Novel method for preparation of highly substituted 6-arylpurines by reactions of 6-alkynylpurines with zirconacyclopentadienes

Article abstract of DOI:10.1135/cccc20050339

Reactions of various zirconacyclopentadienes bearing alkyl and aryl groups with 6-alkynyl-purines in the presence of NiBr₂(PPh₃) ₂ afforded the corresponding 6-arylpurines with highly hydrophobic aryl moieties in low to mo

Full text of DOI:10.1135/cccc20050339

Preparation of Highly Substituted 6-Arylpurines
339
NOVEL METHOD FOR PREPARATION OF HIGHLY SUBSTITUTED
6-ARYLPURINES BY REACTIONS OF 6-ALKYNYLPURINES WITH
ZIRCONACYCLOPENTADIENES
b2
Pavel TUREKa,b, Martin KOTORAa1,b,*, Michal HOCEKb1,* and Ivan VOTRUBA
a
Department of Organic and Nuclear Chemistry, Faculty of Science, Charles University,
1
Hlavova 8, 128 43 Prague 2, Czech Republic; e-mail: kotora@natur.cuni.cz
b
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
1
Flemingovo nám. 2, 166 10 Prague 6, Czech Republic; e-mail: hocek@uochb.cas.cz,
2
votruba@uochb.cas.cz
Received Jan uary 24, 2005
Accepted March 2, 2005
Reaction s of various zircon acyclopen tadien es bearin g alkyl an d aryl groups with 6-alkyn yl-
purin es in th e presen ce of NiBr2(PPh 3)2 afforded th e correspon din g 6-arylpurin es with
h igh ly h ydroph obic aryl m oieties in low to m oderate yields. Som e of th e title purin es
sh owed in terestin g cytostatic activity.
Keyw ord s: Purin es; Nucleosides; Alkyn es; Cyclotrim erization s; Zircon ium ; Nickel; Cytostatic
activity.
6-Arylpurin e derivatives display diverse types of biological activity: som e
substituted 6-arylpurin e bases are an tagon ists of corticotropin -releasin g
h orm on e1 or possess an tim ycobacterial an d an tibacterial activity2, wh ile
6-arylpurin e ribon ucleosides are poten t cytostatics3. Moreover, 6-aryl-
purin es were used as un n atural n ucleobases in artificial base-pairs4 an d as
covalen t base-pair an alogues5. So far, biological activity screen in g an d oth er
application s (e.g. in ch em ical biology) h ave been lim ited to easily available
purin es bearin g sim ple aryl groups, wh ile th ose bearin g h igh ly substituted
an d/or fun ction alized aryl m oieties still rem ain to be explored. As recen tly
m an y bulky an d h ydroph obic aryl C-n ucleosides were also used6 as poten -
tial n ucleobase surrogates in exten sion of th e gen etic alph abet, also 6-aryl-
purin es bearin g bulky h ydroph obic substituen ts are of particular in terest.
6-Arylpurin es h ave been efficien tly prepared by cross-couplin g reaction s7 of
6-h alopurin es with various organ om etallics. Recen tly, we h ave reported8 an
altern ative m eth od for preparation of 6-arylpurin es based on a tran sition
m etal com plex catalyzed [2+2+2]-co-cyclotrim erization of diyn es with
6-alkyn ylpurin es. 6-Alkyn ylpurin es are easily available an d also cytostatic
Collect. Czech. Chem. Commun. (Vol. 70) (2005)
doi:10.1135/cccc20050339

340
Turek, Kotora, Hocek,Votruba:
com poun ds9 an d th erefore we h ave furth er explored th eir applicability in
th e syn th esis of m odified purin e derivatives. Herein , we would like to dis-
close a n ovel procedure for preparation of h igh ly alkylated 6-arylpurin es
startin g from 6-alkyn ylpurin es an d to report on th eir cytostatic activity.
Am on g a n um ber of cyclotrim erization m eth ods, on e of th e m ost con ve-
n ien t an d gen eral m eth od for th e con struction of h igh ly substituted ben -
zen e rin gs is based on th e reaction of zircon acyclopen tadien es10 with al-
kyn es in th e presen ce of a stoich iom etric am oun t of NiBr2(PPh 3)2 (lit.11,12).
Th is approach h as been successfully applied to th e syn th esis of ben zo-
h eterocycles con tain in g group 14 elem en ts13, h aloterph en yls14 an d ferro-
cen ylaryn es15. Th ere are several factors th at favor th e above m en tion ed
m eth od: first, zircon acyclopen tadien es are easily prepared with a great vari-
ety of substituen ts an d th ey are stable at room tem perature an d, secon d,
alkyn ylpurin es can be easily prepared from com m on ly accessible startin g
m aterial. Moreover, NiBr2(PPh 3)2 is a stable an d ch eap com poun d.
RESULTS AND DISCUSSION
Reaction s of zircon acyclopen tadien es 1 with alkyn ylpurin es 2 in th e pres-
en ce of NiBr2(PPh3)2 were carried out under standard conditions11 (Schem e 1).
Th e zircon acyclopen tadien es bearin g Et, Pr an d Ph groups 1a–1c an d th e
bicyclic zircon acyclopen tadien e 1d prepared from 1,8-diph en ylocta-1,7-
diyn e were tested in th e cyclotrim erization reaction s. As to 6-alkyn yl-
purin es16, th ose bearin g h ex-1-yn -1-yl, 2-ph en yleth yn yl an d 2-trim eth yl-
silyleth yn yl m oieties with ben zyl 2aa–2ca or THP 2ab, 2bb protective
groups in position 9 were selected. Th e obtain ed results are sum m arized in
Table I.
R2
R3
R2
R1
R1
R1
ZrCp2
R1
R2
R2
NiBr2(PPh3)2
THF, rt
R3
N
+
N
N
R4
N
N
N
N
R4
N
1
2
3
1
a
b
c
d
R1
R2
Et
2
R3
Bu
Ph
R4
3xyz
x denotes R1, R2
y denotes R3
z denotes R4
aa
ba
ca
Et
Pr
Bn
Bn
Pr
Ph
Ph
TMS Bn
Ph -(CH2)4- ab
Bu
Ph
THP
THP
bb
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Preparation of Highly Substituted 6-Arylpurines
341
TABLE I
Reaction of zircon acyclopen tadien es 1 with alkyn ylpurin es 2
Isolated
yield (%)
Zirconacycle
Alkyne
R
Product
Et
Et
Et
Et
Et
Et
2aa
2ba
2ca
3aaa; R = Bu
3aba; R = Ph
3aca; R = SiMe3
25
24
21
R
N
1a
ZrCp2
Et
N
N
N
Et
N
N
N
N
Bn
Bn
Ph
Ph
Ph
Ph
Ph
Ph
ZrCp2
Ph
Ph
Ph
N
1c
2ba
3cba
24
N
N
N
N
N
Ph
N
N
Bn
Bn
Bu
Ph
Ph
Ph
Bu
N
1d
2aa
3daa
ZrCp2
12
N
N
N
N
N
Ph
N
R
N
Bn
Bn
Et
Et
Et
Et
Et
Et
Et
2ab
2bb
3aab; R = Bu
3abb; R = Ph
19
17
R
N
1a
1b
1c
ZrCp2
N
N
N
N
N
N
N
Et
N
R
N
THP
THP
Pr
Pr
Pr
Pr
Pr
Pr
Pr
2ab
2bb
3bab; R = Bu
3bbb; R = Ph
21
21
R
N
ZrCp2
N
N
N
N
Pr
N
N
THP
THP
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
2bb
3cbb
ZrCp2
Ph
18
N
N
N
N
N
N
THP
THP
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342
Turek, Kotora, Hocek,Votruba:
Gen erally, th e obtain ed yields of th e correspon din g 6-arylpurin es 3 were
rath er low. Th us th e reaction s of tetraeth ylzircon acyclopen tadien e 1a with
ben zyl-protected alkyn es 2aa, 2ba an d 2ca afforded th e correspon din g
arylpurin es 3aaa, 3aba an d 3aca in 25, 24 an d 21% yields, respectively.
Th e reaction of tetraph en ylzircon acyclopen tadien e 1c with 2ba afforded
pen taph en ylph en ylpurin e 3cba in 24% yield. A disappoin tin gly low yield
of th e product 3d aa (12%) was obtain ed in th e reaction of th e bicyclic
zircon acyclopen tadien e 1d with 2aa. Previously, we observed th at th e
ch an ge of a protective group from ben zyl to tetrah ydropyran yl h ad positive
effect on th e yield of cyclotrim erization in catalytic reaction s8b. We h oped
th at th e exch an ge of th e protective group m igh t h ave th e sam e effect in
th is reaction as well. Un fortun ately, our expectation s were n ot m aterial-
ized. Th e yields of th e reaction with THP-protected alkyn ylpurin es were in
th e sam e ran ge as with th e ben zyl-protected on es. Th us th e reaction of
tetraeth ylzircon acyclopen tadien e 1a with THP-protected alkyn es 2ba an d
2bb afforded th e correspon din g arylpurin es in 19 an d 17% yields. Th e use
of tetrapropylzircon acyclopen tadien e 1b with th e sam e alkyn es furn ish ed
arylpurin es in 21% yields. Sim ilarly, th e reaction of tetraph en ylzircon -
acyclopen tadien e 1c with 2bb furn ish ed th e pen taph en ylph en yl-derivative
3cbb in 18% yield. Th e un sym m etrically substituted arylpurin es 3aab–
3d bb, except for th e sym m etrical 3cbb, were obtain ed as 1:1 m ixtures of
diastereoisom ers, because of th e presen ce of a ch iral cen ter in THP m oiety
an d axial ch irality caused by restricted rotation alon g th e C–C bon d con -
n ectin g th e aryl an d th e purin e rin gs.
In addition , an applicability of th is approach in th e syn th esis of m odified
n ucleosides was dem on strated. Th e reaction of tetraph en ylzircon acyclo-
pen tadien e 1c with acetylated 9-(ph en yleth yn yl)purin e ribon ucleosides
2bc was carried out to afford th e correspon din g protected 6-(pen taph en yl-
ph en yl)purin e n ucleoside 3cbc in reason able yield of 40%. Its deprotection
usin g sodium m eth oxide in m eth an ol proceeded sm ooth ly to give 6-(pen ta-
ph en ylph en yl)purin e ribon ucleoside 4 in 85% yield (Sch em e 2).
Th e relatively low isolated yields of th e cyclotrim erization s could be
m ain ly attributed to difficulties en coun tered durin g separation of th e prod-
ucts in reason able purity from th e reaction m ixture. In addition , a part of
th e alkyn ylpurin es m ust h ave been also con sum ed by side-reaction s, be-
cause an alyses of th e reaction m ixtures (NMR, TLC) in dicated th at th e start-
in g alkyn ylpurin es 2 un derwen t in all of th e cases total con version . In th is
regard, on e of th e possible explan ation s m ay lie in th e reaction m ech an ism
of th e wh ole process. It h as been sh own th at in th e course of th e reaction
th e zircon acyclopen tadien es are tran sm etallated in to n ickelacyclopen ta-
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Preparation of Highly Substituted 6-Arylpurines
343
dien es th at in turn react with alkyn es to give th e ben zen es. In th is step
Ni(0) species is also released11; th erefore we assum e th at th e Ni(0) species
partially oligom erized th e alkyn ylpurin es. Th is assum ption was supported
by th e observation an d isolation of a tar-like m aterial wh ich , accordin g to
NMR spectra, seem ed to be a com plex m ixture of products con tain in g pu-
rin e rin gs. Neverth eless, despite th e low to m oderate yields, th is approach is
very straigh tforward an d en ables th e syn th esis of a h igh ly substituted ben -
zen e rin g con tain in g a purin e or n ucleoside m oiety in a sin gle step. More-
over, th e startin g com poun ds are relatively sim ple an d easily available.
Th erefore we believe th at th is m eth odology will fin d furth er application s
in th e syn th esis of h igh ly substituted h ydroph obic n ucleobases an d n ucleo-
sides.
Ph
Ph
Ph
Ph
Ph
Ph
ZrCp2
Ph
Ph
N
Ph
Ph
N
N
NiBr2(PPh3)2
THF, rt
N
N
+
N
N
N
AcO
O
AcO
O
40%
AcO OAc
AcO OAc
1c
2bc
3cbc
Ph
Ph
Ph
Ph
Ph
N
CH3ONa
CH3OH
N
85%
N
N
HO
O
HO OH
4
SCHEME 2
Prelim in ary in vitro cytostatic activity tests of som e represen tative exam -
ples of title com poun ds were perform ed usin g th e followin g cell cultures:
m ouse leukem ia L1210 cells (ATCC CCL 219), h um an prom yelocytic leuke-
m ia HL60 cells (ATCC CCL 240), h um an cervix carcin om a HeLa S3 cells
(ATCC CCL 2.2) an d h um an T lym ph oblastoid CCRF-CEM cell lin e (ATCC
CCL 119). Th e m ost active was 3aba (IC50 = 7.0, 6.4 an d 10.9 µM again st
L1210, HL60 an d CCRF-CEM cell-lin es, respectively). Sligh tly lower activi-
ties were foun d with 3aaa (IC50 = 23.0, 10.0 an d 10.0 µM, respectively) an d
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

344
Turek, Kotora, Hocek,Votruba:
3aca (IC50 = 7.7, 14.0 an d 21.0 µM, respectively), wh ile purin e 3cba an d
n uclerosides 3cbc an d 4 were en tirely in active. Th ough th e activities in
m icrom olar ran ge are probably below th e th erapeutically useful level, th is
n ovel type of com poun ds defin itely represen ts a n ew structural lead in th e
search of an tiproliferative drugs.
In sum m ary, th e reaction of zircon acyclopen tadien es with 6-alkyn yl-
purin es con stitutes th e first application of zircon ocen e-based cyclotri-
m erization m eth od for syn th esis of biologically active com poun ds, n am ely
a sim ple an d straigh tforward m eth od for th e preparation of 6-arylpurin es
with h igh ly substituted h ydroph obic aryl m oieties. In addition , prelim in ary
tests sh owed in terestin g an tiproliferative activity of som e of th e title com -
poun ds in culture cells of leukem ia an d can cer. Furth er in vestigation s will
focus both on th e optim ization of con dition s in order to im prove yields
an d on exten sion of th e series of th is prom isin g class of com poun ds for SAR
(structure–activity relation sh ip) study.
EXPERIMENTAL
All reaction s were carried out un der in ert atm osph ere (Ar). THF was distilled from ben zo-
ph en on e an d sodium prior to use. NiBr2(PPh 3)2 (lit.17) an d alkyn ylpurin es9,16 were prepared
accordin g to previously publish ed procedures. Hex-3-yn e, oct-4-yn e, diph en ylacetylen e,
zircon ocen e dich loride an d butyllith ium (1.6 M solution in h exan es) were purch ased from
Aldrich . All oth er ch em icals an d solven ts were of com m ercial purity an d were used with out
furth er purification .
Meltin g poin ts were determ in ed on a Kofler block. Optical rotation s were m easured on an
.
Autopol III polarim eter; [α]D values are given in 10–1 deg cm 2 g–1 1H NMR (400 MHz) an d
13C NMR (100 MHz) spectra were recorded on a Varian Un ity In ova 400 spectrom eter usin g
tetram eth ylsilan e as an in tern al stan dard. Ch em ical sh ifts are given in ppm (δ-scale), cou-
plin g con stan ts (J) are given in Hz. In frared spectra (waven um bers in cm –1) were recorded
on a PE-640 Perkin –Elm er spectrom eter. Mass spectra were obtain ed on a ZAB-SEQ VG An a-
lytical spectrom eter. Elem en tal an alyses were obtain ed on a Perkin –Elm er 2400 elem en tal
an alyser. TLC was perform ed on Merck Silica Gel 60 F254 alum in ium sh eets an d colum n
ch rom atograph y was perform ed on Fluka Silica Gel 60.
6-(Ph en yleth yn yl)-9-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)-9H-purin e (2bc)
DMF (8 m l) an d Et3N (2 m l) were added th rough a septum to an argon purged flask con tain -
in g 6-ch loro-9-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)purin e (1.3 g, 3.15 m m ol), ph en yl-
acetylen e (1.2 g, 10 m m ol), CuI (100 m g, 0.53 m m ol) an d Pd(PPh 3)4 (100 m g, 0.087 m m ol).
Th e m ixture was stirred at 120 °C for 7 h . Th e solven ts were evaporated an d th e residue was
ch rom atograph ed on a silica gel colum n (200 g, eth yl acetate/petroleum eth er 1:2 to 2:1) to
give th e product (1.2 g, 80%) as brown ish oil. 1H NMR (CDCl3): 2.09, 2.13 an d 2.16 3 × s,
3 × 3 H (CH3); 4.36–4.50 m , 3 H (H-4′ an d 2 × H-5′); 5.69 dd, 1 H, J = 4.6 an d 5.1 (H-3′);
5.99 t, 1 H, J = 5.1 (H-2′); 6.26 d, 1 H, J = 5.1 (H-1′); 7.39–7.44 m , 3 H (H-arom .); 7.73–7.75 m ,
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Preparation of Highly Substituted 6-Arylpurines
345
2 H (H-arom .); 8.30 s, 1 H (H-8); 8.98 s, 1 H (H-2). 13C NMR (CDCl3): 20.33, 20.49 an d
20.71 (3 × CH3); 62.98 (CH2-5′); 70.61 (CH-3′); 73.10 (CH-2′); 80.53 (CH-4′); 83.98 (C≡);
86.55 (CH-1′); 99.00 (C≡); 121.30 (C-i-arom .); 128.45, 130.03, 132.73 (3 × CH-arom .); 134.87
(C-5); 142.47 an d 151.17 (C-4 an d C-6); 148.53 (CH-8); 152.89 (CH-2); 169.30, 169.52 an d
170.25 (3 × CO). IR (CHCl3): 2215, 1751, 1599, 1582, 1489, 1443, 1374, 1334, 1232.
FAB MS, m/z (rel.%): 479 (6) [M + H], 221 (62), 139 (88), 97 (100). Exact m ass (FAB HR MS)
calculated for C24H23N4O7 [M + H]: 479.1567; foun d: 479.1551.
Reaction s of 6-Alkyn ylpurin es with Zircon acyclopen tadien es. Gen eral Procedure
Alkyn ylpurin e 2 (1 m m ol) an d NiBr2(PPh 3)2 (742 m g, 1 m m ol) were added in to a solution of
zircon acyclopen tadien e 1 (1 m m ol) in THF (5 m l) un der Ar atm osph ere an d th e reaction
m ixture was stirred at 20 °C overn igh t. Th en it was quen ch ed with 3 M HCl an d extracted
with EtOAc (3 × 5 m l). Com bin ed organ ic extracts were wash ed with saturated solution s of
NaHCO3, NaCl, an d dried over an h ydrous MgSO4. Colum n ch rom atograph y on silica gel
was used to obtain th e products.
9-Benzyl-6-(2-butyl-3,4,5,6-tetraethylphenyl)-9H-purine (3aaa). Colum n ch rom atograph y on
silica gel (h exan e/EtOAc 3:1) afforded 113 m g (25%) of 3aaa as a colorless solid. M.p. 96–97 °C
(h exan e). 1H NMR (CDCl3): 0.43 t, 3 H, J = 7.3 (CH3); 0.86 t, 3 H, J = 7.3 (CH3); 1.17 t, 3 H,
J = 7.3 (CH3); 1.19 t, 6 H, J = 7.3 (2 × CH3); 2.08–2.15 m , 2 H (CH2); 2.15–2.35 m , 2 H
(CH2); 2.62–2.76 m , 6 H (3 × CH2); 5.45 d, 1 H, J = 15.1 (CH2Ph ); 5.56 d, 1 H, J = 15.1
(CH2Ph ); 7.3–7.4 m , 5 H (Ph ); 8.02 s, 1 H (H-8); 9.09 s, 1 H (H-2). 13C NMR (CDCl3): 13.08,
15.41, 15.74, 15.78, 21.08, 21.93, 22.13, 22.86, 23.69, 25.48, 30.27, 32.87, 47.13, 67.82,
127.61, 128.43, 129.02, 133.29, 133.31, 135.19, 136.09, 137.06, 137.68, 137.87, 141.11,
144.05, 151.34, 152.47, 161.81. IR (CHCl3): 2967, 1589, 1455, 1327. Exact m ass (EI HR MS)
calculated for C30H38N4: 454.3096; foun d: 454.3081. RF 0.50 (h exan e/EtOAc 1:1).
9-Benzyl-6-(6-phenyl-2,3,4,5-tetraethylphenyl)-9H-purine (3aba). Colum n ch rom atograph y on
silica gel (h exan e/EtOAc 3:1) afforded 56 m g (24%) of a wh ite solid. M.p. 174–175 °C
(h exan e). 1H NMR (CDCl3): 0.90 t, 3 H, J = 7.2 (CH3); 0.93 t, 3 H, J = 7.2 (CH3); 1.24 t, 3 H,
J = 7.2 (CH3); 1.28 t, 3 H, J = 7.2 (CH3); 2.38–2.56 m , 2 H (CH2); 2.44 q, 2 H, J = 7.2 (CH2);
2.78 q, 2 H, J = 7.2 (2 × CH2); 5.25 d, 1 H, J = 15.5 (CH2Ph ); 5.44 d, 1 H, J = 15.5 (CH2Ph );
6.76–7.06 m , 7 H (Ph ); 7.30–7.40 m , 3 H (Ph ); 7.87 s, 1 H (H-8); 8.81 s, 1 H (H-2). 13C NMR
(CDCl3): 15.49, 15.52, 15.79, 15.81, 21.92, 22.20, 23.01, 23.66, 46.63, 125.51, 126.05,
126.49, 126.93, 128.20, 128.90, 129.76, 130.42, 132.92, 133.12, 135.33, 136.69, 137.80,
139.16, 139.47, 140.29, 140.96, 143.68, 150.93, 151.75, 161.13. IR (CHCl3): 2973, 1593,
1498, 1455, 1330, 1221. EI MS, m/z (rel.%): 474 (27) [M+], 383 (100). Exact m ass (EI HR MS)
calculated for C32H34N4: 474.2783; foun d: 474.2763. RF 0.42 (h exan e/EtOAc 1:1).
9-Benzyl-6-[2,3,4,5-tetraethyl-6-(trimethylsilyl)phenyl]-9H-purine (3aca). Colum n ch rom atog-
raph y on silica gel (h exan e/EtOAc 3:1) afforded 50 m g (21%) of a wh ite solid. M.p. 128–129 °C
(h exan e). 1H NMR (CDCl3): –0.28 s, 9 H (Si(CH3)3); 0.79 t, 3 H, J = 7.5 (CH3); 1.17 t, 3 H, J =
7.5 (CH3); 1.18 t, 3 H, J = 7.2 (CH3); 1.20 t, 3 H, J = 7.2 (CH3); 2.16–2.32 m , 2 H (CH2);
2.71 q, 2 H, J = 7.5 (CH2); 2.78 q, 2 H, J = 7.5 (CH2); 2.89 q, 2 H, J = 7.5 (CH2); 5.44 d, 1 H,
J = 15.3 (CH2Ph ); 5.54 d, 1 H, J = 15.3 (CH2Ph ); 7.25–7.29 m , 2 H (Ph ); 7.33–7.40 m , 3 H
(Ph ); 8.02 s, 1 H (H-8); 9.04 s, 1 H (H-2). 13C NMR (CDCl3): 2.88, 15.25, 15.61, 16.07, 17.43,
21.72, 22.04, 23.24, 26.46, 47.13, 127.46, 128.44, 129.08, 133.95, 134.42, 135.28, 136.92,
139.41, 141.27, 141.64, 144.03, 146.54, 151.16, 152.07, 162.63. IR (CHCl3): 2974, 2938,
2907, 2877, 1589, 1578, 1499, 1455, 1378, 1331, 1250, 1222, 1218, 861, 844. EI MS, m/z
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

346
Turek, Kotora, Hocek,Votruba:
(rel.%): 470 (9) [M+], 455 (28), 441 (28), 397 (16), 379 (11), 91 (100). Exact m ass (EI HR MS)
calculated for C29H38N4Si: 470.2866; foun d: 470.2893. For C29H38N4Si (470.7) calculated:
74.00% C, 8.14% H, 11.90% N; foun d: 73.90% C, 8.29% H, 11.53% N. RF 0.53 (h exan e/
EtOAc 1:1).
9-Benzyl-6-(2,3,4,5,6-pentaphenylphenyl)-9H-purine (3cba). Colum n ch rom atograph y on sil-
ica gel (h exan e/EtOAc 3:1) afforded 80 m g (24%) of a wh ite solid. M.p. 265–266 °C (h exan e).
1H NMR (CDCl3): 5.28 s, 2 H (CH2Ph ); 6.62–6.70 m , 27 H (Ph ); 7.25–7.30 m , 3 H (Ph );
7.80 s, 1 H (H-8); 8.62 s, 1 H (H-2). 13C NMR (CDCl3): 46.53, 125.33, 125.53, 126.36,
126.58, 128.17, 128.90, 130.36, 130.81, 131.15, 131.21, 131.24, 131.38, 133.15, 134.56,
135.40, 139.49, 139.85, 140.01, 140.28, 140.43, 142.14, 144.02, 150.68, 151.52, 159.91. IR
(CHCl3): 2975, 1593, 1498, 1329. EI MS, m/z (rel.%): 666 (56) [M+], 575 (15), 91 (100). Exact
m ass (EI HR MS) calculated for C48H34N4: 666.2783; foun d: 666.2769. RF 0.39 (h exan e/
EtOAc 1:1).
9-Benzyl-6-(3-butyl-1,4-diphenyl-5,6,7,8-tetrahydro-2-naphthyl)-9H-purine (3d aa). Colum n
ch rom atograph y on silica gel (h exan e/EtOAc 3:1) afforded 32 m g (12%) of a wh ite solid.
M.p. 85–86 °C (h exan e). 1H NMR (CDCl3): 0.23 t, 3 H, J = 7.2 (CH3); 0.56–0.72 m , 2 H
(CH2); 0.94–1.06 m , 1 H (CH2); 1.18–1.30 m , 1 H (CH2); 1.54–1.68 m , 4 H (CH2); 1.96–2.04 m ,
1 H (CH2); 2.14–2.22 m , 1 H (CH2); 2.30–2.40 m , 3 H (CH2); 2.44–2.52 m , 1 H (CH2); 5.33 d,
1 H, J = 15.5 (CH2Ph ); 5.41 d, 1 H, J = 15.5 (CH2Ph ); 6.87–7.13 m , 7 H (Ph ); 7.25–7.45 m ,
8 H (Ph ); 7.88 s, 1 H (H-8); 8.84 s, 1 H (H-2). 13C NMR (CDCl3): 12.92. 22.52, 22.95, 23.09,
28.79, 29.45, 30.66, 32.79, 46.76, 125.86, 126.47, 126.64, 126.94, 127.09, 128.07, 128.16,
128.30, 128.99, 129.57, 129.60, 129.64, 130.07, 132.14, 132.76, 133.16, 135.45, 135.61,
136.50, 139.88, 140.36, 140.87, 141.09, 143.88, 151.01, 151.92, 160.56. IR (CHCl3): 2936,
1590, 1496, 1328. EI MS, m/z (rel.%): 548 (16) [M+], 457 (60), 414 (8), 91 (100). Exact m ass
(EI HR MS) calculated for C38H36N4: 548.2940; foun d: 548.2966. RF 0.47 (h exan e/EtOAc 1:1).
6-(2-Butyl-3,4,5,6-tetraethylphenyl)-9-(tetrahydropyran-2-yl)-9H-purine (3aab). Colum n ch ro-
m atograph y on silica gel (h exan e/EtOAc 3:1) afforded 42 m g (19%) of a yellow liquid.
1H NMR (CDCl3): 0.46 t, 1.5 H, J = 7.4 (CH3); 0.52 t, 1.5 H, J = 7.4 (CH3); 0.84 t, 1.5 H, J =
7.5 (CH3); 0.85 t, 1.5 H, J = 7.5 (CH3); 0.88–1.00 m , 2 H (2 × CH2); 1.16–1.22 m , 9 H (6 ×
CH3); 1.30–1.40 m , 1 H (CH2); 1.66–1.90 m , 4 H (4 × CH2); 2.00–2.30 m , 7 H (7 × CH2);
2.62–2.75 m , 6 H (6 × CH2); 3.80–3.88 m , 1 H (2 × CH2-O); 4.19–4.25 m , 1 H (2 × CH2-O);
5.85–5.92 m , 1 H (2 × CH-O); 8.25 s, 0.5 H (H-8); 8.27 s, 0.5 H (H-8); 9.04 s, 0.5 H (H-2);
9.05 s, 0.5 H (H-2). 13C NMR (CDCl3): 13.12, 13.26, 15.48, 15.84, 21.86, 21.97, 22.18, 22.80,
22.88, 22.96, 23.71, 24.83, 30.31, 30.38, 31.66, 31.75, 32.91, 33.08, 133.24, 133.49, 136.06,
136.19, 137.04, 137.16, 137.68, 137.77, 137.87, 137.94, 141.19, 141.89, 142.05, 150.50,
152.31, 152.36, 161.92, 161.95. IR (CHCl3): 2968, 1590, 1454, 1043. EI MS, m/z (rel.%): 448
(8) [M+], 363 (100), 335 (20), 321 (14), 85 (28). Exact m ass (EI HR MS) calculated for
C
28H40N4O: 448.320212; foun d: 448.318209. RF 0.44 (h exan e/EtOAc 1:1).
6-(6-Phenyl-2,3,4,5-tetraethylphenyl)-9-(tetrahydropyran-2-yl)-9H-purine (3abb). Colum n ch ro-
m atograph y on silica gel (h exan e/EtOAc 2:1) afforded 40 m g (17%) of a yellow liquid.
1H NMR (CDCl3): 0.88 t, 1.5 H, J = 7.5 (CH3); 0.89 t, 1.5 H, J = 7.5 (CH3); 0.90 t, 3 H, J = 7.5
(2 × CH3); 1.24 t, 3 H, J = 7.5 (2 × CH3); 1.26 t, 1.5 H, J = 7.5 (CH3); 1.27 t, 1.5 H, J = 7.5
(CH3); 1.60–1.67 m , 1 H (CH2); 1.67–1.80 m , 2 H (2 × CH2); 1.95–2.12 m , 3 H (3 × CH2);
2.30–2.48 m , 2 H (2 × CH2); 2.43 q, 2 H, J = 7.5 (2 × CH2); 2.77 q, 4 H, J = 7.5 (8 × CH2);
3.70–3.80 m , 1 H (2 × CH2-O); 4.12–4.18 m , 1 H (2 × CH2-O); 5.65–5.71 m , 1 H (2 × CH-O);
6.78–7.08 m , 5 H (2 × Ph ); 8.12 s, 0.5 H (H-8); 8.13 s, 0.5 H (H-8); 8.76 s, 0.5 H (H-2); 8.77 s,
0.5 H (H-2). 13C NMR (CDCl3): 15.53, 15.84, 21.95, 22.23, 22.70, 23.03, 23.64, 24.79, 31.55,
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31.71, 68.70, 81.45, 81.94, 125.62, 125.82, 126.10, 126.47, 126.51, 126.55, 129.55, 129.68,
130.44, 133.08, 133.17, 133.22, 136.71, 136.80, 137.82, 137.94, 139.10, 139.42, 139.52,
140.19, 140.30, 141.00, 141.37, 141.66, 150.00, 151.59, 161.18. IR (CHCl3): 2971, 1590,
1495, 1084, 1042. EI MS, m/z (rel.%): 468 (3) [M+], 383 (65), 43 (100). Exact m ass (EI HR MS)
calculated for C30H36N4O: 468.288912; foun d: 468290024. RF 0.34 (h exan e/EtOAc 1:1).
6-(2-Butyl-3,4,5,6-tetrapropylphenyl)-9-(tetrahydropyran-2-yl)-9H-purine (3bab). Colum n ch ro-
m atograph y on silica gel (h exan e/EtOAc 3:1) afforded 52 m g (21%) of a yellow liquid.
1H NMR (CDCl3): 0.46 t, 1.5 H, J = 7.5 (CH3); 0.53 t, 1.5 H, J = 7.5 (CH3); 0.54 t, 1.5 H, J =
7.5 (CH3); 0.58 t, 1.5 H, J = 7.5 (CH3); 0.84–0.98 m , 2 H (2 × CH2); 1.01 t, 1.5 H, J = 7.2
(CH3); 1.02 t, 3 H, J = 7.2 (2 × CH3); 1.03 t, 1.5 H, J = 7.2; 1.06 t, 3 H, J = 7.2 (2 × CH3);
1.14–1.28 m , 2 H (2 × CH2); 1.28–1.42 m , 2 H (2 × CH2); 1.48–1.60 m , 6 H (6 × CH2);
1.66–1.72 m , 1 H (CH2); 1.72–1.90 m , 2 H (2 × CH2); 1.98–2.22 m , 7 H (7 × CH2); 2.50–2.60 m ,
6 H (6 × CH2); 3.80–3.90 m , 1 H (2 × CH2-O); 4.19–4.26 m , 1 H (2 × CH2-O); 5.85–5.92 m ,
1 H (2 × CH-O); 8.25 s, 0.5 H (H-8); 8.26 s, 0.5 H (H-8); 9.04 s, 1 H (H-2). 13C NMR (CDCl3):
13.10, 13.25, 14.69, 14.74, 15.05, 15.10, 15.13, 22.78, 22.88, 22.97, 24.43, 24.82, 24.88,
30.41, 30.50, 31.65, 31.79, 31.89, 32.17, 32.87, 33.04, 33.32, 68.83, 81.86, 81.93, 133.17,
133.41, 136.06, 136.18, 136.65, 136.69, 136.74, 140.16, 141.89, 142.00, 150.41, 150.46,
152.27, 162.02. IR (CHCl3): 2958, 1587, 1457, 1086. EI MS, m/z (rel.%): 504 (2) [M+], 419
(48), 85 (65), 83 (100). Exact m ass (EI HR MS) calculated for C32H48N4O: 504.382813; foun d:
504.3874638. RF 0.54 (h exan e/EtOAc 1:1).
6-(2-Phenyl-3,4,5,6-tetrapropylphenyl)-9-(tetrahydropyran-2-yl)-9H-purine (3b b b ). Colum n
ch rom atograph y on silica gel (h exan e/EtOAc 3:1) afforded 54 m g (21%) of a yellow liquid.
1H NMR (CDCl3): 0.58 t, 1.5 H, J = 7.3 (CH3); 0.62 t, 1.5 H, J = 7.3 (CH3); 0.66 t, 3 H, J = 7.3
(2 × CH3); 1.07 t, 1.5 H, J = 7.3 (CH3); 1.08 t, 4.5 H, J = 7.3 (3 × CH3); 1.20–1.34 m , 4 H (4 ×
CH2); 1.54–1.80 m , 7 H (7 × CH2); 1.90–2.14 m , 3 H (3 × CH2); 2.14–2.42 m , 4 H (4 × CH2);
2.60–2.68 m , 4 H (4 × CH2); 3.70–3.80 m , 1 H (2 × CH2-O); 4.12–4.18 m , 1 H (2 × CH2-O);
5.64–5.70 m , 1 H (2 × CH-O); 6.76–7.05 m , 5 H (2 × Ph ); 8.10 s, 0.5 H (H-8); 8.12 s, 0.5 H
(H-8); 8.75 s, 0.5 H (H-2); 8.76 s, 0.5 H (H-2). 13C NMR (CDCl3): 14.67, 14.74, 15.12, 22.63,
24.45, 24.76, 24.83, 24.90, 31.63, 31.85, 32.14, 32.57, 33.12, 68.65, 81.47, 81.89, 125.49,
125.72, 125.96, 126.38, 126.46, 129.52, 129.68, 130.35, 133.00, 133.06, 133.13, 135.67,
135.73, 136.63, 136.77, 138.34, 138.44, 139.10, 139.97, 140.22, 140.32, 141.29, 141.59,
149.89, 151.46, 161.23. IR (CHCl3): 2958, 1590, 1457, 1082, 1049. EI MS, m/z (rel.%): 524
(2) [M+], 439 (100), 411 (8). Exact m ass (EI HR MS) calculated for C34H44N4O: 524.351512;
foun d: 524.351352. RF 0.46 (h exan e/EtOAc 1:1).
6-(Pentaphenylphenyl)-9-(tetrahydropyran-2-yl)-9H-purine (3cbb). Colum n ch rom atograph y
on silica gel (h exan e/EtOAc 2:1) afforded 58 m g (18%) of a wh ite solid. M.p. > 350 °C
(CH2Cl2/h exan e). 1H NMR (CDCl3): 1.59–1.77 m , 3 H (1.5 × CH2); 1.83–2.04 m , 3 H (1.5 ×
CH2); 3.70 dt, 1 H, J = 11.6, 2.7 (CH2O); 4.06–4.14 m , 1 H (CH2O); 5.58 dd, 1 H, J = 9.6, 3.3
(CH-O); 6.60–7.04 m , 25 H (5 × Ph ); 8.05 s, 1 H (H-8); 8.58 s, 1 H (H-2). 13C NMR (CDCl3):
22.58, 24.77, 31.65, 68.66, 81.72, 125.29, 125.44, 125.70, 126.22, 126.45, 130.12, 130.39,
130.66, 130.83, 131.14, 131.20, 131.23, 131.25, 131.34, 133.37, 134.46, 139.31, 139.40,
139.87, 139.96, 140.07, 140.30, 140.33, 140.49, 141.63, 142.08, 149.602, 151.20, 159.82. IR
(CHCl3): 2955, 1593, 1442, 1086, 1046. EI MS, m/z (rel.%): 660 (2) [M+], 576 (18), 55 (100).
Exact m ass (EI HR MS) calculated for C28H40N4O: 660.288912; foun d: 660.287432. RF 0.52
(h exan e/EtOAc 1:2).
6-(Pentaphenylphenyl)-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-9H-purine (3cbc). Colum n ch ro-
m atograph y on silica gel (toluen e/EtOAc 5:2) afforded 167 m g (40%) of a wh ite solid. M.p.
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

348
Turek, Kotora, Hocek,Votruba:
137–138 °C, [α]D –13.6 (c 0.14, CHCl3). 1H NMR (CDCl3): 2.02 s, 3 H (CH3); 2.09 s, 3 H
(CH3); 2.12 s, 3 H (CH3); 4.24 m , 1 H (H-5′b); 4.37–4.44 m , 2 H (H-4′, H-5′a); 5.55 m , 1 H
(H-3′); 5.65 t, J2′,3′ = 5.4, J2′,1′ = 5.2, 1 H (H-2′); 6.06 d, J1′,2′ = 5.2, 1 H (H-1′); 6.65–6.98 m ,
25 H (5 × Ph ); 7.98 s, 1 H (H-8); 8.60 s, 1 H (H-2). 13C NMR (CDCl3): 20.25, 20.50, 20.72,
62.89, 70.40, 73.19, 80.27, 86.01, 125.37, 125.65, 125.73, 126.34, 126.47, 126.51, 126.62,
130.30, 130.72, 130.79, 131.14, 131.21, 131.25, 131.37, 133.87, 134.28, 139.30, 139.32,
139.80, 139.81, 140.00, 140.06, 140.25, 140.49,140.51, 141.93, 142.29, 149.95, 151.56,
160.43, 168.99, 169.49, 170.20. IR (CHCl3): 1752, 1595, 1578, 1496, 1443, 1374, 1227, 700.
FAB MS, m/z (rel.%): 835 (10) [M + H], 577 (12), 279 (43). FAB HR MS calculated for
C
52H43N4O7 [M + H]: 835.3132; foun d: 835.3105. RF 0.51 (toluen e/EtOAc 1:1).
6-(Pen taph en ylph en yl)-9-(β-D-ribofuran osyl)-9H-purin e (4)
Com poun d 3cbc (150 m g, 0.18 m m ol) in m eth an ol (9 m l) was treated with 1 M solution of
MeONa in MeOH (36 µl, 0.036 m m ol) at room tem perature for 1 h . Th e reaction m ixture
was extracted with CH2Cl2/H2O an d dried over an h ydrous Na2SO4. Evaporation afforded a
wh ite solid 108 m g (85%). M.p. > 360 °C, [α]D –46.9 (c 0.15, MeOH). 1H NMR (DMSO-d6):
3.50 ddd, Jgem = 12.0, J5′b,OH = 5.6, J5′b,4′ = 4.1, 1 H (H-5′b); 3.62 ddd, Jgem = 12.0, J5′a,OH
5.6, J5′a,4′ = 4.0, 1 H (H-5′a); 3.88 q, J4′,5′ = 4.1, 4.0, J4′,3′ = 4.0, 1 H (H-4′); 4.05 td, J3′,OH
=
=
5.2, J3′,2′ = 5.0, J3′,4′ = 4.0, 1 H (H-3′); 4.30 bq, J2′,OH = 6.4, J2′,1′ = 5.6, J2′,3′ = 5.0, 1 H (H-2′);
5.07 t, JOH,5′ = 5.6, 1 H (OH-5′); 5.21 d, JOH,3′ = 5.2, 1 H (OH-3′); 5.40 d, JOH,2′ = 6.4, 1 H
(OH-2′); 5.81 d, J1′,2′ = 5.6, 1 H (H-1′); 6.61–6.98 m , 25 H (5 × Ph ); 8.51 s, 1 H (H-2); 8.64 s,
1 H (H-8). 13C NMR (DMSO-d6): 61.30, 70.14, 73.89, 85.51, 87.15, 125.69, 126.00, 126.04,
126.33, 126.45, 126.78, 129.80, 130.64, 130.73, 130.90, 130.98, 131.14, 133.66, 134.85,
138.97, 139.63, 139.69, 140.02, 140.17, 141.56, 144.17, 150.28, 150.74, 158.59. IR (KBr):
3368, 1593, 1578, 1496, 1442, 1331. FAB MS, m/z (rel.%): 709 (26) [M + H], 619 (12), 577
(100), 279 (7). FAB HR MS calculated for C46H37N4O4 [M + H]: 709.2815; foun d: 709.2836.
This work is a part of a research project Z4 055 0506. It was supported by the Grant Agency of the
Czech Republic (grant No. 203/03/0035). The authors thank Dr. I. Tišlerová for the measurement of
NMR spectra.
REFERENCES
1. Cocuzza A. J., Chidester D. R., Culp S., Fitzgerald L., Gilligan P.: Bioorg. Med. Chem. Lett.
1999, 9, 1063.
2. a) Bakkestuen A. K., Gundersen L.-L., Langli G., Liu F., Nolsøe J. M. J.: Bioorg. Med. Chem.
Lett. 2000, 10, 1207; b) Andresen G., Gundersen L.-L., Nissen-Meyer J., Rise F., Spilsberg B.:
Bioorg. Med. Chem. Lett. 2002, 12, 567; c) Gundersen L.-L., Nissen-Meyer J., Spilsberg B.:
J. Med. Chem. 2002, 45, 1383.
3. a) Hocek M., Holý A., Votruba I., Dvořáková H.: J. Med. Chem. 2000, 43, 1817; b) Hocek M.,
Holý A., Votruba I., Dvořáková H.: Collect. Czech. Chem. Commun. 2001, 66, 483;
c) Hocek M., Holý A., Dvořáková H.: Collect. Czech. Chem. Commun. 2002, 67, 325;
d) Hocek M., Hocková D., Štambaský J.: Collect. Czech. Chem. Commun. 2003, 68, 837.
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

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4. Hirao I., Ohtsuki T., Fujiwara T., Mitsui T., Yokogawa T., Okuni T., Nakayama H., Takio K.,
Yabuki T., Kigawa T., Kodama K., Yokogawa T., Nishikawa K., Yokoyama S.: Nature
Biotechnol. 2002, 20, 177.
5. Havelková M., Dvořák D., Hocek M.: Tetrahedron 2002, 58, 7431.
6. a) Pathak A. K., Pathak V., Seitz L. E., Suling W. J., Reynolds R. C.: J. Med. Chem. 2004,
47, 273; b) Kool E. T.: Acc. Chem. Res. 2002, 35, 936; c) Kool E. T., Morales J. C.,
Guckian K. M.: Angew. Chem., Int. Ed. 2000, 39, 990.
7. Review: Hocek M.: Eur. J. Org. Chem. 2003, 245.
8. a) Turek P., Kotora M., Hocek M., Císařová I.: Tetrahedron Lett. 2003, 44, 785; b) Turek P.,
Kotora M., Hocek M., Votruba I., Císařová I.: J. Org. Chem. 2004, 69, 9224.
9. a) Hocek M., Votruba I.: Bioorg. Med. Chem. Lett. 2002, 12, 1055; b) Hocek M.,
Dvořáková H., Císařová I.: Collect. Czech. Chem. Commun. 2002, 67, 1560; c) Hocek M.,
Votruba I., Dvořáková H.: Tetrahedron 2003, 59, 607; d) Hocek M., Štěpnička P., Ludvík J.,
Císařová I., Votruba I., Řeha D., Hobza P.: Chem. Eur. J. 2004, 10, 2058; e) Nauš P.,
Votruba I., Hocek M.: Collect. Czech. Chem. Commun. 2004, 69, 1955.
10. a) Negishi E., Holmes S. J., Tour J., Miller J. A., Cederbaum F. E., Swanson D. R.,
Takahashi T.: J. Am. Chem. Soc. 1989, 111, 3336; b) Buchwald S. L., Nielsen R. B.: J. Am.
Chem. Soc. 1989, 111, 2870; c) Negishi E., Cederbaum F. E., Takahashi T.: Tetrahedron
Lett. 1986, 27, 2829.
11. Takahashi T., Tsai F. Y., Li Y. Z., Nakajima K., Kotora M.: J. Am. Chem. Soc. 1999, 121,
11093.
12. For reactions of alkynes with other zirconacycles in the presence of Ni complexes, see:
a) Sharp P. R.: J. Am. Chem. Soc. 2000, 122, 9880; b) Brown J. S., Sharp P. R.:
Organometallics 2003, 22, 3604.
13. Li Y. Z., Ura Y., Tsai F. Y., Xu F., Takahashi T.: Heterocycles 2001, 54, 943.
14. a) Takahashi T., Tsai F.-Y., Li Y.-Z.: Chem. Lett. 1999, 1173; b) Wong K. T., Chen R. T.:
Tetrahedron Lett. 2002, 43, 3313; c) Johnson S. A., Liu F.-Q., Suh M. C., Zürcher S.,
Haufe M., Mao S. S. H., Tilley T. D.: J. Am. Chem. Soc. 2003, 125, 4199; d) Takahashi T.,
Kitamura M., Shen B., Nakajima K.: J. Am. Chem. Soc. 2000, 122, 12876.
15. Dufková L., Matsumura H., Nečas D., Štěpnička P., Uhlík F., Kotora M.: Collect. Czech.
Chem. Commun. 2004, 69, 351.
16. Hocek M., Stará I. G., Starý I., Dvořáková H.: Collect. Czech. Chem. Commun. 2002, 67,
1223.
17. a) Venanzi L. M.: J. Chem. Soc. 1958, 719; b) Jensen K. A., Nielsen P. H., Pedersen C. T.:
Acta Chem. Scand. 1963, 17, 1115.
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