Covalent analogues of DNA base-pairs and triplets IV+. Synthesis of trisubstituted benzenes bearing purine and/or pyrimidine rings by cyclotrimerization of 6-ethynylpurines and/or 5-ethynyl-1,3-dimethyluracil

Article abstract of DOI:10.1135/cccc20021223

Ni-Catalyzed cyclotrimerizations of 6-ethynylpurines 3 or 5-ethynyl-1,3-dimethyluracil (4) afforded the 1,2,4-tris(purin-6-yl)benzenes 7 or 1,2,4-tris(1,3-dimetyhyluracil-5-yl)benzene (9), respectively. The symmetrical 1,3,5-tris(purin-6-yl)benzenes 8 wer

Full text of DOI:10.1135/cccc20021223

DNA Base-Pairs and Triplets
1223
COVALENT ANALOGUES OF DNA BASE-PAIRS AND TRIPLETS IV+.
SYNTHESIS OF TRISUBSTITUTED BENZENES BEARING PURINE
AND/ OR PYRIMIDINE RINGS BY CYCLOTRIMERIZATION OF
6-ETHYNYLPURINES AND/ OR 5-ETHYNYL-1,3-DIMETHYLURACIL
a3
b
Michal HOCEKa1,*, Irena G. STARÁa2, Ivo STARÝ and Hana DVOŘÁKOVÁ
a
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
CZ-16610 Prague 6, Czech Republic; e-mail: hocek@uochb.cas.cz, stara@uochb.cas.cz,
1
2
3
stary@uochb.cas.cz
b
Central Laboratory of NMR, Institute of Chemical Technology, Prague, CZ-16628 Prague 6,
Czech Republic; e-mail: hana.dvorakova@vscht.cz
Received May 20, 2002
Accepted Jun e 16, 2002
Ni-Catalyzed cyclotrim erization s of 6-eth yn ylpurin es 3 or 5-eth yn yl-1,3-dim eth yluracil (4)
afforded th e 1,2,4-tris(purin -6-yl)ben zen es 7 or 1,2,4-tris(1,3-dim etyh yluracil-5-yl)ben zen e
(9), respectively. Th e sym m etrical 1,3,5-tris(purin -6-yl)ben zen es 8 were also form ed as m in or
products in very low yields. Co-cyclotrim erization of 9-ben zyl-6-eth yn ylpurin e (3a) with 4
afforded th e tris(purin yl)ben zen e 7a as a m ajor product alon g with 1,2-bis(9-ben zylpurin -
6-yl)-4-(1,3-dim eth yluracil-5-yl)ben zen e (10) an d a com plex m ixture of oth er derivatives an d
isom ers. Com poun ds 7–10 are an alogues of Hoogsteen base-triplets.
Keyw ord s: Purin es; Pyrim idin es; Nucleobases; Hoogsteen triplets; Cyclotrim erization s;
Nickel; Alkyn es; [2+2+2] Cycloaddition s.
Two m ain h ydrogen bon din g m otifs exist in DNA: th e Watson –Crick m otif
in duplexes an d th e Hoogsteen m otif in triplexes. Hydrogen bon din g is cru-
cial to th e ability of th e two stran ds to stay an n ealed to each oth er but
equally im portan t is th e ability to separate from on e an oth er in th e righ t
m om en t. Th erefore th e effect of m an y clin ically used an titum or agen ts is
based on DNA cross-lin kin g1 or on in tercalation 2 in to DNA. Num erous
m odels an d an alogues of Watson –Crick base pairs con sistin g of an n elated3
or cross-lin ked4 purin e an d pyrim idin e h eterocycles or even m ore sim ple
arom atic rin gs5,6 h ave been prepared. Such base-pair an alogues m ay in ter-
act with DNA (e.g. by in tercalation ); if in corporated in to sin gle-stran ded
+ For Part III see ref.9
Collect. Czech. Chem. Commun. (Vol. 67) (2002)
doi:10.1135/cccc20021223

1224
Hocek, Stará, Starý, Dvořáková:
DNA, th ey are com plem en tary to abasic site of a dam aged DNA stran d; or
altern atively, if in corporated to a duplex, th ey form perm an en t cross-lin ks.
On th e oth er h an d, n o system atic research on covalen t an alogues of an -
oth er im portan t DNA H-bon din g m otif, Hoogsteen triplets (Fig. 1), h as
been reported so far, tripurin ylam in es bein g th e on ly kn own exam ple7.
Very recen tly, we h ave prepared a n ew type of covalen t base-pair an a-
logues con sistin g of various purin e dim ers an d purin e-pyrim idin e con ju-
gates lin ked th rough position s 6 an d 6′ (or position 5 of pyrim idin e) by
acetylen e, diacetylen e, vin ylen e an d eth ylen e8 as well as para- or meta-
ph en ylen e9 lin kers. Such carbon lin kers con n ected to carbon atom s of th e
h eterocycles were expected to be stable towards en zym atic degradation .
Sign ifican t cytostatic activity h as been foun d8 in som e bis(purin -6-yl)-
acetylen es an d diacetylen es, wh ile th e partially an d fully saturated deriva-
tives, ph en ylen e-lin ked an alogues as well as th e purin e-pyrim idin e con ju-
gates were in active. Takin g also in to accoun t th e h igh cytostatic activity of
Natural nucleobase-triplets (examples):
R
N
CH3
N
R
N
N
H
O
N
H
O
N
N
H
H
H
N
N
N
N
H
H
O
N
O
N
CH3
CH3
N
N
N
R
N
R
H
H
N
N
N
N
O
O
R
R
T.AT triplet
A.AT triplet
Covalent triplet analogues:
O
R
O
N
N
N
N
N
N
O
N
O
N
N
N
O
N
N
N
R
N
N
R
N
N
N
N
N
N
N
N
N
O
O
N
O
N
N
N
R
R
FIG. 1
Structure of n atural Hoogsteen triplets an d th eir covalen t an alogues un der study
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

DNA Base-Pairs and Triplets
1225
6-arylpurin e ribon ucleosides10, we h ave decided to prepare a n ew type of
Hoogsteen triplets an alogues con sistin g of ben zen e rin gs bearin g th ree
n ucleobases (purin es or pyrim idin es). A prelim in ary com m un ication on th e
syn th esis of 1,3,4- an d 1,3,5-tris(purin -6-yl)ben zen es h as recen tly been pub-
lish ed11. Th e presen t full-paper gives th e results in full details an d exten ds
th e study towards th e an alogues bearin g purin e an d/or pyrim idin e rin gs
(Fig. 1).
R'
H
for R' = SiMe3
ii)
Cl
N
i)
N
N
N
N
N
N
N
N
N
N
N
R
R
R
2a-2c
3a-3c
1a-1e
R
R
R'
2,3
a
1
a
b
c
d
e
Bn
THP
Me
SiMe3
SiMe3
SiMe3
Bn
THP
Me
i) R'C≡CH, Pd(PPh3)4, CuI, Et3N, DMF, 120 °C, 7 h;
ii) NH3/MeOH, r.t., 3 h
b
c
Bn Bu
Bn Ph
SCHEME 1
Our origin al approach 11 to th e triplet an alogues relies on cyclotrim er-
ization of properly fun ction alized alkyn es. Substituted 6-eth yn ylpurin es 1
are readily available by th e Son ogash ira couplin g of 6-ch loropurin e deriva-
tives 2 with alkyn es (an alogy to th e kn own 12 procedure for 6-alkyn yl-
9-ph en ylpurin e derivatives). Th e term in al acetylen es 3 were prepared in
good yields in two steps con sistin g in th e couplin g of 2 with (trim eth yl-
silyl)acetylen e followed by desilylation usin g m eth an olic am m on ia12
(Sch em e 1). An alogous approach h as been applied to th e syn th esis of
5-eth yn yl-1,3-dim eth yluracil (4) startin g from 5-iodo-1,3-dim eth yluracil (5)
(Sch em e 2). Wh ile th e couplin g of 5 with (trim eth ylsilyl)acetylen e to give
th e kn own 13 TMS-protected acetylen e 6 proceeded quite well, subsequen t
desilylation of 6 usin g m eth an olic am m on ia did n ot lead to th e term in al
acetylen e 4 but to a com plex m ixture of oligo- an d/or polym ers. Equally
un successful were attem pts usin g KF/m eth an ol or K2CO3/m eth an ol. Fin ally
we h ave succeeded m akin g use of TBAF in THF wh ich gave th e desired acet-
ylen e 4 in a m oderate yield of 51%.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1226
Hocek, Stará, Starý, Dvořáková:
O
N
H
O
N
SiMe3
ii)
O
N
I
i)
N
N
N
O
O
O
6
4
5
i) Me3SiC≡CH, Pd(PPh3)4, CuI, Et3N, DMF, 100 °C, 8h; ii) TBAF,THF, 0 °C then r.t., 5 h
SCHEME 2
Th e 9-substituted 6-eth yn ylpurin es 3a an d/or 3b were used as m odel
substrates for a series of cyclotrim erization experim en ts varyin g tran sition
m etal catalysts an d reaction con dition s accordin g to literature proto-
cols14–19 (Sch em e 3). Wh ile TaCl5 in ben zen e, th e Grubbs catalyst
Ph CH=Ru(PCy3)Cl2 in dich lorom eth an e, Pd(PPh 3)4 or Ni(CO)2(PPh 3)2 in
tetrah ydrofuran , an d th e Wilkin son catalyst Rh Cl(PPh 3)3 in eth an ol left th e
startin g alkyn es 3a an d/or 3b un touch ed even un der reflux for a prolon ged
reaction period, th e use of CpCo(CO)2 in decan e at 140 °C with th e con -
com itan t visible ligh t irradiation led to a very com plex m ixture con tain in g
on ly traces of th e target products 7 or 8 (accordin g to th e MS an alysis of th e
crude reaction m ixture). Th e observed low reactivity of th ese alkyn es to-
wards cyclotrim erization m igh t be explain ed in term s of a substan tial de-
crease of th e electron den sity at th e triple bon d due to th e presen ce of th e
electron -deficien t purin e m oiety.
Th e situation dram atically ch an ged wh en applyin g a h igh ly reactive
Ni(COD)2 (COD = cycloocta-1,4-dien e) com plex to en force th e trim er-
ization (Sch em e 3, Table I). Th e THP-protected 3b with a catalytic am oun t
of Ni(COD)2 an d PPh 3 afforded an 8 : 1 m ixture of tris(purin -9-yl)ben zen es
7b an d 8b in good yield (74%; Table I, En try 2). Both regioisom ers were
successfully separated by colum n ch rom atograph y. Th e use of a stoich io-
m etric am oun t of Ni(COD)2 (1/3 equivalen t) with out PPh 3 as a stabilizin g
ligan d gave a 4 : 1 m ixture of 7b an d 8b in m oderate yield (41%; Table I,
En try 3). Com poun d 7b was deprotected by m ean s of wet Dowex 50X8
(H+ form ) in m eth an ol20 to give th e free purin e derivative 7f in 70% yield.
An alogously, th e reaction of th e Bn -protected com poun d 3a with
Ni(COD)2 an d PPh 3 afforded th e un sym m etrical 1,2,4-tris(purin -9-yl)ben -
zen e 7a in 50% yield, wh ile th e sym m etrical product 8a could n ot be
isolated in a pure form (Table I, En try 1). Sim ilarly, th e reaction of
6-eth yn yl-9-m eth ylpurin e (3c) gave th e un sym m etrical trim er 7c in 43%
yield, wh ile th e sym m etrical trim er 8c was just detected in spots an d could
n ot be isolated (Table I, En try 4).
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

DNA Base-Pairs and Triplets
1227
R
R
N
N
N
N
H
N
N
N
NiL2, ligand
N
N
N
N
N
R
N
N
R
N
N
N
N
N
N
+
N
N
N
N
N
N
R
N
3
R
N
3, 7, 8
R
R
8
a
b
Bn
THP
Me
H
7
Dowex 50 (H+)
c
7f
SCHEME 3
TABLE I
Cyclotrim erization s of 6-eth yn ylpurin es 1 an d 3
Yield, %
Startin g
com poun d
En try
Catalyst, ligan d (m ole %)
7
8
1
2
3
4
5
6
7
3a
3b
3b
3c
1d
1e
3a
Ni(COD)2 (20), PPh 3 (50)
Ni(COD)2 (20), PPh 3 (50)
Ni(COD)2 (33)
50
66
33
43
5a
8
8
Ni(COD)2 (20), PPh 3 (50)
Ni(COD)2 (20), PPh 3 (50)
Ni(COD)2 (20), PPh 3 (50)
NiCp2 (20), PPh 3 (50)
traces
on ly traces of cyclotrim ers
on ly traces of cyclotrim ers
35
traces
a
Com poun d 8a was n ot isolated in a pure form (yield estim ated from 1H NMR of th e crude
reaction m ixture).
Th e disubstituted acetylen es 1d an d 1e were also subjected to th e
cyclotrim erization usin g catalytic am oun t of Ni(COD)2 an d PPh 3. However,
th e reaction was very sluggish to form th e trim ers in trace am oun ts on ly
(MS detection ) even after prolon ged reaction tim es an d/or at elevated tem -
perature (up to 60 °C).
An alogously to th e purin es, th e 5-eth yn yl-1,3-dim eth yluracil (4) was also
cyclotrim erized usin g Ni(COD)2 to give th e un sym m etrical trim er 9 in 25%
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1228
Hocek, Stará, Starý, Dvořáková:
yield (Sch em e 4). Th is reaction was m uch slower th an th ose of purin e de-
rivatives, probably due to low solubility of th e startin g com poun d 4 in THF.
Furth erm ore, we h ave also tried a co-cyclotrim erization of purin e 3a with
pyrim idin e 4 in order to get m ixed purin e-pyrim idin e con jugates lin ked by
a ben zen e rin g. Th e co-cyclotrim erization of 3a an d 4 in th e 1 : 1 ratio gave
th e un sym m etrical purin e h om o-trim er 7a as m ajor product (25% yield),
accom pan ied by th e un reacted 4 (30%) an d a com plex m ixture of h om o-
an d h eterotrisubstituted ben zen es. Out of th is m ixture, on ly 1,2-bis-
(9-ben zylpurin -6-yl)-4-(1,3-dim eth yluracil-5-yl)ben zen e (10) was success-
fully isolated in pure form in 5% yield. Th is result was n ot surprizin g wh en
takin g in to accoun t th e lower solubility an d/or reactivity of 4. Neverth eless,
com poun d 10 could be con sidered as th e first an alogue of th e real Pu·Py·Pu
Hoogsteen triplet.
O
H
Ni(COD)2, PPh3
O
O
N
N
N
N
N
H
N
O
O
O
N
4
N
O
O
N
9
N
N
Ni(COD)2, PPh3
N
Bn
3a
Bn
Bn
Bn
N
N
N
N
N
N
N
N
N
N
O
N
N
N
N
N
N
+
complex mixture of
other derivatives and
isomers
O
+
N
N
N
N
(5%)
10
N
7a (25%)
N
Bn
Bn
SCHEME 4
Recen tly, th e use of stable n ickelocen e (NiCp2) in stead of extrem ely air-
sen sitive Ni(COD)2 in couplin g an d cyclization reaction s h as been de-
scribed21. In an alogy, we h ave used NiCp2/PPh 3 catalytic system for th e
cyclotrim erization of 3a to obtain th e un sym m etrical trim er 7a in 35%
yield (Table I, En try 7). Th ough th e yield was som ewh at lower, due to m uch
easier h an dlin g of NiCp2 in com parison to Ni(COD)2, th is altern ative
m eth od could be also advan tageously used for th e trim erization of
6-eth yn ylpurin es.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

DNA Base-Pairs and Triplets
1229
Wh ile th e NMR spectra of th e 1,3,5-trisubstituted ben zen e 8b displayed
very sim ple pattern s due to th eir h igh sym m etry, th e spectra of th e
1,2,4-trisubstituted derivatives 7a–7c an d 7f con tain ed distin ct sets of sig-
n als belon gin g to each purin e rin g. Possessin g ch irality cen ters at th e THP
protectin g groups, com poun ds 7b an d 8b h ave to occur as m ixtures of
diastereoisom ers. In spite of th is, th ese m aterials were ch rom atograph ically
1
h om ogen eous. Alth ough in th e H an d 13C NMR spectra of 7b som e sign als
of th e proxim al purin es were split, th e spectra of 8b exh ibited a perfect
sym m etry. Furth erm ore, n o h in dered rotation was observed in dyn am ic
NMR experim en ts with com poun ds 7a, 7b an d 8b even at low tem peratures
(down to –70 °C) in dicatin g th at th ese com poun ds could easily adopt a pla-
n ar con form ation wh ich is n ecessary for in tercallation in to DNA.
In con clusion , th e Ni-catalyzed cyclotrim erization s of 6-eth yn ylpurin es 3
provided th e un sym m etrical (m ajor) an d sym m etrical (m in or) tri(purin -
6-yl)ben zen es 7 an d 8 as th e n ovel Hoogsteen -triplet an alogues. Th is
m eth od is especially suitable for th e syn th esis of 1,2,4-tris(purin -6-yl)-
ben zen es from term in al eth yn ylpurin es. An alogous cyclotrim erization of
5-eth yn yl-1,3-dim eth yluracil (4) gave also th e un sym m etrical trim er 9. Th e
co-trim erization of 3a an d 4 led to a com plex m ixture con tain in g th e un -
sym m etrical purin e h om o-trim er 7a as a m ajor product an d, th erefore, it is
n ot applicable for th e preparative syn th esis of m ixed trim ers con tain in g
both purin e an d pyrim idin e substituen ts. Th e target triplet-an alogues 7–10
were tested for th eir cytostatic activity (in h ibition of cell growth of th e fol-
lowin g cell cultures: m ouse leukem ia L1210 cells (ATCC CCL 219), m urin e
L929 cells (ATCC CCL 1), human cervix carcinoma HeLaS3 cells (ATCC CCL 2.2)
an d h um an T lym ph oblastoid CCRF-CEM cell lin e (ATCC CCL 119)). Non e
of the com pounds exhibited any considerable activity in these assays22.
EXPERIMENTAL
Un less stated oth erwise, solven ts were evaporated at 40 °C/2 kPa an d com poun ds were dried
at 60 °C/2 kPa over P2O5. Meltin g poin ts were determ in ed on a Kofler block an d are un cor-
rected. NMR spectra were m easured on a Bruker AMX-3 400 (400 MHz for 1H an d 100.6 MHz
for 13C), a Bruker DRX 500 (500 MHz for 1H an d 125.8 MHz for 13C). Ch em ical sh ifts (δ) are
given in ppm , couplin g con stan ts (J) in Hz. TMS was used as in tern al stan dard. Mass spectra
were m easured on a ZAB-EQ (VG An alytical) spectrom eter usin g FAB (ion ization by Xe, ac-
celeratin g voltage 8 kV, glycerol m atrix). Toluen e was degassed in vacuo an d stored over m o-
lecular sieves un der argon . DMF was distilled from P2O5, degassed in vacuo an d stored over
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1230
Hocek, Stará, Starý, Dvořáková:
m olecular sieves un der argon . THF was refluxed with Na an d ben zoph en on e un der argon
an d fresh ly distilled prior to use.
Son ogash ira Reaction s of 6-Ch loropurin es with (Trim eth ylsilyl)acetylen e.
Gen eral Procedure
DMF (10 m l) an d Et3N (4 m l) were added th rough septum to an argon purged flask con tain -
in g a 6-ch loropurin e 2 (6 m m ol), TMSC≡CH (980 m g, 10 m m ol), CuI (100 m g, 0.5 m m ol)
an d Pd(PPh 3)4 (100 m g, 0.087 m m ol). Th e m ixture was th en stirred at 120 °C for 7 h an d
left at am bien t tem perature overn igh t. Th e solven ts were evaporated in vacuo an d th e products
isolated by colum n ch rom atograph y on silica gel (150 g, eth yl acetate/ligh t petroleum 1 : 2).
9-Benzyl-6-[(trimethylsilyl)ethynyl]purine (1a). Wh ite crystals, yield 70%; m .p. 126–128 °C
(h eptan e/CH2Cl2). EI MS, m/z (rel.%): 306 (60) [M], 291 (42) [M – Me], 91 (100). 1H NMR
(400 MHz, CDCl3): 0.33 (s, 9 H, (CH3)3Si); 5.44 (s, 2 H, CH2); 7.27–7.36 (m , 5 H, H-arom .);
8.09 (s, 1 H, H-8); 8.95 (s, 1 H, H-2).13C NMR (100 MHz, CDCl3): –0.44 ((CH3)3Si); 47.38
(CH2); 98.47, 105.46 (C≡C); 127.74, 128.68, 129.16 (CH-arom .); 134.22 (C-arom .); 134.84
(C-5); 141.30 (C-6); 145.21 (C-8); 151.82 (C-4); 152.70 (C-2). For C17H18N4 (306.4) calcu-
lated: 66.63% C, 5.92% H, 18.28% N; foun d: 66.48% C, 6.01% H, 18.26% N.
9-(Tetrahydropyran-2-yl)-6-[(trimethylsilyl)ethynyl]purine (1b ). Wh ite crystals, yield 78%;
m .p. 129–131 °C (h eptan e/CH2Cl2). EI MS, m/z (rel.%): 300 (37) [M], 272 (20), 217 (100)
[M + H – THP], 201 (63), 85 (95) [THP]. 1H NMR (500 MHz, CDCl3): 0.34 (s, 9 H, (CH3)3Si);
1.75–2.17 (m , 6 H, CH2); 3.79 (dt, 1 H, J = 2.5, 11.7, H-5′a); 4.19 (m , 1 H, H-5′b); 5.80 (dd,
1 H, J = 10.4, 2.4, H-1′); 8.34 (s, 1 H, H-8); 8.92 (s, 1 H, H-2). 13C NMR (75 MHz, CDCl3):
0.225 ((CH3)3Si); 23.31, 25.44, 32.46 (CH2); 69.47 (CH2-5′); 82.77 (CH-1′); 99.07, 106.08
(C≡C); 135.02 (C-5); 141.88 (C-6); 143.88 (C-8); 151.58 (C-4); 153.11 (C-2). For C15H20N4OSi
(300.4) calculated: 59.97% C, 6.71% H, 18.65% N; foun d: 59.61% C, 6.74% H, 18.41% N.
9-Methyl-6-[(trimethylsilyl)ethynyl]purine (1c). Brown ish crystals, yield 75%; m .p. 155–158 °C
(h eptan e/CH2Cl2). EI MS, m/z (rel.%): 230 (42) [M], 215 (100). IR (KBr): ν = 2 960, 2 157,
1 581, 1 505, 1 443, 1 394, 1 326 cm –1 1H NMR (400 MHz, CDCl3): 0.32 (s, 9 H, (CH3)3Si);
.
3.90 (s, 3 H, CH3); 8.08 (s, 1 H, H-8); 8.91 (s, 1 H, H-2). 13C NMR (100.6 MHz, CDCl3): –0.45
((CH3)3Si); 29.84 (CH3); 98.45, 105.31 (C≡C); 134.15 (C-5); 141.10 (C-6); 145.86 (CH-8);
152.06 (C-4); 152.52 (CH-2). For C11H14N4Si (230.3) calculated: 57.36% C, 6.13% H, 24.32% N;
foun d: 57.04% C, 6.16% H, 24.23% N.
9-Benzyl-6-(phenylethynyl)purine23 (1d ). Brown ish oil th at solidified to crystals on dryin g,
yield 71%; m .p. 114–117 °C. EI MS, m/z (rel.%): 310 (73) [M], 91 (89), 57 (100), 43 (86).
1H NMR (400 MHz, CDCl3): 5.48 (s, 2 H, CH2Ph ); 7.26–7.75 (m , 10 H, H-arom .); 8.13 (s,
1 H, H-8); 9.00 (s, 1 H, H-2). 13C NMR (100 MHz, CDCl3): 47.41 (CH2Ph ); 84.13, 98.41
(C≡C); 121.38 (C-arom .); 127.81, 128.39, 128.70, 129.19, 129.88, 132.66 (CH-arom .); ca 134,
134.83 (C-5 an d C-arom .); 141.90, 151.66 (C-4 an d C-6); 145.00 (CH-8); 152.77 (CH-2).
EI HRMS, foun d: 310.1215; C20H14N4 [M] requires: 310.1218. For C20H14N4 (310.4) calcu-
lated: 77.40% C, 4.55% H, 18.05% N; foun d: 77.23% C, 4.68% H, 17.70% N.
9-Benzyl-6-(hex-1-yn-1-yl)purine (1e). Brown ish oil th at solidified to crystals on dryin g,
yield 77%; m .p. 71–73 °C. EI MS, m/z (rel.%): 290 (40) [M], 261 (20), 248 (56), 199 (22), 91
(100). 1H NMR (400 MHz, CDCl3): 0.95 (t, 3 H, J = 7.3, CH3); 1.48–1.56 (m , 2 H, CH2);
1.65–1.73 (m , 2 H, CH2); 2.60 (t, 2 H, J = 7.1, CH2C≡); 5.44 (s, 2 H, CH2Ph ); 7.26–7.37 (m ,
5 H, H-arom .); 8.06 (s, 1 H, H-8); 8.93 (s, 1 H, H-2). 13C NMR (100 MHz, CDCl3): 13.56
(CH3); 19.61, 22.10, 30.13 (CH2); 47.34 (CH2Ph ); 76.05, 101.65 (C≡C); 127.79, 128.66,
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

DNA Base-Pairs and Triplets
1231
129.16 (CH-arom .); 134.19, 134.90 (C-5 an d C-arom .); 142.54, 151.45 (C-4 an d C-6); 144.73
(CH-8); 152.75 (CH-2). EI HRMS, foun d: 290.1512; C18H18N4 [M] requires: 290.1531. For
C
18H18N4 (290.4) calculated: 76.46% C, 6.25% H, 19.30% N; foun d: 74.19% C, 6.32% H,
18.92% N.
Desilylation of 6-[(Trim eth ylsilyl)eth yn yl]purin es. Gen eral Procedure
A TMS derivative 1a–1c (10 m m ol) was treated with saturated eth an olic am m on ia (100 m l)
for 3 h , th e solven t was evaporated an d th e products were isolated by colum n ch rom atogra-
ph y on silica gel (150 g, eth yl acetate).
9-Benzyl-6-ethynylpurine (3a ). W h ite crystals, yield 65%; m .p. 158–160 °C (h eptan e/
CH2Cl2). EI MS, m/z (rel.%): 234 (84) [M]; 91 (100). 1H NMR (500 MHz, CDCl3): 3.72 (s, 1 H,
≡CH); 5.46 (s, 2 H, CH2); 7.30–7.37 (m , 5 H, H-arom .); 8.12 (s 1 H, H-8); 8.99 (s, 1 H, H-2).
13C NMR (125 MHz, CDCl3): 47.47 (CH2); 77.94 (C≡); 86.08 (≡CH); 127.89, 128.78, 129.23
(CH-arom .); 134.70 (C-5); 140.68 (C-6); 145.46 (C-8); 151.75 (C-4); 152.73 (C-2). For
C
14H10N4 (234.2) calculated: 71.78% C, 4.30% H, 23.92% N; foun d: 71.46% C, 4.37% H,
23.79% N.
6-Ethynyl-9-(tetrahydropyran-2-yl)purine (3b). Wh ite crystals, yield 70%; m .p. 105–108 °C
(h eptan e/CH2Cl2). EI MS, m/z (rel.%): 228 (26) [M], 200 (18) [M + H – THP], 145 (48), 85
(100) [THP]. 1H NMR (400 MHz, CDCl3): 1.69–2.19 (m , 6 H, CH2); 3.72 (s, 1 H, ≡CH); 3.80
(dt, 1 H, J = 2.6, 11.5, H-5′a); 4.16–4.22 (m , 1 H, H-5′b); 5.81 (dd, 1 H, J = 10.2, 2.4, H-1′);
8.36 (s, 1 H, H-8); 8.95 (s, 1 H, H-2). 13C NMR (75 MHz, CDCl3): 23.31, 25.44, 32.46 (CH2);
69.51 (CH2-5′); 78.59 (≡C); 82.83 (CH-1′); 86.75 (≡CH); 135.67 (C-5); 141.30 (C-6); 144.19
(C-8); 151.55 (C-4); 153.16 (C-2). For C12H12N4O (228.3) calculated: 63.15% C, 5.30% H,
24.55% N; foun d: 63.19% C, 5.01% H, 24.26% N.
6-Ethynyl-9-methylpurine (3c). W h ite crystals, yield 77%; m .p. 220–222 °C (h eptan e/
CH2Cl2). EI MS, m/z (rel.%): 158 (100) [M]. IR (KBr): ν = 3 155, 3 097, 2 101, 1 579, 1 504,
1 437, 1 425, 1 345 cm –1 1H NMR (400 MHz, CDCl3): 3.71 (s, 1 H, ≡CH); 3.94 (s, 3 H, CH3);
.
8.13 (s, 1 H, H-8); 8.97 (s, 1 H, H-2). 13C NMR (100.6 MHz, CDCl3): 29.87 (CH3); 77.95 (C≡);
85.96 (≡CH); 134.78 (C-5); 140.55 (C-6); 146.11 (CH-8); 152.03 (C-4); 152.57 (CH-2). For
C8H6N4 (158.1) calculated: 60.75% C, 3.82% H, 35.42% N; foun d: 60.49% C, 3.79% H,
35.09% N.
1,3-Dim eth yl-5-[(trim eth ylsilyl)eth yn yl]pyrim idin e-2,4-(1H,3H)-dion e (6)
DMF (9 m l) an d Et3N (3 m l) were added to an argon purged flask con tain in g 5 (2.66 g,
10 m m ol), TMSC≡CH (2.1 g, 21 m m ol), CuI (160 m g, 5.2 m m ol) an d Pd(PPh 3)4 (160 m g,
0.14 m m ol). Th e m ixture was stirred un der argon at 100 °C for 8 h . Th en th e solven ts were
evaporated an d th e residue ch rom atograph ed on a colum n of silica gel (150 g, ligh t petro-
leum /eth yl acetate 1 : 1 to 1 : 2) to give 6 (1.794 g, 76%). M.p. – slow decom position over
180 °C (ref.13 gives m .p. 160–162 °C, n o spectral data were given ). EI MS, m/z (rel%): 236
(36) [M], 221 (100). 1H NMR (400 MHz, CDCl3): 0.19 (s, 9 H, SiMe3); 3.15, 3.30 (2 × s, 2 ×
3 H, N-Me); 8.16 (s, H-6). 13C NMR (100 MHz, CDCl3): –0.15 (SiMe3); 27.68, 36.57 (N-Me);
96.03, 96.42, 98.11 (C≡C an d C-5); 148.81 (CH-6); 150.47, 161.20 (C=O-2 an d C=O-4).
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1232
Hocek, Stará, Starý, Dvořáková:
5-Eth yn yl-1,3-dim eth ylpyrim idin e-2,4-(1H,3H)-dion e (4)
A 1 M solution of TBAF·3H2O in THF (10 m l, 10 m m ol) was added to silyl derivative 6
(470 m g, 2 m m ol) at 0 °C an d th e m ixture was stirred at room tem perature for 5 h . Th en
th e solven t was evaporated, th e residue was applied on to a colum n of silica gel (50 g) an d
th e product was eluted with a gradien t of eth yl acetate/MeOH (10 : 0 to 8 : 2). Th e crude
product was crystallized from dich lorom eth an e/h eptan e. Yield 166 m g (51%); m .p.
218–221 °C. EI MS, m/z (rel.%): 164 (100) [M], 107 (25), 79 (28), 66 (15), 42 (93). 1H NMR
(400 MHz, CDCl3): 3.17 (s, 1 H, ≡CH); 3.38, 3.42 (2 × s, 2 × 3 H, 2 × CH3); 7.50 (H-6).
13C NMR (100 MHz, CDCl3): 28.38, 37.37 (N-CH3); 74.92 (C≡); 81.52 (≡CH); ca 142.5 (very
weak, C-5); 146.39 (CH-6); 150.85 (C=O-2); 161.74 (C=O-4). For C8H8N2O2 (164.2) calcu-
lated: 58.53% C, 4.91% H, 17.06% N; foun d: 58.79% C, 4.98% H, 16.74% N.
Ni-Catalyzed Cyclotrim erization s of Acetylen es. Gen eral Procedure
Method A: A 0.065 M solution of Ni(COD)2 in THF (6 m l, 0.4 m m ol) was added dropwise
th rough a septum to a stirred solution of an acetylen e (500 m g, 2 m ol) an d PPh 3 (262 m g,
1 m ol) in THF (10 m l) un der argon (CAUTION! exoth erm ic reaction ). Th e m ixture was
stirred at room tem perature for 5 h an d th en th e solven t was evaporated. Products were sep-
arated by colum n ch rom atograph y of th e residue on silica gel (50 g, ligh t petroleum /eth yl
acetate/m eth an ol (1 : 1 : 0 → 0 : 1 : 0 → 0 : 9 : 1)). For yields of th e particular products, see
Table I.
Method B: THF (10 m l) was added to an argon purged flask con tain in g acetylen e 3a
(1 m m ol), NiCp2 (76 m g, 0.4 m m ol) an d PPh 3 (420 m g, 1.6 m m ol). Th e m ixture was stirred
at room tem perature overn igh t. Th e work-up an d isolation was perform ed in th e sam e way
as in m eth od A to afford product 7a in 35% yield.
1,3,4-Tris(9-benzylpurin-6-yl)benzene (7a). Yellow m icrocrystals; m .p. 155–158 °C (EtOH/
toluen e). FAB MS, m/z (rel.%): 703 (15) [M + H], 91 (100). 1H NMR (500 MHz, CDCl3): 5.40
(s, 4 H, CH2Ph ); 5.49 (s, 2 H, CH2Ph ); 7.24–7.36 (m , 15 H, H-Ph ); 7.84, 7.88, 8.11 (3 × s, 3 ×
1 H, H-8-Pu); 8.47 (d, 1 H, J = 8.2, H-6-ben zen e); 8.69, 8.73, 9.08 (3 × s, 3 × 1 H, H-2-Pu);
9.20 (dd, 1 H, J = 8.2, 1.8, H-5-ben zen e); 9.64 (d, 1 H, J = 1.6, H-3-ben zen e). 13C NMR
(100 MHz, CDCl3): 47.15 (CH2); 127.70, 128.47, 129.06, 131.06, 132.52, 133.23 (CH-arom .);
131.93, 135.19, 136.14, 136.94, 137.79 (CH-arom . an d C-5); 144.16, 144.50 (CH-8); 151.96,
152.54 (CH-2); 151.71, 153.50, 157.36, 157.94 (C-4 an d C-6). FAB HRMS, foun d: 703.2778;
C
42H31N12 [M + H] requires: 703.2795. For C42H30N12·1/2 toluen e (748.8) calculated:
72.98% C, 4.58% H, 22.45% N; foun d: 72.65% C, 4.55% H, 22.26% N.
1,2,4-Tris[9-(tetrahydropyran-2-yl)purin-6-yl]benzene (7b). Yellow am orph ous solid. FAB MS,
m/z (rel.%): 685 (9) [M + H], 601 (3) [M + H – THP], 517 (7) [M + 2 H – 2 THP], 433 (100)
[M + 3 H – 3 THP], 85 (42) [THP]. 1H NMR (500 MHz, CDCl3, particular purin e rin gs desig-
n ated as A, B an d C): 1.60–2.20 (m , 18 H, CH2); 3.80, 4.19 (2 × m , 6 H, CH2O); 5.79 (d, 2 H,
J = 9.6, OCHN); 5.88 (d, 1 H, J = 9.9, OCHN); 8.14 (s, 1/2 H), 8.16 (s, 1 H) an d 8.19 (s,
1/2 H, H-8-PuA,B); 8.36 (s, 1 H, H-8-PuC); 8.46 (d, 1 H, J = 8.2, H-6-ben zen e); 8.68, 8.70,
8.72, 8.74 (4 × s, 4 × 1/2 H, H-2-PuA,B); 9.07 (s, 1 H, H-2-PuC); 9.21 (d, 1 H, J = 8.2,
H-5-ben zen e); 9.60 (s, 1 H, H-3-ben zen e).13C NMR (100 MHz, APT, CDCl3): 23.51, 25.60,
32.43, 32.58 (4 × CH2); 69.48 (CH2O); 82.60, 82.67, 82.76 (OCHN); 131.87 (C-5-ben zen e);
132.25, 132.81 (C-5-PuA,B,C); 133.37 (C-6-ben zen e); 134.11 (C-3-ben zen e); 136.88
(C-2-ben zen e); 137.67 (C-4-ben zen e); 138.54 (C-1-ben zen e); 142.84, 142.90, 143.12
(C-8-PuA,B,C); 151.79 (C-4-PuA,B,C); 152.58 (C-2-PuA,B); 153.13 (C-2-PuC); 154.36
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DNA Base-Pairs and Triplets
1233
(C-6-PuC); 158.13 (C-6-PuA); 158.77 (C-6-PuB). FAB HRMS, foun d: 685.3128; C36H37N12O3
[M + H] requires: 685.3112.
1,3,5-Tris[9-(tetrahydropyran-2-yl)purin-6-yl]benzene (8b). Yellow am orph ous solid. FAB MS,
m/z (rel.%): 685 (27) [M + H], 601 (12) [M + H – THP], 517 (13) [M + 2 H – 2 THP], 433
(100) [M + 3 H – 3 THP]. 1H NMR (400 MHz, CDCl3): 1.65–2.22 (m , 18 H, CH2); 3.84 (dt,
3 H, J = 2.2, 11.5, CH2Oa); 4.22 (d, 3 H, J = 11.3, CH2Ob); 5.90 (dd, 3 H, J = 10.2, 2.4,
OCHN); 8.43 (s, 3 H, H-8-Pu); 9.15 (s, 3 H, H-2-Pu); 10.36 (s, 3 H, H-ben zen e).13C NMR
(100 MHz, APT, CDCl3): 23.54, 25.64, 32.65 (3 × CH2); 69.55 (CH2O); 82.77 (OCHN); 132.21
(C-5-Pu); 134.51 (CH-ben zen e); 137.51 (C-ben zen e); 143.29 (C-8-Pu); 152.62 (C-6-Pu);
153.33 (C-2-Pu); 155.13 (C-4-Pu). FAB HRMS, foun d: 685.3135; C36H37N12O3 [M + H] re-
quires: 685.3112.
1,3,4-Tris(9-methylpurin-6-yl)benzene (7c). Yellowish powder; m .p. 195–199 °C (EtOH/
toluen e). EI MS, m/z (rel.%): 474 (18) [M], 446 (17), 210 (15), 129 (35), 57 (100). 1H NMR
(500 MHz, CDCl3): 3.87 (s, 6 H, CH3); 3.95 (s, 3 H, CH3); 7.91 (d, 1 H, J = 9.5, H-ben zen e);
8.12, 8.20, 8.67, 8.72, 9.07, 9.59 (6 × s, 6 × 1 H, H-Pu); 8.43 (d, 1 H, J = 7.9, H-ben zen e);
9.16–9.21 (m , 1 H, H-ben zen e). 13C NMR (100 MHz, CDCl3): 29.74, 29.86 (CH3); 131.15,
132.57, 133.23 (CH-ben zen e); 131.32, 131.88, 131.93 (C-5-Pu); 136.14, 136.96, 137.81
(C-ben zen e); 144.97, 145.17, 145.36 (CH-8-Pu); 151.85, 151.93, 152.45 (CH-2-Pu); 152.01,
152.09, 153.03, 153.46, 157.30, 157.89 (C-4 an d C-6). EI HRMS, foun d: 474.1759; C24H18N12
[M] requires: 474.1777.
1,2,4-Tris(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)benzene (9). Obtain ed in
43% yield from 4 (reaction tim e 12 h ). Yellow am orph ous solid. FAB MS, m/z (rel.%): 493
(21) [M + H], 279 (30), 75 (100). 1H NMR (500 MHz, CDCl3): 3.25 (s, 3 H); 3.29 (s, 3 H);
3.30 (s, 3 H); 3.32 (s, 6 H); 3.40 (s, 3 H, all CH3); 7.30 (d, 1 H, J = 7.8, H-arom .); 7.51 (s, 1 H,
H-6-U); 7.60–7.64 (m , 3 H, 2 × H-arom . an d H-6-U); 8.05 (s, 1 H, H-6-U). 13C NMR
(125.8 MHz, CDCl3): 27.63, 27.72, 36.30, 36.32, 36.47 (all CH3); 110.73, 111.86, 112.21,
132.45, 132.73, 133.39, 150.87, 151.09, 161.54, 161.60, 161.66 (C-arom .); 127.03, 130.29,
130.66, 142.64, 142.85 (CH-arom .). FAB HRMS, foun d: 493.1864; C24H25N6O6 [M+H] re-
quires: 493.1836.
Co-cyclotrim erization of 3a an d 4
Co-cyclotrim erization of 3a (234 m g, 1 m m ol) an d 4 (164 m g, 1 m m ol) in presen ce of
Ni(COD)2 an d PPh 3 was perform ed in th e sam e way as described above (m eth od A). A col-
um n ch rom atograph y gave 7a (59 m g, 25%), un reacted 4 (49 m g, 30%) an d a com plex m ix-
ture of oth er products wh ich was re-ch rom atograph ed to give com poun d 10 (16 m g, 5%).
1,2-Bis(9-benzylpurin-6-yl)-4-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)benzene
(10). Yellowish am orph ous solid. FAB MS, m/z (rel.%): 633 (9) [M + H], 279 (12), 91 (100).
1H NMR (500 MHz, CDCl3): 3.43, 3.48 (2 × s, 2 × 3 H, CH3-U); 5.39 (s, 4 H, CH2Ph ); 7.25–36
(m , 10 H, H-arom .); 7.54 (s, 1 H, H-6-U); 7.83, 7.85 (2 × s , 2 × 1 H, H-8-Pu); 7.95 (dd, 1 H,
J = 8.2, 1.3, H-5-ben zen e); 8.29 (d, 2 H, J = 8.2, H-6-ben zen e); 8.31 (d, 2 H, J = 1.3,
H-3-ben zen e); 8.65, 8.70 (2 × s, 2 × 1 H, H-2-Pu). 13C NMR (125.8 MHz, CDCl3): 28.28,
37.20 (CH3); 47.19 (CH2Ph ); 113.23 (C-5-U); 127.73, 128.52, 129.09 (CH-arom .-Bn ); 129.53
(C-5-ben zen e); 131.32 (C-3-ben zen e); 131.77 (C-5-Pu); 134.52, 135.00, 135.21, 135.91
(C-arom .); 141.19 (CH-6-U); 144.12 (CH-8-Pu); 151.71 (C=O-2-U an d C-4-Pu); 152.01
(CH-2-Pu); 157.42, 157.85 (C-6-Pu); 161.97 (C=O-4-U). FAB HRMS, foun d: 633.2457;
C
36H29N10O2 [M + H] requires: 633.2475.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1234
Hocek, Stará, Starý, Dvořáková:
1,2,4-Tris(purin -6-yl)ben zen e (7e)
Dowex 50X8 (H+ form , 50 m g) was added to
a
solution of com poun d 7b (120 m g,
0.18 m m ol) in 96% aqueous EtOH (20 m l) an d th e m ixture was refluxed for 3 h (TLC
sh owed com pletion of th e reaction ). Th en th e resin was filtered off an d wash ed with h ot
EtOH (20 m l), saturated eth an olic am m on ia (10 m l) an d EtOH (10 m l). Th e collected fil-
trates were evaporated an d th e residue crystallized from EtOH. Yield 70 m g (90%). Wh ite
m icrocrystals; m .p. 319–322 °C. FAB MS, m/z (rel.%): 433 (100) [M + H]. 1H NMR (500 MHz,
DMSO-d6): 8.36 (d, 1 H, J = 8.1, H-6′′); 8.40 (s, 1 H, H-8A); 8.45 (s, 1 H, H-8B); 8.51 (s, 1 H,
H-2A); 8.59 (s, 1 H, H-8C); 8.61 (s, 1 H, H-2B); 8.97 (s, 1 H, H-8C); 9.21 (dd, 1 H, J = 1.3,
8.1, H-5′′); 9.50 (d, 1 H, J = 1.2, H-3′′). 13C NMR (125 MHz, DMSO-d6): 129.27 (C-5A,B);
129.85 (C-5′′); 130.64 (C-5C); 132.00 (C-6′′); 132.19 (C-3′′); 136.29 (C-2′′); 137.09 (C-1′′);
137.51 (C-4′′); 145.46 (C-8A); 145.74 (C-8B); 148.12 (C-8C); 149.80 (C-6C); 150.86 (C-2A);
151.10 (C-2B,C); 154.27 (C-6A); 154.61 (C-4A); 154.85 (C-4B); 155.12 (C-6B); 156.46 (C-4C).
For C21H12N21·2EtOH (524.5) calculated: 57.24% C, 4.61% H, 32.04% N; foun d: 57.37% C,
4.25% H, 31.78% N. FAB HRMS, foun d: 433.1337; C21H13N12 [M + H] requires: 433.1386.
This work is a part of a research project Z4 055 905. It was supported by the Grant Agency of the
Czech Republic (grants No. 203/00/0036 to M. H. and No. 203/02/0248 to I. S.). The cytostatic activ-
ity was studied by Dr I. Votruba whose contribution is gratefully acknowledged. The authors’ thanks
are also due to Ms K. Havlíčková for excellent technical assistance.
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13. Hirota K., Kitade Y., Isobe Y., Maki Y.: Heterocycles 1987, 26, 355.
14. Co catalysis; review: a) Vollhardt K. P. C.: Angew. Chem., Int. Ed. Engl. 1984, 23, 539;
recent example: b) Stará I. G., Starý I., Kollárovič A., Teplý F., Šaman D., Tichý M.: J. Org.
Chem. 1998, 63, 4046.
15. Rh catalysis: a) Grigg R., Scott R., Stevenson P. J.: J. Chem. Soc., Perkin Trans. 1 1988,
1357; b) Neeson S. J., Stevenson P. J.: Tetrahedron 1989, 45, 6239.
16. Ta catalysis: Štěpnička P., Císařová I., Sedláček J., Vohlídal J., Polášek M.: Collect. Czech.
Chem. Commun. 1997, 62, 1577; and references therein.
17. Ru catalysis; recent examples: a) Blechert S., Peters J.-U.: Chem. Commun. 1997, 1983;
b) Roy R., Das S. K.: Tetrahedron Lett. 1999, 40, 4015.
18. Ni catalysis; recent examples: a) Sato Y., Nishimata T., Mori M.: J. Org. Chem. 1994, 59,
6133; b) Sato Y., Ohashi K., Mori M.: Tetrahedron Lett. 1999, 40, 5231; c) Stará I. G.,
Starý I., Kollárovič A., Teplý F., Vyskočil Š., Šaman D.: Tetrahedron Lett. 1999, 40, 1993.
19. Pd catalysis; review: a) Maitlis P. M.: Acc. Chem. Res. 1976, 9, 93; recent example:
b) Yamamoto Y., Nagata A., Itoh K.: Tetrahedron Lett. 1999, 40, 5035.
20. Hocek M., Holý A.: Collect. Czech. Chem. Commun. 1995, 60, 1386.
21. Leadbeater N. F.: J. Org. Chem. 2001, 66, 7539.
22. Votruba I.: Unpublished results.
23. Bakkestuen A. K., Gundersen L.-L., Langli G., Liu F. S., Nolsoe J. M. J.: Bioorg. Med. Chem.
Lett. 2000, 10, 1207.
Czech. Chem. Commun. (Vol. 67) (2002)