Perfluoroalkylation of 6-iodopurines by trimethyl(perfluoroalkyl)silanes. Synthesis of 6-(perfluoroalkyl)purine bases, nucleosides and acyclic nucleotide analogues

Article abstract of DOI:10.1135/cccc19990229

A Cul/KF mediated perfluoroalkylation reaction of various 9-substituted 6-iodopurines 1 with trimethyl(trifluoromethyl)silane or heptafluoropropyl(trimethyl)silane was used for the synthesis of the corresponding 6-(trifluoromethyl)-and 6-(heptafluoropropy

Full text of DOI:10.1135/cccc19990229

Perfluoroalkylation of 6-Iodopurines
229
PERFLUOROALKYLATION OF 6-IODOPURINES BY
TRIMETHYL(PERFLUOROALKYL)SILANES. SYNTHESIS OF
6-(PERFLUOROALKYL)PURINE BASES, NUCLEOSIDES
AND ACYCLIC NUCLEOTIDE ANALOGUES
1,
2
Michal HOCEK * and Antonín HOLÝ
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
1
2
166 10 Prague 6, Czech Republic; e-mail: hocek@uochb.cas.cz, holy@uochb.cas.cz
Received Decem ber 4, 1998
Accepted Jan uary 5, 1999
Dedicated to the memory of Dr Miroslav Protiva.
A CuI/KF m ediated perfluoroalkylation reaction of various 9-substituted 6-iodopurin es 1
with trim eth yl(trifluorom eth yl)silan e or h eptafluoropropyl(trim eth yl)silan e was used for th e
syn th esis of th e correspon din g 6-(trifluorom eth yl)- an d 6-(h eptafluoropropyl)purin e deriva-
tives (purin e bases, n ucleosides an d acyclic n ucleotide an alogues) in m oderate to good
yields.
Key w ord s: Purin es; Nucleosides; Cross-couplin g reaction s; Trifluorom eth ylation ; Perfluoro-
alkylation ; Cuprates; Fluorin ated com poun ds; Cytostatic activity.
Purin e bases m odified in th e 6-position an d th eir n ucleoside an d n ucleo-
tide derivatives an d an alogues possess a broad spectrum of biological activ-
ity. Th e cytotoxicity of 6-m eth ylpurin e an d its n ucleosides is well kn own 1,
wh ile a prom isin g cytostatic activity of 6-(alkylam in o)purin e derivatives (as
cytokin in es an alogues) h as been recen tly discovered2. Man y 6-(alkyl-
am in o)purin e n ucleosides are im portan t aden osin e receptors an tagon ists3
an d acyclic n ucleotide an alogues derived from 6-[(di)alkylam in o]purin es
are stron g an tivirals, an tin eoplastic agen ts an d im m un om odulators4.
Fluorin ated an alogues of n atural com poun ds exert in terestin g biological
activity5. Also fluorin ated derivatives of n ucleosides h ave been studied, in
particular an tin eoplastic 5-fluorouracil6 an d its n ucleosides, an tiviral
5-(trifluorom eth yl)uracil n ucleosides7, an titum or 2-fluoroaden in e n ucleo-
sides8, as well as n ucleosides with fluorin ated sugar m oiety9. Reactive 2-
an d 6-fluoropurin e derivatives are good startin g com poun ds for n ucleo-
ph ilic substitution reaction s10. 2-Trifluorom eth yl-11 an d 8-trifluorom eth yl-
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

230
Hocek, Holý:
purine12 derivatives are easily prepared by heterocyclization of 5,6-diaminopyrimidines
or 4-am inoim idazole-5-carboxylic acid derivatives by trifluoroacetates and are
reported to possess in terestin g an tirh in ovirus, vasodepressor, platelet
aggregation in h ibitory, ph osph odiesterase in h ibitory an d an titum or activ-
ity. 2-(Trifluorom eth yl)aden osin e an alogues were also prepared13 by
trifluorom ethylation of 2-iodoadenosines by trifluorom ethylzinc brom ide and
CuBr in DMF/HMPA. 6-Fluoroalkylated purines are quite rare in the literature.
6-(Trifluorom eth yl)purin e an d 2-am in o-6-(trifluorom eth yl)purin e were pre-
pared by m ultistep cyclization procedures14 startin g from eth yl
4,4,4-trifluoro-3-oxobutan oate in low overall yields (3 an d 6%, respec-
tively). Trifluorom eth ylation of protected 6-iodopurin e riboside with
trifluorom eth yl iodide an d copper m etal in HMPA gave15 th e
6-(trifluorom eth yl)purin e derivative in m oderate yield; th e fin al
6-(trifluorom eth yl)purin e riboside was reported to exh ibit a m oderate
cytotostatic activity. Except for th e above m en tion ed exam ple, biological
activity of an y 6-(fluoroalkyl)purin e derivative h as n ot been publish ed so
far.
In th is paper we report on th e attem pts to develop a versatile
trifluorom eth ylation an d perfluoroalkylation of 6-h alopurin es, th e use of
th at m eth odology for th e syn th esis of 6-(trifluorom eth yl)- an d 6-(per-
fluoroalkyl)purin e bases, n ucleosides an d acyclic n ucleotide an alogues, as
well as on th e biological activity of th e products.
RESULTS AND DISCUSSION
In th e last decade, with th e developm en t of th e cross-couplin g m eth odol-
ogy, m an y 6-C-substituted purin es h ave been prepared16
.
Th us,
6-h alopurin e derivatives react with alkyl(aryl)zin c or tin reagen ts16a–16e
,
trialkylalum in um 16f or alkylcuprates16g,16h to give th e 6-alkylpurin e deriva-
tives. Also reverse approach based on th e reaction of purin e-6-zin c iodide
with aryl or vin yl h alides h as recen tly been described17
.
For th e syn th esis of th e 6-(perfluoroalkyl)purin e derivatives, our first at-
tem pts focussed on th e application of th e copper-m ediated cross-couplin g
reaction s15,18 of 6-iodopurin es with perfluoroalkyl iodides. In a m odel ex-
perim en t, we treated perfluorobutyl iodide (as an exam ple of a stable,
ch eap an d h igh -boilin g perfluoroalkyl iodide) with 6-iodo-9-(tetrah ydro-
pyran -2-yl)purin e an d copper in DMF at 120 °C for 24 h (con dition s an alo-
gous to th e publish ed procedures18); h owever, n o reaction took place.
Th ough th e problem certain ly con sists in th e activity of th e copper m etal
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Perfluoroalkylation of 6-Iodopurines
231
used, th e lack of reactivity was n ot overcom e even with th e use of th e acti-
vated copper18a
.
For th e system atic structure–activity relation sh ip studies of a series of tar-
get 6-(perfluoroalkyl)purin e derivatives, th ere was a n eed to develop a fac-
ile, reproducible syn th etic m eth od for th e perfluoroalkylation of purin es
usin g com m ercially available reagen ts. Th erefore we in vestigated th e cop-
per(I) iodide/potassium fluoride m ediated cross-couplin g reaction s19 of
trim eth yl(perfluoroalkyl)silan es with 6-h alopurin es. In th e gen eral proce-
dure, th e 6-h alopurin e derivative was treated with trim eth yl(perfluoro-
alkyl)silan e (aproxim ately 1.5 equivalen t), KF an d CuI in a m ixture of DMF
an d N-m eth ylpyrrolidin -2-on e (NMP) in a septum -sealed glass vial at 60 °C
for 20 h . Th e first experim en ts design ed to evaluate th e reactivity of a series
of 6-h alopurin e derivatives towards trim eth yl(trifluorom eth yl)silan e (1a)
revealed th at all th e 6-ch loropurin e derivatives (6-ch loropurin e, 6-ch loro-
9-(tetrahydropyran-2-yl)purine, 6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-
purine and their 2-amino derivatives), as well as the 6-iodopurine bases (6-iodo-
purine and 2-amino-6-iodopurine) are entirely unreactive, whereas the use of the
9-(tetrahydropyran-2-yl)- (THP) protected 6-iodopurine 2 afforded th e 6-tri-
fluorom eth yl derivative 6a in 85% yield. Th erefore, we selected 9-substi-
tuted/protected 6-iodopurin es as suitable startin g m aterials.
Th e THP-protected 6-iodopurin e17 2 an d th e protected 6-iodopurin e
ph osph on ate16e 3 were kn own . Th e bis(THP)-protected 2-am in o-6-iodo-
purin e 4 was prepared by th e reaction of 2-am in o-6-iodopurin e with
3,4-dih ydro-2H-pyran in DMF catalyzed by HCl in 63% yield, an alogously
to th e procedure20 publish ed for its 6-ch loro an alogue. Sin ce it was kn own
th at partial h ydrolysis of th e trifluorom eth yl fun ction took place15 durin g
alkali m ediated deacetylation of som e trifluorom eth ylated n ucleosides, we
selected acidolabile protectin g groups for th e protection of th e n ucleoside
h ydroxy fun ction s. Th us th e kn own 2′,3′-O-isopropyliden e-5′-O-trityl-
aden osin e was iododeam in ated21 usin g a stan dard procedure (reflux with
diiodom eth an e an d isoam yl n itrite in aceton itrile) to give th e 6-iodopurin e
n ucleoside 5 in 36% yield.
For th e syn th esis of th e 6-perfluoroalkylated purin e bases we used th e re-
action of trim eth yl(trifluorom eth yl)silan e (1a) an d h eptafluoropropyl-
(trim eth yl)silan e (1b ) with th e THP-protected 6-iodopurin es 2 an d 4
(Sch em e 1). Th e trifluorom eth ylation of th e protected 6-iodopurin e 2 pro-
ceeded sm ooth ly to give th e product 6a in 85% yield, wh ile in th e sam e re-
action of th e protected 2-am in o-6-iodopurin e 4, th ough th e con version was
quan titative, th e yield of th e product 7a was m uch lower (27%) due to un -
iden tified degradative side reaction s. Th e perfluoropropylation of th e com -
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

232
Hocek, Holý:
poun ds 2 an d 4 was m uch slower an d even th e use of a h igh er excess of th e
silan e reagen t 1b an d lon ger reaction tim e (48 h ) did n ot brin g good yields.
Despite th e fact th at th e con version was n ot quan titative an d in addition to
th e degradation products also som e startin g com poun ds were presen t in th e
reaction m ixture, th e products 6b an d 7b were isolated in m oderate yields
(35 an d 23%, respectively) by colum n ch rom atograph y. Th e THP-protected
derivatives 6 an d 7 were easily deprotected by treatm en t with wet Dowex 50
(H+) in m eth an ol to give th e perfluoroalkylpurin e bases 8 an d 9 in good
yields (ca 90%).
R
I
R
F
F
N
N
N
(i)
(ii)
N
N
N
N
H
N
N
N
N
N
THP
THP
2
6
8
85%
35%
92%
90%
6,8: a R = CF
F
3
b R = CF CF CF
2
F
2
3
I
R
F
R
F
N
N
(i)
N
(ii)
N
N
N
N
N
N
H
THP
N
H
N
THP
N
H
N
H N
2
N
THP
THP
4
7
9
30%
23%
92%
88%
7,9: a R = CF
F
3
b R = CF CF CF
3
F
2
2
o
+
(i) R SiMe , KF, CuI, DMF/NMP, 60 C, 20 h; (ii) Dowex 50 (H ), H O, reflux, 1 h
F
3
THP = tetrahydropyran-2-yl
2
SCHEME 1
An an alogous perfluoroalkylation of th e protected 6-iodopurin e ribo-
n ucleoside 5 was quite facile an d th e products 10a an d 10b were isolated in
acceptable yields of 75 an d 47%, respectively (Sch em e 2). Th e m ost difficult
step was th e deprotection due to th e in stability of th e n ucleosidic bon d in
th e 6-perfluoropurin e ribosides th at easily cleaved to give th e purin e bases.
Th e attem pted deprotection usin g wet Dowex 50 (H+) in refluxin g m eth a-
n ol led to th e deglycosylated purin es 6 as m ajor products (after 3 h , th e
degradation to th e bases 6 was already quan titative). Th erefore, m ilder con -
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Perfluoroalkylation of 6-Iodopurines
233
dition s usin g refluxin g 80% acetic acid were used. Even un der th ese con di-
tion s som e deglycosylation occurred but it was slower th an in th e form er
m eth od. Th e optim um yields of th e deprotected n ucleosides 11 (ca 30%)
were ach ieved after 1 h treatm en t (th e con version bein g aproxim ately 50%)
followed by colum n ch rom atograph y.
I
R
R
F
F
N
N
N
N
N
N
N
N
N
N
O
N
N
(i)
(ii)
TrO
TrO
HO
O
O
O
O
O
O
OH
HO
11
5
10
75%
47%
35%
30%
10,11: a R = CF
F
3
b R = CF CF CF
3
F
2
2
o
(i) R SiMe , KF, CuI, DMF/NMP, 60 C, 20 h; (ii) 80% AcOH, reflux, 1 h
F
3
SCHEME 2
Th e p erflu oroalkylation of th e 9-[2-(d ieth oxyp h osp h on ylm eth oxy)-
et h yl]-6-io d o p u rin e (3) proceeded in a sim ilar m an n er as in th e above
m en tion ed cases to give th e perfluoroalkylated products 12 in 92 an d 46%,
respectively (Sch em e 3). Th e stan dard procedure usin g brom o(trim eth yl)-
silan e (TMSBr) in aceton itrile22 was used for th e cleavage of th e ph os-
ph on ate esters. Th e isolation of th e free ph osph on ates was quite
com plicated. Due to th e absen ce of basic fun ction s in th e m olecule, it was
im possible to use th e stan dard com bin ation of Dowex 50 (H+) followed by
Dowex 1 (AcO–) ion -exch an ge ch rom atograph y22. Ch rom atograph y on
R
R
I
F
F
(ii)
(i)
N
N
N
N
N
N
N
N
N
O
P
O
O
N
N
N
O
OEt
O
P
OH
O
P
OEt
3
12
13
OEt
OH
OEt
12,13: a R = CF
F
92%
46%
82%
31%
3
b R = CF CF CF
3
F
2
2
o
(i) R SiMe , KF, CuI, DMF/NMP, 60 C, 20 h; (ii) TMSBr, acetonitrile
F
3
SCHEME 3
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

234
Hocek, Holý:
DEAE Seph adex, followed by deion ization on Dowex 50 (H+) afforded th e
free ph osph on ates 13 as extrem ely h ygroscopic solids.
1
All n ew com poun ds were fully ch aracterized by H an d 19F NMR (13C NMR
was also recorded for at least on e exam ple of each class of com poun ds), MS
an d HR-MS an d/or m icroan alysis. Sin ce th e m eltin g poin ts foun d for th e
kn own com poun ds 8a, 9a an d 11a differed from th e publish ed values quite
sign ifican tly, th ese com poun ds were also fully ch aracterized. For th e assign -
m en t of th e NMR sign als, stan dard 2D tech n iques were used. 1H-1H spin
n etwork was determ in ed by COSY spectra. Carbon con n ectivities based on
on e-bon d an d th ree-bon d 1H-13C correlation were establish ed by in verse
tech n iques HMQC an d HMBC spectra, respectively. Th e bis(THP)-protected
2-am in opurin es 4 an d 7 were isolated, ch aracterized an d used as diastereo-
m eric m ixtures. Th ey were ch rom atograph ically h om ogen eous but splittin g
of som e carbon sign als was observed in 13C NMR spectra. Due to th eir
stron g h ygroscopicity, th e free ph osph on ates 13 could n ot be ch aracterized
by m icroan alysis. Th erefore, a com bin ation of electroph oresis an d TLC (pu-
rity eviden ce) an d HR-MS were used for th e ch aracterization .
In con clusion , th e perfluoroalkylation m eth odology presen ted in th is pa-
per was successfully used for th e preparation of 6-(trifluorom eth yl)- an d
6-(h eptafluoropropyl)purin e derivatives (purin e bases, n ucleosides an d acy-
clic n ucleotide an alogues). It is th e m ost effective altern ative approach for
th e trifluorom eth ylation of 2-un substituted 6-iodopurin es; th eir h epta-
fluoropropylation , as well as both perfluoroalkylation s of th e protected
2-am in o-6-iodopurin e 4 offered lower, but still acceptable, yields of th e per-
fluoroalkylated products. In com parison with th e Kobayash i approach 15
,
th is m eth od avoids th e use of expen sive gaseous CF3I an d toxic HMPA, as
well as th e preparation of h igh ly activated copper m etal. Th e lim itation s
are th e n ecessity to use 6-iodopurin es as startin g com poun ds
(6-ch loropurin es are un reactive) an d th e accessibility of th e startin g
trialkyl(perfluoroalkyl)silan es wh ich , with th e exception of th e com m er-
cially available com poun ds 1a an d 1b , m ust be prepared23 from
perfluoroalkyl iodides, ch lorotrim eth ylsilan e an d h exaeth ylph osph orous
triam ide.
Th e 6-(perfluoroalkyl)purin es 8, 9, 11 an d 13 were tested for th eir
cytostatic24 (in h ibition of th e cell growth in th e followin g cell cultures:
(i) m ouse leukem ia L1210 cells (ATCC CCL 219); (ii) m urin e L929 cells
(ATCC CCL 1) and (iii) human cervix carcinoma HeLaS3 cells (ATCC CCL 2.2))
an d an tiviral25 activity (DNA viruses: HSV-1, HSV-2, CMV, VZV an d vaccin ia
virus, an d retroviruses: HIV-1, HIV-2 an d MSV). In accord with th e qualita-
tive literature data15, com poun d 11a exh ibited a prom isin g cytostatic activ-
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Perfluoroalkylation of 6-Iodopurines
235
ity; it will be a subject of furth er detailed study an d th e results will be
publish ed elsewh ere. Non e of th e oth er tested com poun ds exh ibited an y
con siderable activity in an y of th e assays.
EXPERIMENTAL
Un less oth erwise stated, solven ts were evaporated at 40 °C/2kPa an d com poun ds were dried
at 60 °C/2kPa over P2O5. Meltin g poin ts were determ in ed on a Kofler block an d are un cor-
rected. Paper electroph oresis was perform ed on a paper Wh atm an No. 3 MM at 40 V/cm for
1 h in 0.05 M trieth ylam m on ium h ydrogen carbon ate (TEAB) at pH 7.5 an d th e electro-
ph oretical m obilities are referen ced to uridin e 3′-ph osph ate. NMR spectra were m easured on
a Bruker AMX-3 400 (400 MHz for 1H, 100.6 MHz for 13C an d 376.5 MHz for 19F n uclei),
Bruker DRX 500 (500 MHz for 1H, 125.7 MHz for 13C an d 470.59 MHz for 19F) an d Varian
Gem in i 300HC (300.075 MHz for 1H an d 75.462 MHz for 13C) spectrom eters. TMS was used
as in tern al stan dard for th e 1H an d 13C NMR spectra; CFCl3 was an in tern al stan dard for
19F NMR spectra. Mass spectra were m easured on a ZAB-EQ (VG An alytical) spectrom eter us-
in g FAB (ion ization by Xe, acceleratin g voltage 8 kV, glycerol m atrix) or EI (electron en ergy
70 eV) tech n iques. DMF was distilled from P2O5, degassed in vacuo an d stored over m olecu-
lar sieves un der Ar. Aceton itrile was refluxed with CaH2 an d distilled. Trim eth yl(trifluoro-
m et h yl)silan e (1 a ) an d h ep t aflu o ro p ro p yl(t rim et h yl)silan e (1 b ) were p u rch ased from
Fluka.
6-Iodo-9-(tetrah ydropyran -2-yl)-2-[(tetrah ydropyran -2-yl)am in o]purin e (4)
A m ixture of 2-am in o-6-iodopurin e26 (3 g, 11.5 m m ol), 4.5 M HCl in DMF (0.1 m l, 0.45
m m ol) an d DMF (100 m l) was stirred at 60 °C un der Ar an d 3,4-dih ydro-2H-pyran (5.3 m l,
58 m m ol) was added dropwise with in 10 m in th rough a septum . Th e stirrin g at 60 °C was
con tin ued for an oth er 6 h an d th en th e solven t was evaporated in vacuo (ca 100 Pa, bath
tem perature 40 °C). Th e dark red oily residue was dissolved in eth yl acetate (100 m l) an d ex-
tracted with saturated aqueous Na2S2O3 (100 m l). Th e aqueous layer was wash ed with eth yl
acetate (100 m l) an d th e com bin ed organ ic layers were dried with MgSO4 an d evaporated.
Colum n ch rom atograph y of th e residue on silica gel (150 g, eth yl acetate–ligh t petroleum
1 : 1) an d crystallization of th e crude product from dich lorom eth an e–h eptan e afforded th e
product 4 as yellowish powder, yield 3.1 g (63%), m .p. 132–134 °C. FAB MS, m/z (rel.%): 430
(55) [M + H]; 346 (90) [M + H – THP]; 304 (15) [M + 2 H – I]; 262 (55) [M + H – 2 THP]; 220
(22) [M + H – I – THP]; 136 (30) [M + H – I – 2 THP]; 85 (100) [THP]. 1H NMR (400 MHz,
CDCl3): 1.45–2.10 (m , 12 H); 3.60–3.80 (m , 2 H); 3.95–4.05 (m , 1 H); 4.10–4.20 (m , 1 H);
5.32–5.41 (m , 1 H); 5.53–5.63 (m , 1 H); 5.68–5.77 (m , 1 H); 7.98 (s, H-8). 13C NMR (75 MHz,
CDCl3): 23.32, 23.38, 25.50, 25.83, 32.02, 32.38 (all CH2); 67.02, 69.24 (CH2O); 80.54,
80.61, 82.13, 82.69 (OCHN); 123.35 (C-5); 140.00, 140.20 (C-8); 149.45, 149.66 (C-4);
157.77, 157.85 (C-2). For C15H20IN5O2 (429.3) calculated: 41.97% C, 4.70% H, 29.56% I,
16.31% N; foun d: 42.01% C, 4.69% H, 29.62% I, 16.61% N.
6-Iodo-9-(2,3-O-isopropyliden e-5-O-trityl-β-D-ribofuran osyl)purin e (5)
A m ixture of 2′,3′-O-isopropyliden e-5′-O-trityladen osin e27 (9.6 g, 17.5 m m ol), CH2I2 (24 m l),
i-Am ONO (12 m l) an d aceton itrile (135 m l) was refluxed for 8 h an d th en allowed to stan d
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

236
Hocek, Holý:
overn igh t at room tem perature. Th e m ixture was th en taken down in vacuo (ca 100 Pa, bath
tem perature ca 40 °C), th e residue was treated with saturated aqueous Na2S2O3 (250 m l) an d
extracted with eth yl acetate (3 × 250 m l). Th e collected organ ic ph ases were dried over
MgSO4 an d evaporated. Colum n ch rom atograph y of th e residue on silica gel (400 g, eth yl
acetate–ligh t petroleum 1 : 2) an d crystallization from dich lorom eth an e–h eptan e afforded
th e product 5 as yellowish powder, yield 4.2 g (36%), m .p. 70–73 °C. FAB MS, m/z (rel.%):
661 (1.5) [M + H]; 401 (4), 243 (100) [Tr]. 1H NMR (400 MHz, CDCl3): 1.40 (s, 3 H, CH3);
1.63 (s, 3 H, CH3); 3.27 (m , 2 H, H-5′); 4.59 (m , 1 H, H-4′); 4.96 (dd, 1 H, J(2′,3′) = 6.2,
J(4′,3′) = 2.3, H-3′); 5.47 (dd, 1 H, J(1′,2′) = 1.9, J(3′,2′) = 6.2, H-2′); 6.14 (d, 1 H, J(2′,1′) = 1.9,
H-1′); 7.18–7.31 (m , 15 H, H-arom .); 8.23 (s, 1 H, H-8); 8.47 (s, 1 H, H-2). For C32H29IN4O4
(660.5) calculated: 58.19% C, 4.43% H, 19.21% I, 8.48% N; foun d: 58.51% C, 4.80% H,
18.60% I, 8.17% N.
Trifluorom eth ylation of 6-Iodopurin e Derivatives. Gen eral Procedure
A m ixture of th e iodopurin e derivative 2–5 (1 m m ol), CF3SiMe3 (206 µl, 1.4 m m ol), KF
(82 m g, 1.4 m m ol), CuI (304 m g, 1.6 m m ol), DMF (1 m l) an d NMP (1 m l) was stirred in a 5 m l
glass vial at 60 °C for 24 h . After coolin g to room tem perature th e solven ts were evaporated
un der low pressure (ca 100 Pa, bath tem perature ca 40 °C) an d th e residue was
ch rom atograph ed on a colum n of silica gel (50 g) usin g a suitable solven t. Th e products
were ch rom atograph ically h om ogen eous (TLC, HPLC).
9-(Tetrahydropyran-2-yl)-6-(trifluoromethyl)purine (6a). Colourless crystals, m .p. 84–89 °C
(CH2Cl2–cycloh exan e); yield 85%, eluen t eth yl acetate–ligh t petroleum 1 : 1. EI MS, m/z
(rel.%): 272 (15) [M]; 244 (8); 189 (20) [M + H – THP]; 119 (8) [M – THP – CF3]; 85 (100)
[THP]. 1H NMR (400 MHz, CDCl3): 1.50–2.30 (m , 6 H); 3.82 (dt, 1 H, J = 11.5, 2.6, OCH2-a);
4.22 (m , OCH2-b); 5.86 (dd, 1 H, J = 10.4, 2.3, NCHO); 8.48 (s, 1 H, H-8); 9.09 (s, 1 H, H-2).
19F NMR (376.5 MHz, CDCl3): –66.67 (s, CF3). For C11H11F3N4O (272.2) calculated: 48.53% C,
4.07% H, 20.94% F, 20.58% N; foun d: 48.56% C, 4.08% H, 20.56% F, 20.24% N.
9-(Tetrahydropyran-2-yl)-2-[(tetrahydropyran-2-yl)amino]-6-(trifluoromethyl)purine (7a). Oil,
yield 27%, eluen t eth yl acetate–ligh t petroleum 1 : 1. FAB MS, m/z (rel.%): 372 (20) [M + H];
288 (100) [M + H – THP]; 204 (62) [M + H – 2 THP]; 85 (81) [THP]. 1H NMR (500 MHz,
CDCl3): 1.50–2.15 (m , 12 H); 3.65–3.70 (m , 1 H); 3.73–3.81 (m , 1 H); 4.00–4.07 (d, 1 H, J =
11.5); 4.15–4.21 (m , 1 H); 5.39–5.48 (m , 1 H); 5.64–5.71 (m , 1 H); 5.84–5.94 (brm , 1 H, NH);
8.12 (s, H-8). 13C NMR (75 MHz, CDCl3): 23.41, 25.53, 25.90, 30.39, 32.06, 32.44 (all CH2);
67.17, 69.36 (CH2O); 80.69, 80.76, 82.25, 82.72 (OCHN); 121.23 (q, 1J(F,C) = 274.9, CF3);
125.00 (C-5); 142.73, 142.91 (C-8); ≈146 (brd, C-6); 155.44, 155.61 (C-4); 158.32 (C-2).
19F NMR (376.5 MHz, CDCl3): –67.45 (s, CF3). For C16H20F3N5O2·1/3 H2O (377.4) calculated:
50.93% C, 5.52% H, 15.10% F, 18.56% N; foun d: 51.25% C, 5.47% H, 14.66% F, 18.29% N.
9-(2,3-O-Isopropylidene-5-O-trityl-β-D-ribofuranosyl)-6-(trifluoromethyl)purine (10a). Foam , yield
75%, eluen t eth yl acetate–ligh t petroleum 1 : 2. FAB MS, m/z (rel.%): 603 (8) [M + H]; 243
(100) [Tr]. 1H NMR (400 MHz, CDCl3): 1.40 (s, 3 H, CH3); 1.64 (s, 3 H, CH3); 3.28–3.31 (m , 2 H,
H-5′); 4.62 (ddd, 1 H, J = 2.5, 2.7, 4.9, H-4′); 4.98 (dd, 1 H, J(2′,3′) = 6.2, J(4′,3′) = 2.5, H-3′);
5.49 (dd, 1 H, J(1′,2′) = 2.3, J(3′,2′) = 6.2, H-2′); 6.22 (d, 1 H, J(2′,1′) = 2.3, H-1′); 7.15–7.32
(m , 15 H, H-arom .); 8.34 (s, 1 H, H-8); 8.94 (s, 1 H, H-2). 19F NMR (376.5 MHz, CDCl3):
–59.58 (s, CF3). 13C NMR (75 MHz, CDCl3): 26.05, 27.81 (CH3); 64.62 (C-5′); 82.04, 84.91,
87.56 (C-2′, C-3′, C-4′); 92.73 (C-1′); 115.18 (CMe2); 121.23 (q, 1J(F,C) = 274.4, CF3);
128.47–129.21 (m , C-arom .); 131.51 (C-5); 146.04 (q, 2J(F,C) = 36.5, C-6); 147.13 (C-8);
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Perfluoroalkylation of 6-Iodopurines
237
152.50 (C-2); 153.45 (C-4). For C33H29F3N4O4 (602.6) calcu lated: 66.77% C, 4.85% H,
9.46% F, 9.30% N; foun d: 66.58% C, 5.17% H, 8.92% F, 8.92% N.
9-[2-(Diethoxyphosphonylmethoxy)ethyl]-6-(trifluoromethyl)purine (12a ). Oil, yield 92%,
eluen t eth yl acetate. FAB MS, m/z (rel.%): 405 (16) [M + Na]; 383 (100) [M + H]. 1H NMR
(500 MHz, CDCl3): 1.28 (t, 6 H, J(CH3,CH2) = 7.0, CH3); 3.79 (d, 2 H, J(P,CH) = 8.0, PCH2);
4.01 (t, 2 H, J(1′,2′) = 4.7, H-2′); 4.08 (dq, 4 H, J(CH3,CH2) ≈ J(P,OCH2) ≈ 7, POCH2); 4.57 (t,
2 H, J(2′,1′) = 4.7, H-1′); 8.45 (s, 1 H, H-8); 9.08 (s, 1 H, H-2). 19F NMR (376.5 MHz, CDCl3):
–66.67 (s, CF3). 13C NMR (125 MHz, CDCl3): 17.05 (d, 3J(P,C) = 5.5, CH3); 44.45 (C-1′);
63.12 (d, 2J(P,C) = 6.8, POCH2); 66.00 (d, 1J(P,C) = 166, PCH2); 71.24 (d, 3J(P,C) = 6.8, C-2′);
121.42 (q, 1J(F,C) = 274, CF3); 130.64 (C-5); 145.74 (q, 2J(F,C) = 37.3, C-6); 149.03 (C-8);
152.49 (C-2); 154.44 (C-4). For C13H18F3N4O4P (382.3) calculated: 40.84% C, 4.75% H,
14.91% F, 14.66% N; foun d: 40.45% C, 4.77% H, 15.13% F, 14.44% N.
Heptafluoropropylation of 6-Iodopurin e Derivatives. Gen eral Procedure
A m ixture of th e iodopurin e derivative 2–5 (1 m m ol), CF3CF2CF2SiMe3 (350 µl, 1.7 m m ol),
KF (82 m g, 1.4 m m ol), CuI (304 m g, 1.6 m m ol), DMF (1 m l) an d NMP (1 m l) was stirred in
a 5 m l glass vial at 60 °C for 48 h . After coolin g to room tem perature th e solven ts were
evaporated un der low pressure (ca 100 Pa, bath tem perature ca 40 °C) an d th e residue was
ch rom atograph ed on a colum n of silica gel (50 g) usin g a suitable solven t. Th e products
were ch rom atograph ically h om ogen eous (TLC, HPLC).
6-(Heptafluoropropyl)-9-(tetrahydropyran-2-yl)purine (6b). Colourless crystals, m .p. 58–60 °C
(CH2Cl2–cycloh exan e); yield 35%, eluen t eth yl acetate–ligh t petroleum 1 : 1. EI MS, m/z
(rel.%): 372 (12) [M]; 289 (17) [M + H – THP]; 169 (8) [CF2CF2CF3]; 85 (100) [THP]. 1H NMR
(400 MHz, CDCl3): 1.60–2.30 (m , 6 H); 3.82 (dt, 1 H, J = 11.6, 2.5, OCH2-a); 4.22 (m ,
OCH2-b); 5.88 (dd, 1 H, J = 10.5, 2.3, NCHO); 8.50 (s, 1 H, H-8); 9.13 (s, 1 H, H-2). 19F NMR
(376.5 MHz, CDCl3): –80.54 (t, J = 9.3, CF3); –114.71 (tq, J = 9.3, 4.5, CF2-2′′); –126.54 (t, J =
4.5, CF2-1′′). 13C NMR (75 MHz, CDCl3): 23.25, 25.47, 32.50 (CH2-2′,3′,4′); 69.63 (CH2-5′);
83.53 (CH-1′); 105–125 (com plex m ultiplet, CF2CF2CF3); 132.97 (C-5); 140–144 (com plex
m ultiplet, C-6); 146.07 (C-8); 152.68 (C-2); 153.79 (C-4). Exact m ass (EI HRMS) foun d:
372.0815; calculated for C13H11F7N4O: 372.0821. For C13H11F7N4O (372.2) calculated:
41.97% C, 2.98% H, 35.73% F, 15.05% N; foun d: 42.56% C, 3.11% H, 35.00% F, 14.95% N.
6-(Heptafluoropropyl)-9-(tetrahydropyran-2-yl)-2-[(tetrahydropyran-2-yl)amino]purine (7b). Oil,
yield 23%, eluen t eth yl acetate–ligh t petroleum 1 : 1. FAB MS, m/z (rel.%): 472 (21) [M + H];
388 (100) [M + H – THP]; 304 (89) [M + H – 2 THP]; 85 (70) [THP]. 1H NMR (500 MHz,
CDCl3): 1.50–2.10 (m , 12 H); 3.60–3.80 (m , 2 H); 3.97–4.04 (m , 1 H); 4.13–4.20 (m , 1 H);
5.34–5.41 (m , 1 H); 5.66 (brt, 1 H); 5.84 (brm , 1 H, NH); 8.11 (s, H-8). 19F NMR (376.5 MHz,
CDCl3): –81.09 (brs, CF3); –115.67 (brs, CF2-2′′); –127.19 (brs, CF2-1′′). Exact m ass (FAB
HRMS) foun d: 472.1572; calculated for C18H21F7N5O2 [M + H]: 472.1583.
6-(Heptafluoropropyl)-9-(2,3-O-isopropylidene-5-O-trityl-β-D-ribofuranosyl)purine (10b ). Foam ,
yield 47%, eluen t eth yl acetate–ligh t petroleum 1 : 2. FAB MS, m/z (rel.%): 703 (14) [M + H];
243 (100) [Tr]. 1H NMR (400 MHz, CDCl3): 1.41 (s, 3 H, CH3); 1.65 (s, 3 H, CH3); 3.31 (d,
2 H, J(4′,5′) = 5.1, H-5′); 4.61 (m , 1 H, ΣJ = 12.4, H-4′); 4.98 (dd, 1 H, J(2′,3′) = 6.2, J(4′,3′) =
2.5, H-3′); 5.48 (dd, 1 H, J(1′,2′) = 2.2, J(3′,2′) = 6.2, H-2′); 6.22 (d, 1 H, J(2′,1′) = 2.2, H-1′);
7.1–7.4 (m , 15 H, H-arom .); 8.35 (s, 1 H, H-8); 8.98 (s, 1 H, H-2). 19F NMR (376.5 MHz,
CDCl3): –81.05 (t, J = 9.0, CF3); –115.05 (q, J = 9.0, CF2-2′′); –126.92 (brs, CF2-1′′). Exact
m ass (FAB HRMS) foun d: 703.2138; calculated for C35H30F7N4O4 [M + H]: 703.2155.
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

238
Hocek, Holý:
9-[2-(Diethoxyphosphonylmethoxy)ethyl]-6-(heptafluoropropyl)purine (12b). Oil, yield 46%,
eluen t eth yl acetate. FAB MS, m/z (rel.%): 483 (100) [M + H]. 1H NMR (500 MHz, CDCl3):
1.30 (t, 6 H, J(CH3,CH2) = 7.0, CH3); 3.82 (d, 2 H, J(P,CH) = 8.1, PCH2); 4.03 (t, 2 H, J(1′,2′) =
4.7, H-2′); 4.10 (dq, 4 H, J(CH3,CH2) ≈ J(P,OCH2) ≈ 7, POCH2); 4.59 (t, 2 H, J(2′,1′) = 4.7,
H-1′); 8.49 (s, 1 H, H-8); 9.14 (s, 1 H, H-2). 19F NMR (376.5 MHz, CDCl3): –73.46 (t, J = 9.2,
CF3); –107.55 (tq, J = 9.2, 4.5, CF2-2′′); –119.45 (t, J = 4.5, CF2-1′′). 13C NMR (125 MHz,
CDCl3): 16.74 (d, 3J(P,C) = 4.7, CH3); 44.18 (C-1′); 62.96 (d, 2J(P,C) = 6.0, POCH2); 65.60 (d,
1J(P,C)
= = 9.2, C-2′); 105–120 (com plex m ultiplet,
166.8, PCH2); 70.93 (d, 3J(P,C)
CF2CF2CF3); 132.10 (C-5); 145.28 (t, 2J(F,C) = 26.9, C-6); 148.94 (C-8); 152.10 (C-2); 153.96
(C-4).
Deprotection of th e THP-Protected Bases 6 an d 7. Gen eral Procedure
A m ixture of th e THP-protected base 6 or 7 (0.6–1.5 m m ol), Dowex 50 X 8 (H+) (ca 300 m g),
m eth an ol (10 m l) an d water (1 m l) was refluxed for 1 h , th en filtered wh ile h ot an d th e
resin was wash ed with a m ixture of 35% aqueous NH3 (1 m l) an d m eth an ol (10 m l). Th e
com bin ed filtrates were evaporated an d th e residue codistilled with toluen e. Crystallization
of th e residue from m eth an ol/toluen e with an addition of h eptan e afforded th e free bases 8
an d 9.
6-(Trifluoromethyl)purine (8a ). Colourless crystals, m .p. 217–219 °C (toluen e) (ref.14
254–255 °C (sublim ed)); yield 92%. EI MS, m/z (rel.%): 188 (100) [M]; 119 (95) [M – CF3].
1H NMR (500 MHz, CDCl3): 8.84 (s, 1 H, H-8); 9.09 (s, 1 H, H-2). 19F NMR (470.59 MHz,
CDCl3): –64.59 (s, CF3). For C6H3F3N4 (188.1) calculated: 38.31% C, 1.61% H, 30.30% F,
29.78% N; foun d: 38.26% C, 1.40% H, 30.43% F, 29.40% N.
6-(Heptafluoropropyl)purine (8b). Colourless crystals, m .p. 162–165 °C (toluen e–h eptan e);
yield 90%. EI MS, m/z (rel.%): 288 (100) [M]; 269 (15 ) [M – F]; 169 (96) [CF2CF2CF3]; 142
(20); 119 (38) [M – CF2CF2CF 3]. 1H NMR (400 MHz, DMSO-d6): 8.90 (s, 1 H, H-8); 9.16 (s,
1 H, H-2); 14.14 (brs, NH). 19F NMR (376.5 MHz DMSO-d6): –80.50 (t, J = 8.7, CF3); –113.98
(brs, CF2-2′′); –126.76 (t, J = 4.5, CF2-1′′). 13C NMR (75 MHz, DMSO-d6): 105–125 (m ,
CF2CF2CF3); 149.53 (C-8); 151.74 (C-2); th e quatern ary carbon sign als of C-4,5,6 were very
weak. Exact m ass (EI HRMS) foun d: 288.0273; calculated for C8H3F7N4: 288.0246. For
C8H3F7N4 (288.1) calculated: 33.35% C, 1.05% H, 46.16% F, 19.45% N; foun d: 33.72% C,
1.08% H, 45.85% F, 19.33% N.
2-Amino-6-(trifluoromethyl)purine (9a). Yellowish crystals, m .p. 282–283 °C (toluen e) (ref.14
360 °C (eth an ol)); yield 92%. EI MS, m/z (rel.%): 203 (100) [M]; 134 (35) [M – CF3]. 1H NMR
(500 MHz, DMSO-d6): 6.88 (brs, 1 H, NH); 8.27 (s, 1 H, H-8). 19F NMR (376.5 MHz,
DMSO-d6): –65.11(s, CF3). 13C NMR (75 MHz, DMSO-d6): 120.99 (q, 1J(F,C) = 274.3, CF3);
≈121 (very weak s, C-5); ≈143 (very weak m , C-6); 144.24 (C-8); 157.98 (C-4); 160.04 (C-2).
For C6H4F3N5 (203.1) calculated: 35.47% C, 1.98% H, 34.48% N; foun d: 35.73% C, 2.18% H,
33.96% N.
2-Amino-6-(heptafluoropropyl)purine (9b). Yellowish crystals, m .p. 213-216 °C (toluen e–-
h eptan e); yield 90%. EI MS, m/z (rel.%): 303 (100) [M]. 1H NMR (400 MHz, DMSO-d6): 6.92
(brs, 2 H, NH2); 8.24 (s, 1 H, H-8); 13.03 (brs, 1 H, NH). 19F NMR (376.5 MHz, DMSO-d6):
–79.37 (brs, CF3); –113.05 (brd, J = 7.2, CF2-2′′); –126.76 (brs, CF2-1′′). 13C NMR (75 MHz,
DMSO-d6): 105–125 (m , CF2CF2CF3); 124.20 (C-5); 143.10 (weak m , C-6); 143.78 (C-8);
156.91 (C-4); 159.93 (C-2). Exact m ass (EI HRMS) foun d: 303.0362; calculated for C8H4F7N5:
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Perfluoroalkylation of 6-Iodopurines
239
303.0355. For C8H4F7N5 (303.1) calculated: 31.70% C, 1.33% H, 23.10% N; foun d: 31.54% C,
1.37% H, 22.79% N.
Deprotection of Nucleosides 10. Gen eral Procedure
A m ixture of th e protected n ucleoside 10 (0.8–1.3 m m ol) an d 80% aqueous AcOH (20 m l)
was refluxed for 1 h , evaporated in vacuo an d codistilled with toluen e (20 m l). Th e residue
was ch rom atograph ed on a colum n of silica gel (50 g, eth yl acetate–m eth an ol 9 : 1). Th e
products were crystallized from i-PrOH–h eptan e.
9-(β-D-Ribofuranosyl)-6-(trifluoromethyl)purine (11a). Colourless crystals, m .p. 145–148 °C
(i-PrOH–h eptan e–cycloh exan e) (ref.15 176 °C (i-PrOH–i-Pr2O)); yield 35%. FAB MS, m/z
(rel.%): 321 (18) [M + H]; 189 (100) [M – Rf]. 1H NMR (500 MHz, DMSO-d6): 3.60–3.63 an d
3.71–3.75 (2 × m , 2 × 1 H, H-5′); 4.02 (ddd, 1 H, J(3′,4′) = 3.8, J(5′a,4′) = 3.8, J(5′b,4′) = 4.0,
H-4′); 4.23 (ddd, 1 H, J(2′,3′) = 5.1, J(OH,3′) = 5.2, J(4′,3′) = 3.8, H-3′); 4.62 (ddd, 1 H, J(1′,2′) =
5.0, J(3′,2′) = 5.1, J(OH,2′) = 5.6, H-2′); 5.13 (t, 1 H, J(5′,OH) = 5.4, 5′-OH); 5.29 (d, 1 H,
J(3′,OH) = 5.2, 3′-OH); 5.62 (d, 1 H, J(2′,OH) = 5.7, 2′-OH); 6.13 (d, 1 H, J(2′,1′) = 5.0, H-1′);
9.12 an d 9.18 (2 × s, 2 × 1 H, H-2 an d H-8). 19F NMR (376.5 MHz, DMSO-d6): –64.49 (s, CF3).
13C NMR (75 MHz, DMSO-d6): 60.91 (C-5′); 70.00 (C-3′); 74.01 (C-2′); 85.71 (C-4′); 88.10
(C-1′); 120.82 (q, 1J(F,C) = 274.5, CF3); 130.12 (C-5); 142.90 (q, 2J(F,C) = 36.8, C-6); 147.96
(C-8); 151.65 (C-2); 153.64 (C-4). Exact m ass (FAB HRMS) foun d: 321.0846; calculated for
C
11H12F3N4O4 [M + H]: 321.0810. For C11H11F3N4O4 (320.2) calculated: 41.26% C, 3.46% H,
17.80% F, 17.50% N; foun d: 41.50% C, 3.51% H, 17.61% F, 17.88% N.
6-(Heptafluoropropyl)-9-(β-D-ribofuranosyl)purine (11b). Colourless crystals, m .p. 89–92 °C
(i-PrOH–h eptan e); yield 30%. FAB MS, m/z (rel.%): 421 (18) [M + H]; 289 (100) [M – Rf].
1H NMR (400 MHz, CDCl3): 3.83 an d 4.00 (2 × brs, 2 × 1 H, H-5′); 4.38 (brs, 1 H, H-4′); 4.54
(brs, 1 H, H-3′); 4.92 (brs, 1 H, H-2′); 6.04 (d, 1 H, J(2′,1′) = 6.4, H-1′); 8.51 (s, 1 H, H-8); 9.10
(s, 1 H, H-2). 19F NMR (376.5 MHz, CDCl3): –80.56 (t, J = 8.1, CF3); –114.77 (brd, J = 8.4,
CF2-2′′); –126.49 (brs, CF2-1′′). Exact m ass (FAB HRMS) foun d: 421.0683; calculated for
C
13H12F7N4O4 [M + H]: 421.0746. For C13H11F7N4O4 (420.2) calculated: 37.16% C, 2.64% H,
31.65% F, 13.33% N; foun d: 37.17% C, 2.66% H, 31.73% F, 13.70% N.
Deprotection of Ph osph on ates 12. Gen eral Procedure
A m ixture of th e ph osph on ate diesters (0.5–1.2 m m ol), TMSBr (1 m l) an d aceton itrile (5 m l)
was stirred overn igh t at am bien t tem perature, th en evaporated an d codistilled with toluen e
(10 m l). Th e residue was dissolved in a m ixture of water (5 m l) an d trieth ylam in e (1 m l)
an d, after stan din g at room tem perature for 10 m in , evaporated in vacuo. Th e residue was
applied on a colum n of DEAE-Seph adex A-25 (≈50 m l), wash ed with water an d eluted with a
lin ear gradien t 0.01–1 M aqueous TEAB (1 l each ; detection at 260 n m ). Th e appropriate
product-con tain in g fraction s were evaporated an d th e residue deion ized on a Dowex 50 X 8
(H+) colum n (≈50 m l, eluen t water). Evaporation an d/or freeze-dryin g of th e appropriate
aqueous fraction s afforded th e free ph osph on ates as extrem ely h ygroscopic com poun ds; an y
attem pts to crystallize th em failed.
9-[2-(Phosphonomethoxy)ethyl]-6-(trifluoromethyl)purine (13a). Yield 82%, EUp 0.95. FAB MS,
m/z (rel.%): 327 (28) [M + H]; 162 (100). 1H NMR (400 MHz, DMSO-d6): 3.60 (d, 2 H, J(P,CH) =
8.6, PCH2); 3.95 (t, 2 H, J(1′,2′) = 5.0, H-2′); 4.54 (t, 2 H, J(2′,1′) = 5.0, H-1′); 8.86 (s, 1 H,
H-8); 9.13 (s, H-2). 19F NMR (376.5 MHz, DMSO-d6): –64.37 (s, CF3). Exact m ass (FAB HRMS)
foun d: 327.0452; calculated for C9H11F3N4O4P [M + H]: 327.0470.
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

240
Hocek, Holý:
6-(Heptafluoropropyl)-9-[2-(phosphonomethoxy)ethyl]purine (13b). Yield 31%, EUp 0.86. FAB
MS, m/z (rel.%): 449 (16) [M + Na]; 427 (100) [M + H]. 1H NMR (400 MHz, DMSO-d6): 3.63
(d, 2 H, J(P,CH) = 8.4, PCH2); ≈4.0 (h idden in a H2O sign al, H-2′); 4.55 (t, 2 H, J(2′,1′) = 5.2,
H-1′); 8.86 (s, 1 H, H-8); 9.18 (s, H-2). 19F NMR (376.5 MHz, DMSO-d6): –79.30 (t, J = 8.7,
CF3); –112.46 (q, J = 8.7, CF2-2′′); –125.37 (brs, CF2-1′′). 13C NMR (75 MHz, DMSO-d6): 43.10
(C-1′); 66.14 (d, 1J(P,C) = 159.3, PCH2); 69.58 (d, 3J(P,C) = 10.8, C-2′); 105–120 (com plex
m ultiplet, CF2CF2CF3); 132.20 (C-5); 142.19 (m , C-6); 150.29 (C-8); 151.30 (C-2); 153.82
(C-4). Exact m ass (FAB HRMS) foun d: 427.0395; calculated for C11H11F7N4O4P [M + H]:
427.0406.
This work was supported by the Grant Agency of the Czech Republic (grants No. 203/98/P027, No.
203/96/0005 and No. 203/96/K001) and by Gilead Sciences (Foster City, CA, U.S.A.). The cytostatic
activity was determined by Dr I. Votruba of this Institute. The antiviral activity was studied by Dr G.
Andrei, Dr R. Snoeck, Prof J. Balzarini and Prof E. De Clercq, Rega Institute for Medical Research,
Catholic University Leuven, Belgium. The NMR spectra were measured and interpreted by Dr H.
Dvořáková, Central NMR Laboratory, Prague Institute of Chemical Technology. The contribution of
these scientists is gratefully acknowledged. The authors’ thanks are also due to the staff of the mass
spectrometry and analytical departments of this Institute.
REFERENCES AND NOTES:
1. Montgomery J. A., Hewson K.: J. Med. Chem. 1968, 11, 48.
2. Havlíček L., Hanuš J., Veselý J., Leclercq S., Meier L., Shaw G., Strnad M.: J. Med. Chem.
1997, 40, 408.
3. Review: Jacobson K. A., van Galen P. J. M., Williams M.: J. Med. Chem. 1992, 35, 407.
4. a) Holý A., Zídek Z., Votruba I.: Collect. Czech. Chem. Commun. (Special Issue) 1996, 61,
S182; b) Meerbach A., Neyts J., Holý A., Wutzler P., De Clercq E.: Antivir. Chem.
Chemother. 1998, 9, 275.
5. Review: Resnati G.: Tetrahedron 1993, 49, 9385.
6. a) Duschinsky R., Pleven E., Heidelberger C.: J. Am. Chem. Soc. 1957, 79, 494;
b) Heidelberger C.: Prog. Nucleic Acid Res. 1965, 4, 1.
7. a) Kaufman H. E.: Ann. N.Y. Acad. Sci. 1965, 130, 168; b) Kaufman H. E., Heidelberger C.:
Science 1962, 145, 985.
8. a) Montgomery J. A.: Cancer Res. 1982, 42, 3911; b) Montgomery J. A.: Med. Res. Rev.
1982, 2, 271.
9. Recent examples: a) Wachtmeister J., Classon B., Samuelsson B., Kvarstrom I.: Tetrahedron
1997, 53, 1861; b) Kotra L. P., Newton M. G., Chu C. K.: Carbohydr. Res. 1998, 306, 69.
10. Gray N. S., Kwon S., Schultz P. G.: Tetrahedron Lett. 1997, 35, 1161.
11. a) Nagano H., Inoue S., Saggiomo A. J., Nodiff E. A.: J. Med. Chem. 1964, 7, 215;
b) Gough G. R., Maguire M. H.: J. Med. Chem. 1967, 10, 475; c) Gough G. R., Nobbs D. M.,
Middleton J. C., Penglis-Caredes F., Maguire M. H.: J. Med. Chem. 1978, 21, 520;
d) Kelley J. L., Linn J. A., Selway J. W. T.: J. Med. Chem. 1989, 32, 218 and 1757;
e) Bourgignon J. J., Desaubry L., Raboisson P., Wermuth C. G., Luguier C.: J. Med. Chem.
1997, 40, 1768; f) Meyer R. B., Shuman D. A., Robins R. K.: J. Am. Chem. Soc. 1974, 96,
4962.
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Perfluoroalkylation of 6-Iodopurines
241
12. a) Albert A.: J. Chem. Soc. B 1966, 438; b) Fenn M. D., Lister J. H.: J. Chem. Soc., Perkin
Trans. 1 1975, 485; c) Chea M. Y., Swenn K., Kanugula S., Dolan M. E., Pegg A. E.,
Moschel R. C.: J. Med. Chem. 1995, 38, 359.
13. a) Nair V., Buenger G. S.: J. Am. Chem. Soc. 1989, 111, 8502; b) Nair V., Purdy D. F., Sells T. B.:
J. Chem. Soc., Chem. Commun. 1989, 878.
14. Giner-Sorolla A., Bendich A.: J. Am. Chem. Soc. 1958, 80, 5744.
15. Kobayashi Y., Yamamoto K., Asai T., Nakano M., Kumadaki I.: J. Chem. Soc., Perkin Trans. 1
1980, 2755.
16. a) Gundersen L. L.: Tetrahedron Lett. 1994, 35, 3155; b) Gundersen L. L., Bakkestuen A. K.,
Aasen A. J., Oeveras H., Rise F.: Tetrahedron 1994, 50, 9743; c) Van Aerschot A. A.,
Mamos P., Weyns N. J., Ikeda S., De Clercq E., Herdewijn E.: J. Med. Chem. 1995, 36,
2938; d) Hocek M., Masojídková M., Holý A.: Tetrahedron 1997, 53, 2291; e) Hocek M.,
Masojídková M., Holý A.: Collect. Czech. Chem. Commun. 1997, 62, 136; f) Hirota K.,
Kitade Y., Kanbe Y., Maki Y.: J. Org. Chem. 1992, 57, 5268; g) Dvořáková H., Dvořák D.,
Holý A.: Tetrahedron Lett. 1996, 37, 1285; h) Dvořáková H., Dvořák D., Holý A.: Collect.
Czech. Chem. Commun. 1998, 63, 2065.
17. a) Stevenson T. M., Prasad A. S. B., Citineni J. B., Knochel P.: Tetrahedron Lett. 1996, 37,
8375; b) Prasad A. S. B., Stevenson T. M., Citineni J. B., Nyzam V., Knochel P.:
Tetrahedron 1997, 53, 7237.
18. a) Mc Loughlin V. C. R., Thrower J.: Tetrahedron 1969, 25, 5921; b) Leroy J., Rubinstein M.,
Wakselman C.: J. Fluorine Chem. 1985, 27, 291; c) Chen G. J., Tamborski C.: J. Fluorine
Chem. 1989, 43, 207; d) Chen G. J., Tamborski C.: J. Fluorine Chem. 1990, 46, 137.
19. Urata H., Fuchikami T.: Tetrahedron Lett. 1991, 32, 91.
20. Hocek M., Holý A.: Collect. Czech. Chem. Commun. 1995, 60, 1386.
21. Nair V., Richardson S. G.: J. Org. Chem. 1980, 45, 3969.
22. Holý A., Rosenberg I.: Collect. Czech. Chem. Commun. 1987, 52, 2801.
23. Krishnamurti R., Bellew D. R., Prakash G. K. S.: J. Org. Chem. 1991, 56, 984.
24. Votruba I.: Unpublished results.
25. Andrei G., Snoeck R., Balzarini J., De Clercq E.: Unpublished results.
26. Bisacchi G. S., Singh J., Godfrey J. D., Kissick T. P., Mitt T., Malley M. F., Di Marco J. D.,
Gougoutas J. Z., Mueller R. H., Zahler R.: J. Org. Chem. 1995, 60, 2902.
27. Altman J., Ben-Ishai D.: J. Heterocycl. Chem. 1968, 5, 679.
Collect. Czech. Chem. Commun. (Vol. 64) (1999)