).
HRMS (FAB): for C13H17N5NaO2 calculated 298.1274, foun d 298.1278. 1H NMR (400 MHz,
CDCl3): 1.62–1.86 an d 1.99–2.18 (2 × m , 6 H, CH2-THP); 2.79 (d, 3 H, J = 4.9, CH3); 3.77
(dt, 1 H, J = 11.7, 2.6, bCH2O-THP); 4.12–4.21 (m , 1 H, CH2O-THP); 4.16 an d 4.17 (2 × s,
2 H, CH2-6); 5.76 (dd, 1 H, J = 10.1 an d 2.6, CHO-THP); 7.38 (bs, 1 H, NH); 8.27 (s, 1 H,
H-8); 8.89 (s, 1 H, H-2). 13C NMR (100.6 MHz, CDCl3): 22.66, 24.76 an d 31.72 (CH2-THP);
26.37 (CH3); 40.05 (CH2-6); 68.81 (CH2O-THP); 82.05 (CHO-THP); 132.81 (C-5); 142.41
(CH-8); 150.36 (C-4); 152.10 (CH-2); 155.67 (C-6); 167.97 (CO). IR (CCl4): 3358, 2948, 2857,
1686, 1598, 1334, 1211, 1088.
6-[(Dimethylcarbamoyl)methyl]-9-tetrahydropyran-2-yl-9H-purine (8b). Prepared from ester 2b
(0.5 m m ol) an d 5.6 M solution of dim eth ylam in e in EtOH (893 µl, 5 m m ol) as yellowish
crystals, yield 49%, m .p. 142–144 °C. MS (FAB): 600 (100, 2 M + Na), 312 (40, M + Na), 289
(10, M + H). HRMS (FAB): for C14H19N5NaO2 calculated 312.1431, foun d 312.1435. 1H NMR
(400 MHz, CDCl3): 1.60–1.88 an d 1.98–2.18 (2 × m , 6 H, CH2-THP); 2.99 an d 3.12 (2 × s, 2 ×
3 H, 2 × CH3); 3.78 (dt, 1 H, J = 11.6, 2.5, bCH2O-THP); 4.13-4.21 (m , 1 H, CH2O-THP); 4.28
an d 4.31 (2 × d, 2 H, Jgem = 15.4, CH2-6); 5.77 (dd, 1 H, J = 9.9, 2.6, CHO-THP); 8.25 (s, 1 H,
H-8); 8.91 (s, 1 H, H-2). 13C NMR (100.6 MHz, CDCl3): 22.73, 24.83 an d 31.83 (CH2-THP);
35.59 an d 37.72 (2 × CH3); 38.56 (CH2-6); 68.82 (CH2O-THP); 82.01 (CHO-THP); 133.21
(C-5); 142.14 (CH-8); 150.27 (C-4); 152.42 (CH-2); 156.07 (C-6); 168.32 (CO). IR (CCl4):
2947, 2857, 1664, 1593, 1495, 1395, 1335, 1211, 1088. For C14H19N5O2·1/5H2O (292.9) cal-
culated: C 57.40%, H 6.68%, N 23.91%; foun d: C 57.49%, H 6.55%, N 23.49%.
6-[(Piperidine-1-carbonyl)methyl]-9-tetrahydropyran-2-yl-9H-purine (9b). Prepared from ester
2b (0.5 m m ol) an d piperidin e (494 µl, 5 m m ol) as yellowish crystals, yield 41%, m .p.
151–155 °C. MS (FAB): 681 (100, 2 M + Na), 352 (55, M + Na), 330 (20, M + H). HRMS
(FAB): for C17H23N5NaO2 calculated 352.1744, foun d 352.1748. 1H NMR (600 MHz, CDCl3):
1.55 (m , 4 H, H-3,5-pip); 1.63 (m , 2 H, H-4-pip); 1.66–1.70, 1.73–1.85 an d 2.00–2.20 (3 × m ,
6 H, CH2-THP); 3.50 an d 3.53 (2 × ddd, 2 × 1 H, Jgem = 13.2, Jvic = 11.1, 4.9, H-2,6-pip); 3.58
an d 3.61 (2 × dt, 2 × 1 H, Jgem = 13.2, Jvic = 5.4, H-2,6-pip); 3.80 (dt, 1 H, J = 11.8, 2.6,
bCH2O-THP); 4.19 (ddt, 1 H, J = 11.8, 4.3, 1.9, aCH2O-THP); 4.28 an d 4.35 (2 × d, 2 H,
Jgem = 15.2, CH2CO); 5.80 (dd, 1 H, J = 10.4, 2.5, CHO-THP); 8.27 (s, 1 H, H-8); 8.92 (s, 1 H,
H-2). 13C NMR (100.6 MHz, CDCl3): 22.73(CH2-THP); 24.43 (CH2-4-pip); 24.83 (CH2-THP);
25.38 an d 26.26 (CH2-3,5-pip); 31.83 (CH2-THP); 38.59 (CH2CO); 42.94 an d 47.15
(CH2-2,6-pip); 68.85 (CH2O-THP); 81.98 (CHO-THP); 133.15 (C-5); 142.12 (CH-8); 150.26
(C-4); 152.43 (CH-2); 156.31 (C-6); 166.47 (CO). IR (CCl4): 2943, 2858, 1657, 1593, 1442,
1334, 1211, 1088. For C17H23N5O2·1/5H2O (333.0) calculated: C 61.32%, H 7.08%, N 21.03%;
foun d: C 61.34%, H 6.94%, N 20.96%.
6-[(Cyclopropylcarbamoyl)methyl]-9-tetrahydropyran-2-yl-9H-purine (10b). Prepared from ester
2b (0.5 m m ol) an d cyclopropylam in e (346 µl, 5 m m ol) as a wh ite foam , yield 66%. MS (FAB):
624 (100, 2 M + Na), 324 (45, M + Na), 302 (10, M + H). HRMS (FAB): for C15H19N5NaO2
calculated 324.1431, foun d 324.1434. 1H NMR (400 MHz, CDCl3): 0.46–0.51 an d 0.70–0.76
(2 × m , 2 × 2 H, 2 × CH2); 1.61–1.87 an d 2.01–2.19 (2 × m , 6 H, CH2-THP); 2.71 (m , 1 H,
CH-N); 3.79 (dt, 1 H, J = 11.6, 2.7, bCH2O-THP); 4.16 (ddt, 1 H, J = 11.6, 3.7, 2.2,
aCH2O-THP); 4.14 (s, 2 H, CH2CO); 5.80 (dd, 1 H, J = 10.1, 2.5, CHO-THP); 7.5 (bs, 1 H,
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

1052
Hasník, Pohl, Klepetářová, Hocek:
NH); 8.27 (s, 1 H, H-8); 8.89 (s, 1 H, H-2). 13C NMR (100.6 MHz, CDCl3): 6.42 (CH2CH);
22.69 (CH2-THP); 22.70 (CHNH); 24.80 (CH2-THP); 31.76 (CH2-THP); 40.18 (CH2CO); 68.86
(CH2O-THP); 82.08 (CHO-THP); 132.83 (C-5); 142.38 (CH-8); 150.40 (C-4); 152.09 (CH-2);
155.60 (C-6); 168.66 (CO). IR (CCl4): 3331, 2949, 2857, 1689, 1597, 1497, 1334, 1210, 1088.
6-[(Methylcarbamoyl)methyl]-9-[2,3,5-tri-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-9H-purine
(7d ). Prepared from ester 2d (1020 m g, 1.5 m m ol) an d 33% solution of m eth ylam in e in
EtOH (1.75 m l, 15 m m ol) an d addition al eth an ol (5 m l). Yield 66%, wh ite foam . MS (FAB):
666 (25, M + 1), 192 (20), 93 (50), 73 (100). HRMS (FAB): for C31H60N5O5Si3 calculated
666.3902, foun d 666.3926. 1H NMR (400 MHz, CDCl3): –0.23, –0.03, 0.10, 0.11, 0.14 an d
0.15 (6 × s, 6 × 3 H, CH3Si); 0.79, 0.94 an d 0.96 (3 × s, 3 × 9 H, (CH3)3C); 2.83 (d, 3 H,
JCH3,NH = 4.8, CH3N); 3.80 (dd, 1 H, Jgem = 11.5, J5′b,4′ = 2.6, H-5′b); 4.03 (dd, 1 H, Jgem
=
11.5, J5′a,4′ = 3.8, H-5′a); 4.16 (td, 1 H, J4′,3′ = 3.9, J4′,5′ = 3.8, 2.6, H-4′); 4.20 (s, 2 H,
CH2-pur); 4.33 (t, 1 H, J3′,2′ = 4.3, J3′,4′ = 3.9, H-3′); 4.63 (t, 1 H, J2′,1′ = 4.9, J2′,3′ = 4.3, H-2′);
6.12 (d, 1 H, J1′,2′ = 4.9, H-1′); 7.45 (bs, 1 H, NH); 8.47 (s, 1 H, H-8); 8.90 (s, 1 H, H-2).
13C NMR (100.6 MHz, CDCl3): –5.39, –5.37, –5.05, –4.72, –4.68 an d –4.39 (CH3Si); 17.83,
18.06 an d 18.53 (C(CH3)3); 25.62, 25.82 an d 26.08 ((CH3)3C); 26.38 (CH3N); 40.09
(CH2-pur); 62.37 (CH2-5′); 71.75 (CH-3′); 76.06 (CH-2′); 85.50 (CH-4′); 88.36 (CH-1′); 132.27
(C-5); 143.54 (CH-8); 150.94 (C-4); 152.06 (CH-2); 155.66 (C-6); 168.05 (CO). IR (CCl4):
3354, 2931, 2859, 1686, 1597, 1463, 1255, 1149, 839. For C31H59N5O5Si3 (666.8) calculated:
C 55.90%, H 8.93%, N 10.51%; foun d: C 55.69%, H 9.00%, N 10.22%.
6-[(Dimethylcarbamoyl)methyl]-9-[2,3,5-tri-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-
9H-purine (8d ). Prepared from ester 2d (1020 m g, 1.5 m m ol) an d 5.6 M solution of dim eth yl-
am in e in EtOH (3 m l, 16.8 m m ol) an d addition al eth an ol (3 m l). Yield 39%, wh ite foam .
MS (FAB): 680 (20, M + 1), 206 (25), 73 (100). HRMS (FAB): for C32H62N5O5Si3 calculated
680.4058, foun d 680.4065. 1H NMR (600 MHz, CDCl3): –0.21, –0.03, 0.10, 0.11, 0.13 an d
0.14 (6 × s, 6 × 3 H, CH3Si); 0.80, 0.94 an d 0.95 (3 × s, 3 × 9 H, (CH3)3C); 3.01 an d 3.10
(2 × s, 2 × 3 H, (CH3)2N); 3.80 (dd, 1 H, Jgem = 11.4, J5′b,4′ = 2.8, H-5′b); 4.04 (dd, 1 H, Jgem
=
11.4, J5′a,4′ = 3.9, H-5′a); 4.15 (td, 1 H, J4′,3′ = 4.2, J4′,5′ = 3.9, 2.8, H-4′); 4.31 an d 4.34 (2 × d,
2 H, Jgem = 15.5, CH2-pur); 4.34 (t, 1 H, J3′,2′ = J3′,4′ = 4.2, H-3′); 4.66 (t, 1 H, J2′,1′ = 4.8,
J2′,3′ = 4.2, H-2′); 6.11 (d, 1 H, J1′,2′ = 4.8, H-1′); 8.42 (s, 1 H, H-8); 8.91 (s, 1 H, H-2).
13C NMR (151 MHz, CDCl3): –5.36, –5.01, –4.76, –4.73 an d –4.38 (CH3Si); 17.83, 18.06 an d
18.54 (C(CH3)3); 25.64, 25.82 an d 26.09 ((CH3)3C); 35.60 an d 37.72 ((CH3)2N); 38.52
(CH2-pur); 62.32 (CH2-5′); 71.62 (CH-3′); 75.78 (CH-2′); 85.25 (CH-4′); 88.45 (CH-1′); 133.62
(C-5); 143.26 (CH-8); 150.79 (C-4); 152.37 (CH-2); 155.93 (C-6); 168.41 (CO). IR (CCl4):
2956, 2930, 2859, 1664, 1593, 1472, 1392, 1333, 1295, 1148, 839. For C32H61N5O5Si3
(679.4) calculated: C 56.51%, H 9.04%, N 10.30%; foun d: C 56.65%, H 9.04%, N 9.78%.
6-[(Piperidine-1-carbonyl)methyl]-9-[2,3,5-tri-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-
9H-purine (9d ). Prepared from ester 2d (1.5 m m ol) an d piperidin e (15 m m ol) as a wh ite
foam , yield 49%. MS (FAB): 720 (75, M + H), 288 (100). HRMS (FAB): for C35H65N5NaO5Si3
calculated 742.4185, foun d 742.4188. IR (CCl4): 2931, 2859, 1655, 1592, 1472, 1256.
Mesylation an d Nucleoph ilic Substitution of Purin es 6a, 6d . Gen eral Procedure
To a stirred solution of purin e 6a (127 m g, 0.5 m m ol), m eth an esulfon ic an h ydride (104 m g,
0.6 m m ol) an d DMAP (3 m g) in CH2Cl2 (4 m l) Et3N (105 µl, 0.75 m m ol) was added. After
fin ish in g th e reaction (0.5 h ), th e reaction m ixture was ch rom atograph ed on a silica gel
colum n (CHCl3) an d th e eluate was evaporated at room tem perature. Crude product was
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

Synthesis of (Purin-6-yl)acetates
1053
dilluted with MeOH (25 m l), 1 M MeONa in MeOH (0.75 m l, 0.75 m m ol) was added,
th e m ixture was stirred overn igh t an d th en con cen trated. Purin e 11a was obtain ed after
purification on silica gel colum n (h exan es/eth yl acetate), yield 76%.
9-Benzyl-6-(2-methoxyethyl)-9H-purine (11a). Yield 76%, oil. 1H NMR spectra were in accord
with th e previously publish ed data27
.
9-Benzyl-6-[2-(dimethylamino)ethyl]-9H-purine (12a). Prepared from
(0.5 m l, 1 m m ol) in MeCN (5 m l). Yield 88%, wh ite crystals. 1H NMR spectra were in accord
with previously publish ed data27
2 M MeNH2 in THF
.
9-Benzyl-6-[2-(methylsulfanyl)ethyl]purine (13a). Prepared from MeSNa (35 m g, 0.5 m m ol)
in eth an ol (15 m l), yield 60%, yellowish crystals. 1H NMR spectra were in accord with previ-
ously publish ed data27
.
6-(2-Methoxyethyl)-9-[2,3,5-tri-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-9H-purine (11d ).
Prepared from purin e 6d (320 m g, 0.5 m m ol) an d MeONa in MeOH (0.75 m l,
1
M
0.75 m m ol) as a yellowish oil, yield 63%. MS (ESI): 675 (55, M + Na), 653 (100, M + H).
HRMS (ESI): for C31H61N4O5Si3 calculated 653.3944, foun d 653.3945. 1H NMR (499.8 MHz,
CDCl3): –0.27, –0.05, 0.109, 0.113, 0.13 an d 0.14 (6 × s, 6 × 3 H, CH3Si); 0.78, 0.94 an d 0.95
(3 × s, 3 × 9 H, (CH3)3C); 3.35 (s, 3 H, CH3O); 3.49 (t, 2 H, Jvic = 6.6, CH2-pur); 3.80 (dd,
1 H, Jgem = 11.4, J5′b,4′ = 2.9, H-5′b); 3.97 (t, 2 H, Jvic = 6.6, CH2O); 4.03 (dd, 1 H, Jgem = 11.4,
J5′a,4′ = 4.0, H-5′a); 4.15 (ddd, 3 H, J4′,5′ = 4.0, 2.9, J4′,3′ = 3.6, H-4′); 4.33 (dd, 1 H, J3′,2′ = 4.3,
J3′,4′ = 3.6, H-3′); 4.70 (dd, 1 H, J2′,1′ = 5.3, J2′,3′ = 4.3, H-2′); 6.10 (d, 1 H, J1′,2′ = 5.3, H-1′);
8.37 (s, 1 H, H-8); 8.88 (s, 1 H, H-2). 13C NMR (100.6 MHz, CDCl3): –5.38, –5.37, –5.14,
–4.71, –4.69 an d –4.41 (CH3Si); 17.82, 18.08 an d 18.53 (C(CH3)3); 25.62, 25.83 an d 26.08
((CH3)3C); 33.52 (CH2-pur); 58.66 (CH3O); 62.51 (CH2-5′); 70.51 (CH2O); 71.95 (CH-3′);
75.78 (CH-2′); 85.57 (CH-4′); 88.23 (CH-1′); 133.69 (C-5); 142.90 (CH-8); 150.59 (C-4);
152.30 (CH-2); 159.82 (C-6). IR (CCl4): 2956, 2931, 2859, 1597, 1472, 1333, 1257, 1113.
Deprotection of THP-Protected Purin es 2b, 6b, 7b, 8b, 9b, 10b. Gen eral Procedure
To a stirred solution of purin e 2b (290 m g, 1 m m ol) in 96% EtOH (20 m l) was added a cata-
lytic am oun t of Dowex 50 (H+ form ). Th e reaction was stirred at 70 °C for 3 h , filtered, th e
resin was wash ed with eth an olic am m on ia an d th e filtrate was evaporated to dryn ess. Crude
product was ch rom atograph ed (ch loroform /m eth an ol) to give a wh ite solid. Purin e base 2g
was obtain ed by crystallization from m eth an ol/propan -2-ol/h eptan e as wh ite crystals, yield
192 m g (93%).
6-[2-(Ethoxycarbonyl)methyl]-9H-purine (2g). Wh ite crystals, m .p. 133–135 °C (lit.30 135 °C).
MS (FAB): 207 (45, M + 1), 73 (100). HRMS (FAB): for C9H11N4O2 calculated 207.0882, foun d
207.0880. 1H NMR (500 MHz, DMSO-d6): 1.17 (t, 3 H, Jvic = 7.1, CH3CH2); 4.11 (q, 2 H,
Jvic = 7.1, CH2CH3); 4.16 (s, 2 H, CH2-pur); 8.58 (bs, 1 H, H-8); 8.82 (s, 1 H, H-2); 13.46 (bs,
1 H, NH). 13C NMR (125.7 MHz, DMSO-d6 + DCl): 14.56 (CH3CH2); 39.20 (CH2-pur); 62.24
(CH2CH3); 127.55 (C-5); 148.59 (C-6); 149.43 (CH-2); 149.58 (CH-8); 154.98 (C-4); 167.83
(CO). IR (KBr): 2985, 2708, 1723, 1613, 1403, 1325, 1197. For C9H10N4O2·1/6H2O (209.2)
calculated: C 51.67%, H 4.98%, N 26.78%; foun d: C 51.99%, H 4.71%, N 26.65%.
6-(2-Hydroxyethyl)-9H-purine (6g). Yield 75%, wh ite crystals, m .p. 170–172 °C. MS (FAB):
165 (75, M + 1), 102 (100). HRMS (FAB): for C7H9N4O calculated 165.0776, foun d 165.0771.
1H NMR (600 MHz, DMSO-d6 + DCl): 3.45 (t, 2 H, Jvic = 6.1, CH2-pur); 3.92 (t, 2 H, Jvic = 6.1,
CH2O); 9.10 (s, 1 H, H-8); 9.22 (s, 1 H, H-2). 13C NMR (151 MHz, DMSO-d6 + DCl): 34.28
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1054
Hasník, Pohl, Klepetářová, Hocek:
(CH2-pur); 59.64 (CH2O); 129.23 (C-5); 146.74 (CH-2); 150.87 (CH-8); 153.69 (C-6); 156.33
(C-4). IR (KBr): 3392, 3262, 2824, 1619, 1569, 1379, 1239, 1042.
6-[(Methylcarbamoyl)methyl]-9H-purine (7g). Yield 64%, wh ite solid, m .p. 228–231 °C.
MS (ESI): 214 (100, M + Na), 192 (20, M + H). HRMS (ESI): for C8H10N5O calculated
192.0880, foun d 192.0878. 1H NMR (600.1 MHz, DMSO-d6): 2.60 (d, 3 H, J = 4.7, CH3N);
3.94 (s, 2 H, CH2-pur); 8.10 (bq, 1 H, J = 4.7, NH); 8.55 (s, 1 H, H-8); 8.79 (s, 1 H, H-2).
13C NMR (150.9 MHz, DMSO-d6): 26.00 (CH3N); 40.61 (CH2-pur); 129.70 (C-5); 145.56
(CH-8); 151.85 (CH-2); 153.42 (C-6); 155.00 (C-4); 168.36 (CO). IR (KBr): 3244, 3073, 2828,
1643, 1622, 1563, 1379, 1333. For C8H9N5O·3/5H2O (202.0) calculated: C 47.57%, H 5.09%,
N 34.67%; foun d: C 47.87%, H 4.60%, N 34.33%.
6-[(Dimethylcarbamoyl)methyl]-9H-purine (8g). Yield 58%, wh ite solid. MS (ESI): 432 (100,
2 M + Na), 228 (75, M + Na), 206 (60, M + H). HRMS (ESI): for C9H12N5O calculated
206.1036, foun d 206.1036. 1H NMR (500.0 MHz, DMSO-d6): 2.85 an d 3.10 (2 × s, 2 × 3 H,
CH3N); 4.17 (s, 2 H, CH2-pur); 8.55 (s, 1 H, H-8); 8.79 (s, 1 H, H-2). 13C NMR (125.7 MHz,
DMSO-d6): 35.22 an d 37.54 (CH3N); 39.20 (CH2-pur); 129.50 (C-5); 145.44 (CH-8); 151.85
(CH-2); 153.71 (C-6); 154.92 (C-4); 168.36 (CO). IR (KBr): 3405, 3112, 2968, 1648, 1601,
1395, 1325.
6-[(Piperidine-1-carbonyl)methyl]-9H-purine (9g). Yield 75%, wh ite solid. MS (ESI): 513 (100,
2 M + Na), 268 (65, M + Na), 246 (15, M + H). HRMS (ESI): for C12H16N5O calculated
246.1349, foun d 246.1349. 1H NMR (500.0 MHz, DMSO-d6): 1.43, 1.47 an d 1.58 (3 × m , 3 ×
2 H, CH2-pip); 3.42 an d 3.51 (CH2N-pip); 4.17 (s, 2 H, CH2-pur); 8.55 (s, 1 H, H-8); 8.79 (s,
1 H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 24.22, 25.51 an d 26.18 (CH2-pip); 38.58
(CH2-pur); 42.42 an d 46.76 (CH2N-pip); 129.68 (C-5); 145.49 (CH-8); 151.84 (CH-2); 153.80
(C-6); 154.70 (C-4); 166.52 (CO). IR (KBr): 3422, 2936, 1641, 1597, 1442, 1324, 1225.
6-[(Cyclopropylcarbamoyl)methyl]-9H-purine (10g). Yield 67%, wh ite solid. MS (ESI): 240
(100, M + Na), 218 (30, M + H). HRMS (ESI): for C10H12N5O calculated 218.1036, foun d
218.1029. 1H NMR (500.0 MHz, DMSO-d6): 0.43 an d 0.62 (2 × m , 2 × 2 H, CH2-cycloprop);
2.63 (tq, 1 H, J = 7.2, 4.2, CH-cycloprop); 3.89 (s, 2 H, CH2-pur); 8.32 (bd, 1 H, J = 4.2, NH);
8.55 (s, 1 H, H-8); 8.79 (s, 1 H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 5.93 (CH2-cycloprop);
22.77 (CH-cycloprop); 40.57 (CH2-pur); 129.63 (C-5); 145.62 (CH-8); 151.86 (CH-2); 153.48
(C-6); 154.88 (C-4); 169.11 (CO). IR (KBr): 3303, 3108, 2813, 1642, 1604, 1544, 1331, 1237.
For C10H11N5O (217.2) calculated: C 55.29%, H 5.10%, N 32.24%; foun d: C 55.09%, H 5.14%,
N 31.74%.
Deprotection of Purin e Nucleosides 2d , 2f, 6d , 6f an d 7d , 8d , 9d . Gen eral Procedure
Et3N·3HF (407 µl, 2.5 m m ol) was added to th e solution of 2d (340 m g, 0.5 m m ol) in THF
(1.5 m l) an d th e reaction m ixture was vigorously stirred at room tem perature overn igh t. Sol-
ven ts were evaporated in vacuo an d th e residue was ch rom atograph ed on silica gel colum n
(eth yl acetate/m eth an ol). Product was lyoph ilized to give 163 m g (96%) of 2h as a wh ite solid.
6-[(2-Ethoxycarbonyl)methyl]-9-(β-D-ribofuranosyl)-9H-purine (2h ). MS (FAB): 339.1 (70, M + 1),
207 (95), 93 (100). HRMS (FAB): for C14H19N4O6 calculated 339.1305, foun d 339.1302.
1H NMR (400 MHz, DMSO-d6): 1.18 (t, 3 H, J = 7.1, CH3CH2); 3.37 (ddd, 1 H, Jgem = 12.0,
J5′b,OH = 6.0, J5′b,4′ = 4.1, H-5′b); 3.69 (ddd, 1 H, Jgem = 12.0, J5′a,OH = 5.2, J5′a,4′ = 4.2, H-5′a);
3.98 (q, 1 H, J4′,5′ = 4.2, 4.1, J4′,3′ = 3.4, H-4′); 4.11 (q, 2 H, J = 7.1, CH2CH3); 4.18 (s, 2 H,
CH2-pur); 4.19 (td, 1 H, J3′,OH = 5.0, J3′,2′ = 4.9, J3′,4′ = 3.4, H-3′); 4.66 (q, 1 H, J2′,OH = 6.0,
J2′,1′ = 5.8, J2′,3′ = 4.9, H-2′); 5.11 (t, 1 H, JOH,5′ = 6.0, 5.2, OH-5′); 5.26 (d, 1 H, JOH,3′ = 5.0,
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

Synthesis of (Purin-6-yl)acetates
1055
OH-3′); 5.57 (d, 1 H, JOH,2′ = 6.0, OH-2′); 6.04 (d, 1 H, J1′,2′ = 5.8, H-1′); 8.82 (s, 1 H, H-8);
8.88 (s, 1 H, H-2). 13C NMR (100.6 MHz, DMSO-d6): 14.13 (CH3CH2); 38.82 (CH2-pur); 60.91
(CH2CH3); 61.48 (CH2-5′); 70.55 (CH-3′); 73.80 (CH-2′); 85.97 (CH-4′); 87.83 (CH-1′); 133.16
(C-5); 145.06 (CH-8); 150.93 (C-4); 151.99 (CH-2); 154.47 (C-6); 169.12 (CO). IR (CHCl3):
20
3326, 2988, 2933, 1734, 1603, 1500, 1336, 1248, 1189, 1084. [α]D –40.8 (c 2.62, H2O). For
C
14H18N4O6·1/2H2O (347.3) calculated: C 48.41%, H 5.51%, N 16.13%; foun d: C 48.39%,
H 5.48%, N 15.83%.
9-(2-Deoxy-β-D-erythro-pentofuranosyl)-6-[(2-ethoxycarbonyl)methyl]-9H-purine (2i). Prepared
from purin e 2f (550 m g, 1 m m ol) an d Et3N·3HF (570 µl, 3.5 m m ol) in THF (3 m l). Product
was lyoph ilized to give 226 m g (69%) of 2i as a yellow oil. MS (FAB): 667 (100), 345 (80,
M
+ Na), 323 (M + H). HRMS (FAB): for C14H18N4NaO5 calculated 345.1175, foun d
345.1166. 1H NMR (400 MHz, DMSO-d6): 1.17 (t, 3 H, J = 7.1, CH3CH2); 2.36 (ddd, 1 H,
Jgem = 13.3, J2′b,1′ = 6.3, J2′b,3′ = 3.5, H-2′b); 2.81 (ddd, 1 H, Jgem = 13.3, J2′a,1′ = 7.3, J2′a,3′
5.9, H-2′a); 3.53 (ddd, 1 H, Jgem = 11.7, J5′b,OH = 5.6, J5′b,4′ = 4.6, H-5′b); 3.62 (dt, 1 H, Jgem
=
=
11.7, J5′a,OH = 5.6, J5′a,4′ = 4.7, H-5′a); 3.89 (td, 1 H, J4′,5′ = 4.7, 4.6, J4′,3′ = 3.0, H-4′); 4.11 (q,
2 H, J = 7.1, CH2CH3); 4.17 (s, 2 H, CH2-pur); 4.45 (dq, 1 H, J3′,2′ = 5.9, 3.5, J3′,OH = 4.2,
J3′,4′ = 3.0, H-3′); 4.99 (t, 1 H, JOH,5′ = 5.6, OH-5′); 5.37 (d, 1 H, JOH,3′ = 4.2, OH-3′); 6.47 (t,
1 H, J1′,2′ = 7.3, 6.3, H-1′); 8.77 (s, 1 H, H-8); 8.87 (s, 1 H, H-2). 13C NMR (100.6 MHz,
DMSO-d6): 14.22 (CH3CH2); 38.80 (CH2-pur); 39.36 (CH2-2′); 60.89 (CH2CH3); 61.75
(CH2-5′); 70.84 (CH-3′); 84.00 (CH-1′); 88.21 (CH-4′); 133.16 (C-5); 144.98 (CH-8); 150.63
(C-4); 151.90 (CH-2); 154.34 (C-6); 169.13 (CO). IR (KBr): 3326, 3007, 1735, 1602, 1336,
1204, 1104. For C14H18N4O5·1/3H2O (328.3) calculated: C 51.21%, H 5.73%, N 17.06%;
foun d: C 51.29%, H 5.57%, N 16.67%.
6-(2-Hydroxyethyl)-9-(β-D-ribofuranosyl)-9H-purine (6h ). Prepared from purin e 6d (320 m g,
0.5 m m ol) an d Et3N·3HF (407 µl, 2.5 m m ol) in THF (1.5 m l). Product was lyoph ilized to give
136 m g (92%) of 6h as a wh ite solid. MS (FAB): 297 (20, M + 1), 241 (45), 185 (40), 93 (100).
HRMS (FAB): for C12H17N4O5 calculated 297.1198, foun d 297.1206. 1H NMR (400 MHz,
DMSO-d6): 3.25 (t, 2 H, Jvic = 6.8, CH2-pur); 3.57 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 6.1, J5′b,4′
4.1, H-5′b); 3.68 (ddd, 1 H, Jgem = 12.0, J5′a,OH = 4.9, J5′a,4′ = 4.3, H-5′a); 3.92 (td, 2 H, Jvic
6.8, JOH = 5.6, CH2-O); 3.98 (q, 1 H, J4′,5′ = 3.9, 3.9, J4′,3′ = 3.7, H-4′); 4.18 (td, 1 H, J3′,OH
=
=
=
4.9, J3′,2′ = 4.9, J3′,4′ = 3.7, H-3′); 4.64 (q, 1 H, J2′,OH = 6.1, J2′,1′ = 5.8, J2′,3′ = 4.9, H-2′); 4.78 (t,
1 H, J = 5.6, OH); 5.14 (t, 1 H, JOH,5′ = 5.9, 5.3, OH-5′); 5.26 (d, 1 H, JOH,3′ = 4.9, OH-3′); 5.54
(d, 1 H, JOH,2′ = 6.1, OH-2′); 6.02 (d, 1 H, J1′,2′ = 5.8, H-1′); 8.76 (s, 1 H, H-8); 8.83 (s, 1 H,
H-2). 13C NMR (100.6 MHz, DMSO-d6): 36.46 (CH2-pur); 59.38 (CH2OH); 61.30 (CH2-5′);
70.35 (CH-3′); 73.56 (CH-2′); 85.69 (CH-4′); 87.55 (CH-1′); 133.08 (C-5); 144.08 (CH-8);
150.21 (C-4); 151.67 (CH-2); 159.72 (C-6). IR (KBr): 3413, 2926, 1603, 1407, 1335, 1212,
20
1052. [α]D –44.4 (c 3.19, H2O). For C12H16N4O5·3/4H2O (309.8) calculated: C 46.52%, H 5.69%,
N 18.09%; foun d: C 46.63%, H 5.73%, N 17.63%.
9-(2-Deoxy-β-D-erythro-pentofuranosyl)-6-(2-hydroxyethyl)-9H-purine (6i). Prepared from pu-
rin e 6f (360 m g, 0.7 m m ol) an d Et3N·3HF (400 µl, 2.5 m m ol) in THF (3 m l). Product was
lyoph ilized to give 135 m g (69%) of 6i as a wh ite foam . MS (FAB): 281 (15, M + 1), 154
(100), 136 (85). HRMS (FAB): for C12H17N4O4 calculated 281.1249, foun d 281.1245. 1H NMR
(400 MHz, DMSO-d6): 2.34 (ddd, 1 H, Jgem = 13.3, J2′b,1′ = 6.3, J2′b,3′ = 3.4, H-2′b); 2.79 (ddd,
1 H, Jgem = 13.3, J2′a,1′ = 7.4, J2′a,3′ = 5.9, H-2′a); 3.24 (t, 2 H, Jvic = 6.8, CH2-pur); 3.52 (ddd,
1 H, Jgem = 11.7, J5′b,OH = 5.7, J5′b,4′ = 4.7, H-5′b); 3.62 (ddd, 1 H, Jgem = 11.8, J5′a,OH = 5.4,
J5′a,4′ = 4.7, H-5′a); 3.89 (td, 1 H, J4′,5′ = 4.7, 4.6, J4′,3′ = 2.7, H-4′); 3.92 (bt, 2 H, Jvic = 6.8,
JOH = 5.6, CH2-O); 4.44 (m , 1 H, J3′,2′ = 5.9, 3.4, J3′,OH = 4.2, J3′,4′ = 2.7, H-3′); 4.76 (bt, 1 H,
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

1056
Hasník, Pohl, Klepetářová, Hocek:
J = 5.6, OH); 5.00 (t, 1 H, JOH,5′ = 5.6, OH-5′); 5.36 (d, 1 H, JOH,3′ = 4.2, OH-3′); 6.46 (t, 1 H,
J1′,2′ = 7.4, 6.3, H-1′); 8.72 (s, 1 H, H-8); 8.82 (s, 1 H, H-2). 13C NMR (100.6 MHz, DMSO-d6):
36.41 (CH2-pur); 39.09 (CH2-2′); 59.32 (CH2OH); 61.52 (CH2-5′); 70.61 (CH-3′); 83.61
(CH-1′); 87.89 (CH-4′); 133.02 (C-5); 143.91 (CH-8); 149.87 (C-4); 151.53 (CH-2); 159.52
20
(C-6). IR (KBr): 3401, 2928, 1601, 1400, 1335, 1213, 1055. [α]D –15.8 (c 2.72, H2O). For
C
12H14N4O4·1/2H2O (289.2) calculated: C 49.82%, H 5.92%, N 19.37%; foun d: C 50.12%,
H 5.76%, N 19.14%.
6-[(Methylcarbamoyl)methyl]-9-(β-D-ribofuranosyl)-9H-purine (7h ). Prepared from purin e 7d
(500 m g, 0.75 m m ol) an d Et3N·3HF (612 µl, 3.75 m m ol) in THF (2.5 m l). Product was
lyoph ilized to give 213 m g (88%) of 7h as a wh ite solid. MS (FAB): 324 (10, M + 1), 192 (100),
161 (60), 135 (55). HRMS (FAB): for C13H18N5O5 calculated 324.1308, foun d 324.1316.
1H NMR (499.8 MHz, DMSO-d6): 2.60 (d, 3 H, J = 4.7, CH3N); 3.57 (ddd, 1 H, Jgem = 12.0,
J5′b,OH = 6.1, J5′b,4′ = 4.1, H-5′b); 3.69 (ddd, 1 H, Jgem = 12.0, J5′a,OH = 5.2, J5′a,4′ = 4.1, H-5′a);
3.96 (s, 2 H, CH2-pur); 3.98 (td, 1 H, J4′,5′ = 4.1, J4′,3′ = 3.6, H-4′); 4.19 (td, 1 H, J3′,OH = J3′,2′
=
4.9, J3′,4′ = 3.6, H-3′); 4.65 (ddd, 1 H, J2′,OH = 6.1, J2′,1′ = 5.8, J2′,3′ = 4.9, H-2′); 5.13 (dd, 1 H,
JOH,5′ = 6.1, 5.2, OH-5′); 5.25 (d, 1 H, JOH,3′ = 4.9, OH-3′); 5.56 (d, 1 H, JOH,2′ = 6.1, OH-2′);
6.03 (d, 1 H, J1′,2′ = 5.8, H-1′); 8.08 (bq, 1 H, J = 4.7, NH); 8.78 (s, 1 H, H-8); 8.84 (s, 1 H,
H-2). 13C NMR (125.7 MHz, DMSO-d6): 25.99 (CH3N); 38.87 (CH2-pur); 61.53 (CH2-5′);
70.60 (CH-3′); 73.82 (CH-2′); 85.96 (CH-4′); 87.86 (CH-1′); 133.47 (C-5); 144.75 (CH-8);
150.79 (C-4); 151.91 (CH-2); 156.36 (C-6); 168.23 (CO). IR (CCl4): 3317, 2928, 1657, 1602,
20
1409, 1336, 1210, 1154. [α]D –35.2 (c 3.29, H2O).
6-[(Dimethylcarbamoyl)methyl]-9-(β-D-ribofuranosyl)-9H-purine (8h ). Prepared from purin e 8d
(340 m g, 0.5 m m ol) an d Et3N·3HF (408 µl, 2.5 m m ol) in THF (3 m l). Product was
lyoph ilized to give 153 m g (91%) of 8h as wh ite solid. MS (FAB): 338 (30, M + 1), 241 (85),
157 (50), 93 (100). HRMS (FAB): for C14H20N5O5 calculated 338.1464, foun d 338.1474.
1H NMR (499.8 MHz, DMSO-d6): 2.85 an d 3.11 (2 × s, 2 × 3 H, CH3N); 3.57 (ddd, 1 H, Jgem
=
12.1, J5′b,OH = 6.0, J5′b,4′ = 4.1, H-5′b); 3.69 (ddd, 1 H, Jgem = 12.1, J5′a,OH = 5.2, J5′a,4′ = 4.1,
H-5′a); 3.98 (td, 1 H, J4′,5′ = 4.1, J4′,3′ = 3.6, H-4′); 4.19 (td, 1 H, J3′,OH = J3′,2′ = 4.9, J3′,4′ = 3.6,
H-3′); 4.21 (s, 2 H, CH2-pur); 4.66 (ddd, 1 H, J2′,OH = 6.1, J2′,1′ = 5.8, J2′,3′ = 4.9, H-2′); 5.12
(dd, 1 H, JOH,5′ = 6.0, 5.2, OH-5′); 5.25 (d, 1 H, JOH,3′ = 4.9, OH-3′); 5.56 (d, 1 H, JOH,2′ = 6.1,
OH-2′); 6.03 (d, 1 H, J1′,2′ = 5.8, H-1′); 8.77 (s, 1 H, H-8); 8.84 (s, 1 H, H-2). 13C NMR
(125.7 MHz, DMSO-d6): 35.17 an d 37.52 (CH3N); 38.06 (CH2-pur); 61.55 (CH2-5′); 70.61
(CH-3′); 73.77 (CH-2′); 85.98 (CH-4′); 87.84 (CH-1′); 133.43 (C-5); 144.67 (CH-8); 150.67
(C-4); 151.87 (CH-2); 156.69 (C-6); 168.23 (CO). IR (CCl4): 3409, 2927, 1637, 1600, 1403,
20
1336, 1211, 1056. [α]D –40.0 (c 3.86, H2O).
6-[(Piperidine-1-carbonyl)methyl]-9-(β-D-ribofuranosyl)-9H-purine (9h ). Prepared from purin e
9d (525 m g, 0.73 m m ol) an d Et3N·3HF (596 µl, 3.65 m m ol) in THF (3 m l). Product was
lyoph ilized to give 270 m g (98%) of 9h as a wh ite solid. MS (FAB): 400 (100, M + Na), 378
(20, M + H). HRMS (FAB): for C17H24N5O5 calculated 378.1772, foun d 378.1770. 1H NMR
(400 MHz, DMSO-d6): 1.42 an d 1.49 (2 × m , 2 × 2 H, H-3,5-pip); 1.57 (m , 2 H, H-4-pip); 3.43
an d 4.52 (2 × t, 2 × 2 H, J = 5.4, H-2,6-pip); 3.58 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 5.9, J5′b,4′
4.2, H-5′b); 3.67 (ddd, 1 H, Jgem = 12.0, J5′a,OH = 5.2, J5′a,4′ = 4.2, H-5′a); 3.98 (q, 1 H, J4′,5′
=
=
4.2, 4.1, J4′,3′ = 3.6, H-4′); 4.18 (td, 1 H, J3′,OH = 4.9, J3′,2′ = 4.9, J3′,4′ = 3.4, H-3′); 4.20 (s, 2 H,
CH2-pur); 4.66 (q, 1 H, J2′,OH = 5.9, J2′,1′ = 5.8, J2′,3′ = 4.9, H-2′); 5.11 (t, 1 H, JOH,5′ = 5.5,
OH-5′); 5.23 (d, 1 H, JOH,3′ = 4.9, OH-3′); 5.54 (d, 1 H, JOH,2′ = 5.9, OH-2′); 6.02 (d, 1 H,
J1′,2′ = 5.8, H-1′); 8.77 (s, 1 H, H-8); 8.84 (s, 1 H, H-2). 13C NMR (100.6 MHz, DMSO-d6):
23.87 (CH2-4-pip); 25.15 an d 25.85 (CH2-3,5-pip); 37.69 (CH2-pur); 42.05 an d 46.42
Collect. Czech. Chem. Commun. 2009, Vol. 74, Nos. 7–8, pp. 1035–1059

Synthesis of (Purin-6-yl)acetates
1057
(CH2-2,6-pip); 61.23 (CH2-5′); 70.28 (CH-3′); 73.46 (CH-2′); 85.65 (CH-4′); 87.51 (CH-1′);
133.05 (C-5); 144.33 (CH-8); 150.35 (C-4); 151.52 (CH-2); 156.41 (C-6); 166.07 (CO).
20
IR (KBr): 3461, 3205, 2924, 2854, 1648, 1566, 1400, 1225. [α]D –32.2 (c 0.20, H2O).
Sin gle Crystal X-ray Structure An alysis
Th e diffraction data of sin gle crystals of 2a (yellowish , 0.08 × 0.20 × 0.48 m m ), 6a (wh ite,
0.14 × 0.23 × 0.34 m m ) an d 9a (yellowish , 0.11 × 0.16 × 0.28 m m ) were collected on
Xcalibur X-ray diffractom eter with CuKα (λ = 1.54180 Å) at 295 (2a), 150 (6a) an d 298 K
31
(9a). All structures were solved by direct m eth ods with SIR92
an d refin ed by full-m atrix,
least-squares m eth ods based on F with CRYSTALS 32. Th e h ydrogen atom s were located in
a differen ce m ap, but th ose attach ed to carbon atom s were reposition ed geom etrically an d
th en refin ed with ridin g con strain ts, wh ile all oth er atom s were refin ed an isotropically in
both cases.
Crystal data for 2a: C16H16N4O2, triclin ic, space group P-1, a = 8.4835(7) Å, b = 9.0266(7) Å,
c = 11.4610(10) Å, α = 68.357(8)°, β = 68.845(8)°, γ = 83.135(7)°, V = 760.71(12) Å3, Z = 2,
M = 296.33, 10 494 reflection s m easured, 3 059 in depen den t reflection s. Fin al R = 0.0579,
wR = 0.0767, GOF = 1.0550 for 2 491 reflection s with I > 1.96σ(I) an d 200 param eters.
Crystal data for 6a: C14H14N4O1, triclin ic, space group P-1, a = 5.6172(7) Å, b = 9.9556(8) Å,
c = 11.3924(9) Å, α = 104.037(7)°, β = 92.518(8)°, γ = 93.687(8)°, V = 615.62(11) Å3, Z = 2,
M = 254.29, 8 392 reflection s m easured, 2 454 in depen den t reflection s. Fin al R = 0.0362,
wR = 0.0361, GOF = 1.2047 for 2 302 reflection s with I > 1.96σ(I) an d 173 param eters.
Crystal data for 9a : C19H21N5O1, triclin ic, space group P-1, a = 11.5005(5) Å, b =
12.3904(6) Å, c = 13.0988(6) Å, α = 77.743(4)°, β = 75.914(4)°, γ = 89.505(4)°, V =
1767.31(15) Å3, Z = 4, M = 335.41, 55 857 reflection s m easured, 7 451 in depen den t reflec-
tion s. Fin al R = 0.0389, wR = 0.0442, GOF = 1.1029 for 3 681 reflection s with I > 1.5σ(I) an d
452 param eters.
CCDC 638672 (2a ), 638673 (6a ), 724480 (9a ) con tain th e supplem en tary crys-
tallograph ic data for th is paper. Th ese data can be obtain ed free of ch arge via
www.ccdc.cam .ac.uk/con ts/retrievin g.h tm l (or from th e Cam bridge Crystallograph ic
Data Cen tre, 12, Un ion Road, Cam bridge, CB2 1EZ, UK; fax: +44 1223 336033; or
deposit@ccdc.cam .ac.uk).
This work is a part of the research project Z4 055 0506. It was supported by the Centre for New
Antivirals and Antineoplastics (1M0508), by the Programme of Targeted Projects of Academy of
Sciences of the Czech Republic (1QS400550501) and by Gilead Sciences, Inc. (Foster City (CA), USA).
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