Cobalt-induced synthesis of 6-(pyridin-2-yl)purines by microwave-enhanced [2+2+2] cyclotrimerization

Article abstract of DOI:10.1002/ejoc.200800205

A novel, efficient, and atom-economic methodology for the preparation of a large series of diversely substituted (pyridin-2-yl)purines has been developed. Thus, microwave-enhanced [2+2+2] cyclotrimerization of 6-(diynyl)purines with nitriles in the presence of a stoichiometric or catalytic amount of [CpCo(CO)₂] afforded the corresponding products in good yields. The reactions carried out with various alkyl, aryl, and heteroaryl cyanides poceeded with exclusive regioselectivity, affording 6-(pyridin-2-yl)purines. In an analogous manner, [2+2+2] cyclotrimerizations of 1,8-bis(purinyl)-1,7-octadiynes with nitriles were conducted, yielding 1,4-bis(purin-6-yl)-5,6,7,8- tetrahydroisoquinolines. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800205

FULL PAPER
DOI: 10.1002/ejoc.200800205
Cobalt-Induced Synthesis of 6-(Pyridin-2-yl)purines by Microwave-Enhanced
[2+2+2] Cyclotrimerization
[b]
[b]
[b]
Pavel Turek,[a,b] Michal Hocek,* Radek Pohl, Blanka Klepetárová, and
ˇ
Martin Kotora*[a,b]
Keywords: Cyclotrimerization / Cobalt / Pyridines / Purines / Microwave reactions
A novel, efficient, and atom-economic methodology for the
preparation of a large series of diversely substituted (pyridin-
heteroaryl cyanides poceeded with exclusive regioselectivity,
affording 6-(pyridin-2-yl)purines. In an analogous manner,
2-yl)purines has been developed. Thus, microwave-en- [2+2+2] cyclotrimerizations of 1,8-bis(purinyl)-1,7-octadiynes
hanced [2+2+2] cyclotrimerization of 6-(diynyl)purines with
nitriles in the presence of a stoichiometric or catalytic amount
of [CpCo(CO)2] afforded the corresponding products in good
yields. The reactions carried out with various alkyl, aryl, and
with nitriles were conducted, yielding 1,4-bis(purin-6-yl)-
5,6,7,8-tetrahydroisoquinolines.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
statics with moderate antiviral activity. As the mechanism
of action is not yet known, one way to gain more insight
into the structure–activity relationships (SARs) of this class
of compounds is to synthesize a larger series of modified
derivatives by adding additional structural features onto the
pyridine ring. Herein, we would like to report a pathway
for the synthesis of new 6-pyridylpurines based on cobalt-
induced cyclotrimerization under microwave conditions.
Introduction
The cyclotrimerization of alkynes catalyzed by transi-
tion-metal compounds is a convenient method for assemb-
ling aromatic molecules with a high degree of complexity
within a single step under mild reaction conditions.[1] Since
the seminal work of Wakatsuki and Yamazaki[2] and
Vollhardt and Bergman[3] this process has also been ex-
tended to cobalt-catalyzed reactions of alkynes with sub-
strates bearing unsaturated C–N bonds such as nitriles,
opening up a straightforward and atom-economic route for
the synthesis of heteroaromatics.[1,4,5] The synthetic attrac-
tion of this method is supported by its numerous applica-
Results and Discussion
We have demonstrated that substituted 6-arylpurines can
tions in the synthesis of natural compounds.[5] Nonetheless, be prepared by a transition-metal-catalyzed [2+2+2] cyclo-
its potential has not been exhausted yet and could inspire trimerization of 6-alkynylpurines with alkynes or diynes un-
the development of new, biologically active compounds.
der mild reaction conditions.[8] Clearly, the same strategy
6-Arylpurines and their derivatives exhibit a broad spec- can be envisioned for the synthesis of 6-heteroarylpurines.
trum of biological activities, including antitumor, antiviral, Generally, there are two possible cyclotrimerization ap-
antimycobacterial, and receptor-modulating activities.[6] proaches to 6-(pyridin-2-yl)purines (Scheme 1): (i) Reaction
Several purine ribonucleosides bearing five- or six-mem- of 6-cyanopurines with α,ω-diynes and (ii) reaction of purin-
bered heterocycles in the 6-position possess significant cyto- yldiynes with nitriles (Scheme 1). The former was attempted
static and anti-HCV activity.[7] Among them, the 6-(pyr- by studying the reactions of 9-benzyl-6-cyanopurine[9] with
idin-2-yl)purine nucleoside is one of the most active cyto- diverse diynes catalyzed by [CpCo(CO)2].[1a,3] However,
none of the reactions gave any cyclotrimerization product
probably due to the electron-withdrawing effect of the
for New Antivirals and Antineoplastics, Faculty of Science, purine moiety on the CN group. Therefore we decided to
[a] Department of Organic and Nuclear Chemistry, and the Centre
Charles University,
pursue the latter approach starting from purinyldiynes.
Hlavova 8, 12843 Praha 2, Czech Republic
Interestingly, the synthesis of the starting diynes 1 was
not as simple a task as had initially been assumed. Al-
though the Sonogashira reaction[10] of 6-halopurines with
terminal alkynes has been reported to proceed well to give
6-alkynylpurines in good yields,[11] the same reaction in-
volving α,ω-diynes often furnished the corresponding
monopurinyldiynes in rather low yields. Thus, the coupling
Fax: +420-221-951-326
E-mail: kotora@natur.cuni.cz
[b] Institute of Organic Chemistry and Biochemistry, Academy of
Sciences of the Czech Republic, Gilead Sciences & IOCB Re-
search Center,
Flemingovo n. 2, 16610 Praha 6, Czech Republic
E-mail: hocek@uochb.cas.cz
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 3335–3343
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3335

P. Turek, M. Hocek, R. Pohl, B. Klepetárˇová, M. Kotora
FULL PAPER
the Co complex to increase the yield, but 4aa was obtained
in just 43% yield. The use of a mixture of the complex
with a stabilizing ligand (PPh3) gave exactly the same result.
Although these results were not encouraging, we found that
heating of the reaction mixture accompanied by light irradi-
ation in mesitylene resulted in a considerable improvement
of the product yields. The results of the cyclotrimerizations
of various nitriles (Scheme 3) with 1a are presented in
Table 1 (conditions A). Thus 4aa was isolated in 74% yield
when the reaction was conducted in excess PhCN as sol-
vent. Cyclotrimerizations with other nitriles such as 3c, 3e,
3f, and 3i were carried out in mesitylene and the corre-
sponding pyridylpurines 4ac, 4ae, 4af, and 4ai were ob-
tained in reasonable isolated yields of 56, 37, 36, and 58%,
respectively. Interestingly, the reaction with acetonitrile 3h
did not yield the desired product.
Scheme 1. Retrosynthetic analysis of [2+2+2] cyclotrimerization
approaches to 6-(pyridin-2-yl)purines.
reactions of benzyl- or THP-protected 6-chloropurines with
1,7-octadiyne were carried out initially in DMF, but the
corresponding products 1a (28%) or 1b (35%) along with
small amounts of the hitherto unreported 1,8-bis(purinyl)-
1,7-octadiynes 2a (14%) or 2b (19%) were formed in rather
low yields. Nonetheless, after considerable effort we found
that the use of MeCN as solvent and copper-free reaction
conditions allowed the synthesis of 6-octadiynylpurines 1a
(benzyl protecting group) and 1b (THP protecting group)
in reasonable yields of 53 and 58% yields, respectively
(Scheme 2). In addition, 1,8-bis(purinyl)-1,7-octadiynes 2a
and 2b were obtained in increased yields of 25 and 28%,
respectively. The dipropargyl ether derivative 1c was pre-
pared under the same conditions in a low yield of 17%;
note that under the former conditions it was obtained in
only 8% yield. When 6-iodo-9-benzylpurine was coupled
with 1,7-octadiyne under the above-mentioned conditions,
compounds 2a and 2b were obtained in yields of 66 and
27%, respectively.
Scheme 3. Cyclotrimerization of 1 with nitriles 3 to yield pyridyl-
purines 4.
Table 1. Thermal- and microwave-initiated cyclotrimerization of
1a,1b with nitriles 3 in the presence of [CpCo(CO)2].
Nitrile
Purine
Yield [%][a]
Purine
% Yield[a]
B[c]
A[b]
B[c]
3a
3b
3c
3d
3e
3f
3g
3h
3i
4aa
4ac
74[d]
77[d]
4ba
4bb
4bc
4bd
4be
4bf
89[d]
29
30
57
40
56
39
4ae
4af
4ag
4ah
4ai
37
36
34
39
47
36
0
58
71[e]
53[f]
4bh
4bi
50[e]
50[f]
[a] Isolated yields. [b] Conditions A: [CpCo(CO)2] (100 mol-%), hν,
140 °C, mesitylene unless otherwise noted. [c] Conditions B:
[CpCo(CO)2] (100 mol-%), MW irradiation, 200 °C, THF unless
otherwise noted. [d] In PhCN. [e] In MeCN. [f] In EtCN.
Scheme 2. Synthesis of octadiynylpurines 1a–1c and bis(purinyl)-
octadiynes 2a and 2b.
Initially we tried to cyclotrimerize 6-octadiynyl-9-ben-
Nonetheless, a desire to shorten the reaction times (usu-
zylpurine (1a) with an excess of benzonitrile (3a) in the ally 6 or more hours) prompted us to look for new reaction
presence of a catalytic amount of [CpCo(CO)2] (20 mol-%) conditions. It has been shown before that “CpCo” is the
under standard thermal conditions (140 °C, 6 h). However, active species involved in the cyclotrimerization process and
the product 4aa was obtained in only 22% yield. The reac- its formation is caused by CO dissociation from the mother
tion was also carried out with a stoichiometric amount of complex.[4a] It is well known that microwave irradiation has
3336
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3335–3343

Cobalt-Induced Synthesis of 6-(Pyridin-2-yl)purines
positive effects on the course of various reactions.[12] It is
It has been shown before that “CpCo” is the species in-
most likely that its effect on the enhancement of CO disso- volved in the cyclotrimerization reaction and its formation
ciation from [CpCo(CO)2] is the underlying strategy for its is caused by CO dissociation from the mother complex.[4a]
successful application in the cyclotrimerizations of alkynes In this regard it is reasonable to assume that the increased
with nitriles to pyridines reported by us[13] and others.[14] In reaction rate of cyclotrimerization is related to the enhance-
this regard we were interested to know whether its applica- ment of CO dissociation by microwave irradiation.
tion could also be successful for the above-mentioned cyclo-
Bis(purinyl)octadiynes 2a and 2b were also subjected
trimerizations. Gratifyingly, cyclotrimerization under mi- to the above-mentioned cyclotrimerization protocol
crowave irradiation proceeded successfully in all cases (Scheme 5). Reaction of the benzyl-protected substrate 2a
within 10 min to give the corresponding pyridylpurines 4ay with benzonitrile (3a) and acetonitrile (3h) afforded the 2,5-
in 34–77% isolated yields (Table 1, conditions B). The bis(purinyl)pyridines 5aa and 5ah in reasonable yields of 31
yields of the pyridines obtained were in the range of those and 33%, respectively. Similar results were obtained with
obtained under light irradiation. However, it is noteworthy the THP-protected substrate 2b in its reactions with benzo-
that under these conditions it was possible to carry out the nitrile (3a) and 4-trifluorobenzonitrile (3d); the correspond-
cyclotrimerization of acetonitrile 3h to afford 4ah in a good ing 2,5-bis(purinyl)pyridines 5ba and 5bd were isolated in
71% yield.
42 and 28%, respectively.
Next, the cyclotrimerization was carried out with the
synthetically more attractive THP-protected purine deriva-
tive 1b under identical conditions (Table 1). The corre-
sponding THP-protected pyridylpurines 4by were obtained
in good-to-excellent yields (30–89%). The structure 4ba was
confirmed by single-crystal X-ray analysis (Figure 1). In ad-
dition, the cyclotrimerization of the dipropargyl ether deriv-
ative 1c with benzonitrile 3a to pyridylpurine 4ca under the
same reaction conditions was successfully carried out
(Scheme 4).
Scheme 5. Cyclotrimerization of bis(purinyl)diynes 2 with nitriles 3
to terpyridines 5.
Although, the early results obtained from the thermal-
and light-initiated reactions did not provide strong support
for the idea of developing a catalytic cyclotrimerization re-
action using [CpCo(CO)2], we were curious as to whether
the use of microwave irradiation would prove otherwise.
Thus, the cyclotrimerizations of 6-octadiynyl-9-benzylpu-
rine (1a) and 6-octadiynyl-9-(tetrahydropyranyl)purine (1b)
with nitriles 3 were carried out in the presence of a catalytic
amount of [CpCo(CO)2] (20 mol-%) under microwave irra-
diation (Table 2). Gratifyingly, in all cases the yields of the
corresponding products 4ay and 4by were comparable to
those obtained with a stoichiometric amount of the catalyst
or even better. The most pronounced improvement was ob-
served for the cyclotrimerization of acetonitrile (3h) and
propionitrile (3i) for which the 6-pyridylpurines 4ah, 4ai,
and 4bh were isolated in 75, 64, and 61% yields, respec-
tively.
Figure 1. ORTEP drawing of 4ba. Thermal ellipsoids are drawn at
the 50% probability level.
Note that the application of a recently published pro-
cedure for the cyclotrimerization of diynes with nitriles cat-
alyzed by a system composed of [CoCl2·6H2O]/dppe/Zn[4d]
for the reaction of 1b with 3a afforded only a small amount
of the expected product 4ab (18%, as determined by 1H
NMR of an inseparable mixture of the product and diyne).
Scheme 4. Cyclotrimerization of 1c with 3a to 4ca.
Eur. J. Org. Chem. 2008, 3335–3343
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3337

P. Turek, M. Hocek, R. Pohl, B. Klepetárˇová, M. Kotora
FULL PAPER
Table 2. Microwave-initiated catalytic cyclotrimerization of nitriles prompt a revision of previous unsuccessful attempts to
3 with 1a and 1b.[a]
carry out transition-metal-mediated or -catalyzed [2+2+2]
Nitrile
Purine
% Yield[b]
79[c]
Purine
% Yield[b]
cycloaddition reactions. Although, the prepared com-
pounds did not exhibit any interesting biological activity,
these results could provide useful information for the fur-
ther elaboration of the pyridine ring of the most active 6-
pyridylpurines.
3a
3b
3c
3d
3e
3f
3g
3h
3i
4aa
4ba
4bb
4bc
4bd
4be
4bf
91[c]
32
43
46
42
4ac
31
4ae
4af
4ag
4ah
4ai
39
42
47
42
Experimental Section
75[d]
64[e]
4bh
61[d]
General: All reaction under microwave irradiation were carried in
1
a microwave reactor Biotage Initiator (300 W). H and 13C NMR
[a] Conditions C: [CpCo(CO)2] (20 mol-%), MW irradiation,
200 °C, THF unless otherwise noted. [b] Isolated yields. [c] In
PhCN. [d] In MeCN. [e] In EtCN.
spectra were recorded with a Bruker AVANCE 400, AVANCE 500,
or AVANCE 600 spectrometer. Mass spectra were recorded with a
ZAB-SEQ (VG-Analytical) instrument. Infrared spectra were re-
corded with a Bruker IFS 55 spectrometer. 1,7-Octadiyne and
CpCo(CO)2 were purchased from Aldrich.
This clearly indicates the superiority of the above-men-
tioned procedure. In addition, an attempt to cyclotrimerize
the same substrates by catalysis with [Cp*RuCl(cod)][15] did
not yield pyridylpurine 4ab.
Finally, two selected THP-protected pyridylpurines, 4ba
and 4bd, were deprotected to the free bases 6a and 6d in
good 70 and 67% isolated yields, respectively (Scheme 6).
General Procedure for the Cross-Coupling Reactions of 6-Chloro-
purine with Diynes. Method B: (The results obtained by Method A
are presented in the Supporting Information.) Acetonitrile
(18 mL), diyne (12 mmol), and triethylamine (2.5 mL) were added
to an argon-purged mixture of 9-benzyl-6-chloro- or 6-chloro-9-
(tetrahydropyran-2-yl)purine (6 mmol), PPh3 (63 mg, 0.24 mmol),
and [Pd(OAc)2] (27 mg, 0.12 mmol) and the mixture was stirred at
70 °C overnight. The solvents were evaporated under reduced pres-
sure and the residue was purified by chromatography on silica gel
column.
9-Benzyl-6-(octa-1,7-diyn-1-yl)-9H-purine (1a) and 1,8-Bis(9-benzyl-
9H-purin-6-yl)octa-1,7-diyne (2a): Column chromatography on sil-
ica gel (hexane/EtOAc, 1:1) afforded 1006 mg (53%) of 1a as a
yellowish solid and further elution (EtOAc/MeOH, 10:1) gave
390 mg (25%) of 2a as a brownish solid. Recrystallization of 1a
from EtOAc/heptane gave yellowish crystals.
1
1a: M.p. 94–95 °C (EtOAc/heptane). Rf (EtOAc) = 0.54. H NMR
Scheme 6. Deprotection of 4 leading to free bases 6.
(400 MHz, CDCl3): δ = 1.75, 1.85 (2 m, 2ϫ2 H, 4Ј-H and 5Ј-H),
1.95 (t, J8Ј,6Ј = 2.7 Hz, 1 H, 8Ј-H), 2.26 (td, J6Ј,5Ј = 6.9, J6Ј,8Ј
=
In vitro cytostatic activity tests of some representative
examples of the prepared 6-pyridylpurines were performed
using the following cell cultures: Human cervix carcinoma
HeLa S3 cells (ATCC CCL 2.2), human T lymphoblastoid
CCRF-CEM cell line (ATCC CCL 119), and human pro-
myelocytic leukemia HL60 cells (ATCC CCL 240). Unfor-
tunately, none of the prepared pyridylpurines showed any
desirable activity. On the other hand two of the starting
alkynes, 1c (HeLa, IC50 = 3–4 µ; CEM, IC50 = 1.2–1.6 µ)
and 2a (HeLa, IC50 = 1.2–1.8 µ), were found to exhibit
interesting levels of activity.
2.7 Hz, 2 H, 6Ј-H), 2.65 (t, J3Ј,4Ј = 6.9 Hz, 2 H, 3Ј-H), 5.45 (s, 2 H,
CH2-Ph), 7.27–7.40 (m, 5 H, Ph), 8.07 (s, 1 H, 8-H), 8.93 (s, 1 H,
2-H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 17.94 (CH2-6Ј),
19.45 (CH2-3Ј), 27.00 (CH2-4Ј), 27.55 (CH2-5Ј), 47.36 (CH2Ph),
68.66 (CH-8Ј), 76.33 (C-1Ј), 83.89 (C-7Ј), 100.75 (C-2Ј), 127.80
(CH-m-Ph), 128.68 (CH-p-Ph), 129.18 (CH-o-Ph), 134.22 (C-5),
134.86 (C-i-Ph), 142.33 (C-6), 144.81 (CH-8), 151.47 (C-4), 152.74
(CH-2) ppm. IR (CHCl ): ν = 3308, 2234, 1584, 1498, 1405,
˜
3
1329 cm–1. MS (FAB): m/z (%) = 315 (40) [M + H]+, 91 (100).
HRMS (FAB): calcd. for C20H19N4 [M + H]+ 315.1610; found
315.1617. C20H18N4: C 76.41, H 5.77, N 17.82; found C 76.09, H
5.78, N 17.37.
2a: M.p. 198–201 °C. Rf (EtOAc/MeOH, 5:1) = 0.50. 1H NMR
(400 MHz, CDCl3): δ = 1.95 (m, 4 H, 4Ј-H), 2.68 (m, 4 H, 3Ј-H),
5.44 (s, 4 H, CH2Ph), 7.29 (m, 4 H, o-Ph-H), 7.31–7.39 (m, 6 H,
m,p-Ph-H), 8.06 (s, 2 H, 8-H), 8.92 (s, 2 H, 2-H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 19.49 (CH2-3Ј), 27.22 (CH2-4Ј), 47.34
(CH2Ph), 76.47 (C-1Ј), 100.67 (C-2Ј), 127.79 (CH-o-Ph), 128.66
(CH-p-Ph), 129.17 (CH-m-Ph), 134.23 (C-5), 134.88 (C-i-Ph),
142.32 (C-6), 144.80 (CH-8), 151.46 (C-4), 152.73 (CH-2) ppm. IR
Conclusions
In conclusion, we have shown that various 6-pyridyl-
purines can be conveniently synthesized by cobalt-mediated
or -catalyzed cyclotrimerization of diynylpurines with ni-
triles under microwave conditions. In some cases it was even
possible to carry out the reaction with substrates that did
not react under thermal of photochemical conditions. From
a synthetic point of view, the above-mentioned results pro-
vide new insights into the cyclotrimerization reactions of
(CHCl ): ν = 2996, 2234, 1584, 1498, 1444, 1405, 1329 cm–1. MS
˜
3
(FAB): m/z (%) = 523 (13) [M + H]+, 91 (100). HRMS (FAB):
calcd. for C32H27N8 [M + H]+ 523.2359; found 523.2368.
6-(Octa-1,7-diyn-1-yl)-9-(tetrahydropyran-2-yl)-9H-purine (1b) and
heterocyclic alkyne substrates with nitriles and it could also 1,8-Bis[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]octa-1,7-diyne (2b):
3338
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3335–3343

Cobalt-Induced Synthesis of 6-(Pyridin-2-yl)purines
Column chromatography on silica gel (hexane/EtOAc, 1:1) afforded
1064 mg (58%) of 1b a yellowish oil and further elution (EtOAc/
MeOH, 10:1) afforded 2b as a yellowish oil, which after co-evapo-
ration with acetone gave 422 mg (28%) of a white foam.
Procedure with Nitrile 3 as Solvent (Method C2): Diynylpurine 1
(0.4 mmol) was placed in a vial filled with argon. Then nitrile 3
(4 mL) and the cobalt catalyst [CpCo(CO)2] (11 µL, 0.08 mmol)
were added to the starting material under argon. The vial was
placed in the microwave reactor and irradiated for 10 min. Then
the solvent was evaporated under reduced pressure and the residue
was purified by chromatography on silica gel to give the corre-
sponding product 4.
1b: Rf (EtOAc) = 0.54. 1H NMR (600 MHz, CDCl3): δ = 1.64–1.89
(m, 7 H, 4Ј-H, 5Ј-H and CH2-THP), 1.96 (t, J8Ј,6Ј = 2.7 Hz, 1 H,
8Ј-H), 2.03–2.19 (m, 3 H, CH2-THP), 2.27 (td, J6Ј,5Ј = 7.1, J6Ј,8Ј
=
2.7 Hz, 2 H, 6Ј-H), 2.65 (t, J3Ј,4Ј = 7.1 Hz, 2 H, 3Ј-H), 3.79 (td, J
= 11.8, 2.6 Hz, 1 H, CHaHbO-THP), 4.19 (ddt, J = 11.8, 4.4,
1.9 Hz, 1 H, CHaHbO-THP), 5.80 (dd, J = 10.5, 2.5 Hz, 1 H, CHO-
THP), 8.31 (s, 1 H, 8-H), 8.90 (s, 1 H, 2-H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 17.93 (CH2-6Ј), 19.44 (CH2-3Ј), 22.68 and
24.78 (CH2-THP), 26.98 (CH2-4Ј), 27.54 (CH2-5Ј), 31.79 (CH2-
THP), 68.65 (CH-8Ј), 68.84 (CH2O-THP), 76.29 (C-1Ј), 82.02
(CHO-THP), 83.89 (C-7Ј), 100.75 (C-2Ј), 134.39 (C-5), 142.29 (C-
6), 142.80 (CH-8), 150.59 (C-4), 152.52 (CH-2) ppm. IR (CHCl3):
9-Benzyl-6-(3-phenyl-5,6,7,8-tetrahydroisoquinolin-1-yl)-9H-purine
(4aa) (Method C2): Column chromatography on silica gel (hexane/
EtOAc/CHCl3, 5:5:1) afforded 132 mg (79 %) of a white solid.
Recrystallization from CH2Cl2/heptane gave white crystals, m.p.
225–226 °C (CH2Cl2/heptane). 1H NMR (500 MHz, CDCl3): δ =
1.76 (m, 2 H, 7Ј-H), 1.86 (m, 2 H, 6Ј-H), 2.75 (t, Jvic = 6.4 Hz, 2
H, 8Ј-H), 2.92 (t, Jvic = 6.2 Hz, 2 H, 5Ј-H), 5.49 (s, 2 H, CH2-Bn),
7.30–7.42 (m, 8 H, Bn and m + p-H-Ph), 7.54 (s, 1 H, 4Ј-H), 7.96
(m, 2 H, o-H-Ph), 8.08 (s, 1 H, 8-H), 9.13 (s, 1 H, 2-H) ppm. 13C
NMR (125.7 MHz, CDCl3): δ = 22.08 (CH2-6Ј), 22.72 (CH2-7Ј),
25.88 (CH2-8Ј), 29.63 (CH2-5Ј), 47.35 (CH2-Bn), 121.81 (CH-4Ј),
127.12 (CH-o-Ph), 127.99, 128.32, 128.47, 128.64, and 129.17 (CH-
Ph), 130.96 (C-8Јa), 132.26 (C-5), 135.05 (C-i-Bn), 139.58 (C-i-Ph),
144.88 (CH-8), 148.01 (C-4Јa), 152.32 (C-4), 152.51 (CH-2), 152.88
ν = 3308, 2233, 1586, 1443, 1333, 1326, 1087, 1046 cm–1. MS
˜
(FAB): m/z (%) = 309 (22) [M + H]+, 225 (100). HRMS (FAB):
calcd. for C18H21N4O [M + H]+ 309.1715; found 309,1724.
1
2b: Rf (EtOAc/MeOH, 5:1) = 0.40. H NMR (400 MHz, CDCl3):
δ = 1.64–1.87 (m, 6 H, CH2-THP), 1.96 (m, 4 H, 4Ј-H), 2.01–2.20
(m, 6 H, CH2-THP), 2.69 (m, 4 H, 3Ј-H), 3.79 (td, J = 11.6, 2.6 Hz,
2 H, CHaHbO-THP), 4.19 (ddt, J = 11.6, 4.1, 1.9 Hz, 2 H,
CHaHbO-THP), 5.79 (dd, J = 10.2, 2.5 Hz, 2 H, CHO-THP), 8.30
(s, 2 H, 8-H), 8.89 (s, 2 H, 2-H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 19.49 (CH2-3Ј), 22.68 and 24.80 (CH2-THP), 27.23
(CH2-4Ј), 31.80 (CH2-THP), 68.82 (CH2O-THP), 76.45 (C-1Ј),
82.04 (CHO-THP), 100.65 (C-2Ј), 134.43 (C-5), 142.30 (C-6),
(C-1Ј), 154.37 (C-3Ј), 157.60 (C-6) ppm. IR (CHCl ): ν = 2987,
˜
3
2944, 1591, 1580, 1553, 1500, 1434, 1328, 728, 698 cm–1. MS (EI):
m/z (%) = 417 (91) [M]+, 389 (5), 326 (100), 91 (55). HRMS: calcd.
for C27H23N5 [M]+ 417.1953; found 417.1944. C27H23N5: C 77.67,
H 5.55, N 16.77; found: C 77.22, H 5.45, N 16.58. Rf (hexane/
EtOAc, 1:3) = 0.55.
142.79 (CH-8), 150.60 (C-4), 152.50 (CH-2) ppm. IR (CHCl ): ν =
˜
3
9-Benzyl-6-[3-(4-methoxycarbonylphenyl)-5,6,7,8-tetrahydroisoquin-
olin-1-yl]-9H-purine (4ac) (Method C1): Column chromatography
on silica gel (hexane/EtOAc/CHCl3, 5:5:1) afforded a yellowish so-
lid, which after co-evaporation with acetone formed 59 mg (31%)
of a yellowish foam. Crystallization from CH2Cl2/heptane gave yel-
lowish crystals, m.p. 168–171 °C (CH2Cl2/heptane). Rf (hexane/
EtOAc, 1:3) = 0.50. 1H NMR (400 MHz, CDCl3): δ = 1.73–1.90
(m, 4 H, 7Ј-H and 6Ј-H), 2.76 (t, Jvic = 6.3 Hz, 2 H, 8Ј-H), 2.94 (t,
Jvic = 6.3 Hz, 2 H, 5Ј-H), 3.91 (s, 3 H, CH3O), 5.50 (s, 2 H, CH2-
Ph), 7.35–7.42 (m, 5 H, Ph), 7.60 (s, 1 H, 4Ј-H), 8.06 (s, 4 H, o,m-
C6H4-H), 8.10 (s, 1 H, 8-H), 9.14 (s, 1 H, 2-H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 22.00 and 22.63 (CH2-6Ј and CH2-7Ј),
25.95 (CH2-8Ј), 29.65 (CH2-5Ј), 47.41 (CH2-Ph), 52.05 (CH3O),
122.16 (CH-4Ј), 126.98 (CH-o-C6H4), 128.03 (CH-o-Ph), 128.69
(CH-p-Ph), 129.19 (CH-m-Ph), 129.79 (C-p-C6H4), 129.84 (CH-m-
C6H4), 131.98 (C-8Јa), 132.22 (C-5), 134.99 (C-i-Ph), 143.71 (C-i-
C6H4), 144.99 (CH-8), 148.30 (C-4Јa), 152.38 (C-4), 152.53 (CH-
2), 152.99 (C-3Ј), 153.19 (C-1Ј), 157.28 (C-6), 167.04 (CO) ppm. IR
2995, 2953, 2234, 1585, 1443, 1334, 1326, 1087, 1046 cm–1. MS
(FAB): m/z (%) = 511 (15) [M + H]+, 343 (32), 93 (100). HRMS
(FAB): calcd. for C28H31N8O2 [M + H]+ 511.2570; found 511.2562.
6-[3-(Prop-2-ynyloxy)prop-1-ynyl]-9-(tetrahydropyran-2-yl)-9H-
purine (1c): Column chromatography on silica gel (hexane/EtOAc,
2:3) afforded 300 mg (17%) of a yellowish solid. Recrystallization
from EtOAc/heptane gave colorless crystals, m.p. 80–82 °C (EtOAc/
heptane). 1H NMR (400 MHz, CDCl3): δ = 1.65–1.88 and 2.01–
2.21 (2 m, 2ϫ3 H, CH2-THP), 2.49 (t, J7Ј,5Ј = 2.4 Hz, 1 H, 7Ј-H),
3.80 (td, J = 11.7, 2.7 Hz, 1 H, CHaHbO-THP), 4.20 (ddt, J = 11.7,
4.4, 1.8 Hz, 1 H, CHaHbO-THP), 4.41 (d, J5Ј,7Ј = 2.4 Hz, 2 H, 5Ј-
H), 4.66 (s, 2 H, 3Ј-H), 5.80 (dd, J = 10.3, 2.5 Hz, 1 H, CHO-
THP), 8.34 (s, 2 H, 8-H), 8.94 (s, 2 H, 2-H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 22.67, 24.79, and 31.81 (CH2-THP),
56.88 (CH2-5Ј), 57.03 (CH2-3Ј), 68.87 (CH2O-THP), 75.35 (CH-
7Ј), 78.68 (C-6Ј), 81.49 (C-1Ј), 82.15 (CHO-THP), 93.68 (C-2Ј),
134.57 (C-5), 140.97 (C-6), 143.31 (CH-8), 150.86 (C-4), 152.52
(CHCl ): ν = 2989, 2952, 1718, 1590, 1581, 1500, 1437, 1328, 1281,
˜
(CH-2) ppm. IR (CHCl ): ν = 3308, 2238, 1585, 1443, 1352, 1342,
3
˜
3
1192, 1117, 1107 cm–1. MS (FAB): m/z (%) = 476 (15) [M + H]+,
91 (100). HRMS (FAB): calcd. for C29H25N5O2 [M + H]+ 476.2087;
found 476.2092.
1334, 1087, 1046 cm–1. MS (FAB): m/z (%) = 297 (9) [M + H]+,
185 (27), 93 (100). HRMS (FAB): calcd. for C16H17N4O2 [M +
H]+ 297.1352; found 297.1359. C16H16N4O2: C 64.85, H 5.44, N
18.91; found C 64.81, H 5.39, N 18.65. Rf (EtOAc) = 0.53.
9-Benzyl-6-[3-(furan-2-yl)-5,6,7,8-tetrahydroisoquinolin-1-yl]-9H-
purine (4ae) (Method C1): Column chromatography on silica gel
(hexane/EtOAc/chloroform, 5:5:1) afforded a yellowish oil, which
after co-evaporation with acetone formed 64 mg (39%) of a yellow-
ish foam. Crystallization from CH2Cl2/heptane gave yellowish crys-
tals, m.p. 182–185 °C (CH2Cl2/heptane). Rf (hexane/EtOAc, 1:3) =
General Procedure for the [CpCo(CO)2]-Catalyzed Cyclotrimeri-
zation of 6-Diynylpurines 1 with Nitriles 3 under Microwave Irradia-
tion. Method C: Procedure with THF as Solvent (Method C1): (The
results obtained by Method A and B are presented in the Support-
ing Information.) Diynylpurine 1 (0.4 mmol) was placed in a vial
filled with argon. Then nitrile 3 (2 mmol), THF (4 mL), and the
cobalt catalyst [CpCo(CO)2] (11 µL, 0.08 mmol) were added to the
starting material under argon. Vial was placed into the microwave
reactor and irradiated for 10 min. Then the solvent was evaporated
under reduced pressure and the residue was purified by chromatog-
raphy on silica gel to give the corresponding product 4.
1
0.44. H NMR (400 MHz, CDCl3): δ = 1.77 and 1.83 (2 m, 4 H,
7Ј-H and 6Ј-H), 2.69 (t, Jvic = 6.2 Hz, 2 H, 8Ј-H), 2.89 (t, Jvic
=
6.4 Hz, 2 H, 5Ј-H), 5.49 (s, 2 H, CH2-Ph), 6.45 (dd, J4,3 = 3.4, J4,5
= 1.8 Hz, 1 H, 4-furyl-H), 6.95 (dd, J3,4 = 3.4, J3,5 = 0.8 Hz, 1 H,
3-furyl-H), 7.32–7.42 (m, 5 H, Ph), 7.47 (dd, J5,4 = 1.8, J5,3
=
0.8 Hz, 1 H, 5-furyl-H), 7.51 (s, 1 H, 4Ј-H), 8.07 (s, 1 H, 8-H), 9.13
Eur. J. Org. Chem. 2008, 3335–3343
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3339

P. Turek, M. Hocek, R. Pohl, B. Klepetárˇová, M. Kotora
FULL PAPER
(s, 1 H, 2-H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 21.99 and
29.37 (CH2-5Ј), 30.97 (CH2CH3), 47.34 (CH2-Ph), 122.89 (CH-4Ј),
22.64 (CH2-6Ј and CH2-7Ј), 25.99 (CH2-8Ј), 29.52 (CH2-5Ј), 47.35 127.97 (CH-o-Ph), 128.64 (CH-p-Ph), 129.15 (CH-m-Ph), 129.29
(CH2-Ph), 108.26 (CH-3-furyl), 111.69 (CH-4-furyl), 119.67 (CH- (C-8Јa), 132.07 (C-5), 135.04 (C-i-Ph), 144.83 (CH-8), 147.64 (C-
4Ј), 127.96 (CH-o-Ph), 128.64 (CH-p-Ph), 129.17 (CH-m-Ph),
4Јa), 152.20 and 152.23 (C-4 and C-1Ј), 152.70 (CH-2), 157.71 (C-
130.93 (C-8Јa), 132.21 (C-5), 135.05 (C-i-Ph), 142.78 (CH-5-furyl), 6), 160.02 (C-3Ј) ppm. IR (CHCl ): ν = 2974, 2942, 1592, 1580,
˜
3
144.87 (CH-8), 146.32 (C-3Ј), 147.94 (C-4Јa), 152.33 (C-4), 152.56
1500, 1329 cm–1. MS (FAB): m/z (%) = 370 (100) [M + H]+, 91
(CH-2), 152.91 (C-1Ј), 153.56 (C-2-furyl), 157.26 (C-6) ppm. IR (90). HRMS (FAB): calcd. for C23H24N5 [M + H]+ 370.2032; found
(CHCl ): ν = 2989, 2944, 1593, 1582, 1499, 1329 cm–1. MS (FAB):
370.2039.
˜
3
m/z (%) = 408 (100) [M + H]+. HRMS (FAB): calcd. for
6-(3-Phenyl-5,6,7,8-tetrahydroisoquinolin-1-yl)-9-(tetrahydropyran-
2-yl)-9H-purine (4ba) (Method C2): Column chromatography on
C25H22N5O [M + H]+ 408.1824; found 408,1834.
9-Benzyl-6-[3-(pyridin-4-yl)-5,6,7,8-tetrahydroisoquinolin-1-yl]-9H- silica gel (hexane/EtOAc/CHCl3, 10:10:1) afforded 149 mg (91%)
purine (4af) (Method C1): Column chromatography on silica gel
(EtOAc/MeOH/CHCl3, 10:1:1) afforded a brownish oil, which after
co-evaporation with CHCl3 formed 70 mg (42 %) of a brownish
foam. Crystallization from CH2Cl2/heptane gave brownish crystals,
m.p. 248–253 °C (CH2Cl2/heptane). Rf (EtOAc/MeOH, 5:1) = 0.37.
1H NMR (400 MHz, CDCl3): δ = 1.74–1.91 (m, 4 H, 7Ј-H and 6Ј-
of a yellowish solid. Recrystallization from CH2Cl2/heptane gave
colorless crystals, m.p. 182–187 °C (CH2Cl2/heptane). Rf (hexane/
EtOAc, 2:5) = 0.37. 1H NMR (500 MHz, CDCl3): δ = 1.65–1.89
(m, 7 H, 6Ј,7Ј-H and CH2-THP), 2.06–2.22 (m, 3 H, CH2-THP),
2.70 and 2.75 (2 dt, Jgem = 17.2, Jvic = 6.1 Hz, 2 H, 8Ј-H), 2.92 (t,
Jvic = 6.2 Hz, 2 H, 5Ј-H), 3.83 (td, J = 11.7, 2.6 Hz, 1 H, CHaHbO-
H), 2.77 (t, Jvic = 6.5 Hz, 2 H, 8Ј-H), 2.94 (t, Jvic = 6.2 Hz, 2 H, THP), 4.21 (ddt, J = 11.7, 4.3, 1.9 Hz, 1 H, CHaHbO-THP), 5.88
5Ј-H), 5.51 (s, 2 H, CH2-Ph), 7.34–7.43 (m, 5 H, Ph), 7.62 (s, 1 H, (dd, J = 10.4, 2.8 Hz, 1 H, CHO-THP), 7.33 (m, 1 H, p-H-Ph),
4Ј-H), 7.91 (br. m, 2 H, m-H-Py), 8.11 (s, 1 H, 8-H), 8.67 (br. m, 2 7.39 (m, 2 H, m-H-Ph), 7.54 (s, 1 H, 4Ј-H), 7.96 (m, 2 H, o-H-Ph),
H, o-H-Py), 9.14 (s, 1 H, 2-H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 21.91 and 22.53 (CH2-6Ј and CH2-7Ј), 26.03 (CH2-8Ј),
29.65 (CH2-5Ј), 47.44 (CH2-Ph), 121.36 (CH-m-Py), 122.01 (CH-
4Ј), 128.05 (CH-m-Ph), 128.72 (CH-p-Ph), 129.20 (CH-o-Ph),
8.39 (s, 1 H, 8-H), 9.09 (s, 1 H, 2-H) ppm. 13C NMR (125.7 MHz,
CDCl3): δ = 22.09 (CH2-6Ј), 22.71 (CH2-7Ј), 22.77 and 24.88 (CH2-
THP), 25.84 (CH2-8Ј), 29.64 (CH2-5Ј), 31.89 (CH2-THP), 68.87
(CH2O-THP), 82.05 (CHO-THP), 121.74 (CH-4Ј), 127.12 (CH-o-
132.18 (C-5), 133.07 (C-8Јa), 134.93 (C-i-Ph), 145.08 (CH-8), Ph), 128.31 (CH-p-Ph), 128.46 (CH-m-Ph), 130.94 (C-8Јa), 132.48
146.51 (C-p-Py), 148.59 (C-4Јa), 150.25 (CH-o-Py), 151.32 (C-3Ј), (C-5), 139.59 (C-i-Ph), 142.87 (CH-8), 147.99 (C-4Јa), 151.49 (C-
152.40 (C-4), 152.51 (CH-2), 153.45 (C-1Ј), 156.99 (C-6) ppm. IR 4), 152.36 (CH-2), 152.88 (C-1Ј), 154.35 (C-3Ј), 157.67 (C-6) ppm.
(CHCl ): ν = 2985, 2947, 1591, 1581, 1500, 1329 cm–1. MS (EI):
IR (CHCl ): ν = 2984, 2948, 1591, 1579, 1496, 1434, 1332, 1326,
˜
˜
3
3
m/z (%) = 418 (55) [M]+, 326 (100), 91 (39). HRMS (EI): calcd. for
1086, 1045 cm–1. MS (EI): m/z (%) = 411 (8) [M]+, 327 (95), 224
(27), 57 (100). HRMS (EI): calcd. for C25H25N5O [M]+ 411.2059;
found 411.2080.
C26H22N6 [M]+ 418.1906; found 418.1891.
9-Benzyl-6-[3-(pyridin-3-yl)-5,6,7,8-tetrahydroisoquinolin-1-yl]-9H-
purine (4ag) (Method C1): Column chromatography on silica gel
(EtOAc/MeOH/CHCl3, 10:1:1) afforded a brownish oil, which after
co-evaporation with CHCl3 formed 70 mg (42%) of a yellowish
foam. Crystallization from CH2Cl2/heptane gave yellowish crystals,
m.p. 179–182 °C (CH2Cl2/heptane). Rf (EtOAc/MeOH, 5:1) = 0.37.
1H NMR (600 MHz, CDCl3): δ = 1.78 and 1.87 (2 m, 4 H, 7Ј-H
6-[3-(4-Methoxyphenyl)-5,6,7,8-tetrahydroisoquinolin-1-yl]-9-(tetra-
hydropyran-2-yl)-9H-purine (4bb) (Method C1): Column
chromatography on silica gel (hexane/EtOAc/CHCl3, 10:10:1) af-
forded 57 mg (32%) of a yellowish oil. Crystallization from EtOAc/
heptane gave greyish crystals, m.p. 146–151 °C (EtOAc/heptane).
Rf (EtOAc) = 0.59. 1H NMR (500 MHz, CDCl3): δ = 1.65–1.90
and 6Ј-H), 2.77 (t, Jvic = 6.4 Hz, 2 H, 8Ј-H), 2.94 (t, Jvic = 6.3 Hz, (m, 7 H, 7Ј,6Ј-H and CH2-THP), 2.06–2.23 (m, 3 H, CH2-THP),
2 H, 5Ј-H), 5.51 (s, 2 H, CH2-Ph), 7.33 (br. dd, J5,4 = 7.9, J5,6
=
2.68 and 2.78 (2 dt, Jgem = 17.2, J8Ј,7Ј = 6.0 Hz, 2 H, 8Ј-H), 2.90
(t, J5Ј,6Ј = 6.2 Hz, 2 H, 5Ј-H), 3.82 (s, 3 H, CH3O), 3.83 (td, J =
11.3, 2.3 Hz, 1 H, CHaHbO-THP), 4.21 (ddt, J = 11.3, 4.2, 1.7 Hz,
1 H, CHaHbO-THP), 5.88 (dd, J = 10.6, 2.5 Hz, 1 H, CHO-THP),
4.8 Hz, 1 H, 5-py-H), 7.34–7.41 (m, 5 H, Ph), 7.57 (s, 1 H, 4Ј-H),
8.11 (s, 1 H, 8-H), 8.31 (ddd, J4,5 = 7.9, J4,6 = 2.2, J4,2 = 1.7 Hz, 1
H, 4-py-H), 8.59 (br. m, 1 H, 6-py-H), 9.14 (s, 1 H, 2-H), 9.16 (br.
m, 1 H, 2-py-H) ppm. 13C NMR (151 MHz, CDCl3): δ = 21.94 and 6.92 (m, 2 H, m-C6H4OMe-H), 7.48 (s, 1 H, 4Ј-H), 7.92 (m, 2 H,
22.57 (CH2-6Ј and CH2-7Ј), 25.91 (CH2-8Ј), 29.62 (CH2-5Ј), 47.40 o-C6H4OMe-H), 8.32 (s, 1 H, 8-H), 9.09 (s, 1 H, 2-H) ppm. 13C
(CH2-Ph), 121.80 (CH-4Ј), 123.45 (CH-5-py), 128.01 (CH-o-Ph), NMR (125.7 MHz, CDCl3): δ = 22.11 and 22.74 (CH2-6Ј and CH2-
128.68 (CH-p-Ph), 129.18 (CH-m-Ph), 131.95 (C-8Јa), 132.16 (C-5), 7Ј), 22.77 and 24.86 (CH2-THP), 25.79 (CH2-8Ј), 29.62 (CH2-5Ј),
134.66 (CH-4-py), 134.94 (C-i-Ph), 135.04 (C-3-py), 145.04 (CH-8), 31.87 (CH2-THP), 55.26 (CH3O), 68.87 (CH2O-THP), 82.00
148.25 (CH-2-py), 148.51 (C-4Јa), 149.40 (CH-6-py), 151.53 (C-3Ј), (CHO-THP), 113.82 (CH-m-C6H4OMe), 121.02 (CH-4Ј), 128.30
152.34 (C-4), 152.51 (CH-2), 153.35 (C-1Ј), 157.12 (C-6) ppm. IR (CH-o-C6H4OMe), 130.21 (C-8Јa), 132.29 (C-i-C6H4OMe), 132.43
(CHCl ): ν = 2986, 2946, 1590, 1580, 1500, 1329 cm–1. MS (FAB):
(C-5), 142.82 (CH-8), 147.85 (C-4Јa), 151.43 (C-4), 152.35 (CH-2),
152.67 (C-1Ј), 153.98 (C-3Ј), 157.77 (C-6), 159.95 (C-p-
˜
3
m/z (%) = 419 (100) [M + H]+, 91 (18). HRMS (FAB): calcd. for
C26H23N6 [M + H]+ 419.1984; found 419.1992.
C H OMe) ppm. IR (CHCl ): ν = 2981, 2947, 1610, 1591, 1580,
˜
6 4 3
1515, 1496, 1441, 1332, 1326, 1249, 1207, 1176, 1086, 1045 cm–1.
MS (FAB): m/z (%) = 442 (24) [M + H]+, 358 (72), 57 (100). HRMS
(FAB): calcd. for C26H28N5O2 [M + H]+ 442.2243; found 442.2259.
9-Benzyl-6-(3-ethyl-5,6,7,8-tetrahydroisoquinolin-1-yl)-9H-purine
(4ai) (Method C2): Column chromatography on silica gel (EtOAc/
chloroform, 10:1) afforded 95 mg (64 %) of a yellowish oil. Rf
(EtOAc/MeOH, 10:1) = 0.45. 1H NMR (400 MHz, CDCl3): δ = 6-[3-(4-Methoxycarbonylphenyl)-5,6,7,8-tetrahydroisoquinolin-1-yl]-
1.28 (t, Jvic = 7.6 Hz, 3 H, CH3CH2), 1.72 (m, 2 H, 7Ј-H), 1.81 (m,
2 H, 6Ј-H), 2.63 (t, Jvic = 6.4 Hz, 2 H, 8Ј-H), 2.82 (t, Jvic = 6.8 Hz, chromatography on silica gel (hexane/EtOAc/CHCl3, 10:10:1) af-
2 H, 5Ј-H), 2.83 (q, Jvic = 7.6 Hz, 2 H, CH2CH3), 5.48 (s, 2 H, forded 80 mg (43%) of a yellowish oil. Crystallization from EtOAc/
9-(tetrahydropyran-2-yl)-9H-purine (4bc) (Method C1): Column
CH2-Ph), 7.01 (s, 1 H, 4Ј-H), 7.31–7.41 (m, 5 H, Ph), 8.06 (s, 1 H, heptane gave white crystals, m.p. 204–206 °C (EtOAc/heptane). Rf
1
8-H), 9.11 (s, 1 H, 2-H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = (EtOAc) = 0.62. H NMR (500 MHz, CDCl3): δ = 1.66–1.90 (m,
14.27 (CH3CH2), 22.09 (CH2-6Ј), 22.74 (CH2-7Ј), 25.68 (CH2-8Ј), 7 H, 7Ј,6Ј-H and CH2-THP), 2.07–2.28 (m, 3 H, CH2-THP), 2.71
3340
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3335–3343

Cobalt-Induced Synthesis of 6-(Pyridin-2-yl)purines
and 2.77 (2 dt, Jgem = 17.4, J8Ј,7Ј = 6.5 Hz, 2 H, 8Ј-H), 2.93 (t, J5Ј,6Ј 147.93 (C-4Јa), 151.45 (C-4), 152.39 (CH-2), 152.89 (C-1Ј), 153.57
= 6.2 Hz, 2 H, 5Ј-H), 3.83 (td, J = 11.7, 2.6 Hz, 1 H, CHaHbO- (C-2-furyl), 157.30 (C-6) ppm. IR (CHCl ): ν = 2987, 2948, 1594,
˜
3
THP), 3.92 (s, 3 H, CH3O), 4.22 (ddt, J = 11.7, 4.3, 1.7 Hz, 1 H,
1580, 1497, 1410, 1332, 1326, 1234, 1207, 1087, 1045 cm–1. MS
CHaHbO-THP), 5.88 (dd, J = 10.4, 2.5 Hz, 1 H, CHO-THP), 7.60 (FAB): m/z (%) = 402 (30) [M + H]+, 318 (100). HRMS (FAB):
(s, 1 H, 4Ј-H), 8.07 (m, 4 H, o,m-C6H4COOMe-H), 8.34 (s, 1 H, 8- calcd. for C23H24N5O2 [M + H]+ 402.1930; found 402.1927.
H), 9.10 (s, 1 H, 2-H) ppm. 13C NMR (125.7 MHz, CDCl3): δ =
6-[3-(Pyridin-4-yl)-5,6,7,8-tetrahydroisoquinolin-1-yl]-9-(tetrahydro-
21.99 and 22.59 (CH2-6Ј and CH2-7Ј), 22.76 and 24.85 (CH2-THP),
pyran-2-yl)-9H-purine (4bf) (Method C1): Column chromatography
25.90 (CH2-8Ј), 29.63 (CH2-5Ј), 31.86 (CH2-THP), 52.05 (CH3O),
on silica gel (EtOAc/MeOH/CHCl3, 10:1:1) afforded 78 mg (47%)
68.89 (CH2O-THP), 82.04 (CHO-THP), 122.12 (CH-4Ј), 126.96
of a yellowish oil. Crystallization from CH2Cl2/heptane gave yel-
(CH-o-C6H4COOMe), 129.76 (C-p-C6H4COOMe), 129.83 (CH-m-
lowish crystals, m.p. 179–184 °C (CH2Cl2/heptane). Rf (EtOAc/
C6H4COOMe), 131.94 (C-8Јa), 132.40 (C-5), 143.00 (CH-8), 143.70
MeOH, 5:1) = 0.32. 1H NMR (600 MHz, CDCl3): δ = 1.67–1.90
(C-i-C6H4COOMe), 148.28 (C-4Јa), 151.50 (C-4), 152.37 (CH-2),
(m, 7 H, 7Ј,6Ј-H and CH2-THP), 2.03–2.24 (m, 3 H, CH2-THP),
152.95 (C-3Ј), 153.17 (C-1Ј), 157.32 (C-6), 167.04 (CO) ppm. IR
2.73 and 2.78 (2 dt, Jgem = 17.5, J8Ј,7Ј = 6.3 Hz, 2 H, 8Ј-H), 2.95
(CHCl ): ν = 2952, 2933, 1718, 1591, 1579, 1496, 1437, 1331, 1326,
˜
3
(t, J5Ј,6Ј = 6.3 Hz, 2 H, 5Ј-H), 3.84 (td, J = 11.8, 2.6 Hz, 1 H,
CHaHbO-THP), 4.22 (ddt, J = 11.8, 4.3, 1.9 Hz, 1 H, CHaHbO-
THP), 5.89 (dd, J = 10.5, 2.7 Hz, 1 H, CHO-THP), 7.62 (s, 1 H,
4Ј-H), 7.89 (m, 2 H, 3,5-Py-H), 8.35 (s, 1 H, 8-H), 8.65 (m, 2 H,
2,6-Py-H), 9.11 (s, 1 H, 2-H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 21.89 and 22.49 (CH2-6Ј and CH2-7Ј), 22.78 and 24.89 (CH2-
THP), 25.97 (CH2-8Ј), 29.61 (CH2-5Ј), 31.84 (CH2-THP), 68.90
(CH2O-THP), 82.02 (CHO-THP), 121.24 (CH-3,5-Py), 121.98
(CH-4Ј), 132.35 (C-5), 133.01 (C-8Јa), 143.09 (CH-8), 146.46 (C-4-
Py), 148.56 (C-4Јa), 150.17 (CH-2,6-Py), 151.29 (C-3Ј), 151.51 (C-
1281, 1116, 1107, 1086, 1045 cm–1. MS (FAB): m/z (%) = 470 (6)
[M + H]+, 386 (29), 57 (100). HRMS (FAB): calcd. for C27H28N5O3
[M + H]+ 470.2195; found 470.2188. C27H27N5O3: C 69.07, H 5.80,
N 14.92; found C 68.73, H 5.71, N 14.72.
6-{3-[4-(Trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-1-yl}-
9-(tetrahydropyran-2-yl)-9H-purine (4bd) (Method C1): Column
chromatography on silica gel (hexane/EtOAc/CHCl3, 10:10:1) af-
forded 88 mg (46%) of a colorless oil. Rf (hexane/EtOAc, 2:5) =
0.45. 1H NMR (500 MHz, CDCl3): δ = 1.67–1.90 (m, 7 H, 7Ј,6Ј-H
and CH2-THP), 2.04–2.23 (m, 3 H, CH2-THP), 2.72 and 2.77 (2
dt, Jgem = 17.4, J8Ј,7Ј = 6.4 Hz, 2 H, 8Ј-H), 2.94 (td, J5Ј,6Ј = 6.3,
J5Ј,4Ј = 0.8 Hz, 2 H, 5Ј-H), 3.84 (td, J = 11.9, 2.6 Hz, 1 H,
CHaHbO-THP), 4.22 (ddt, J = 11.9, 4.4, 1.9 Hz, 1 H, CHaHbO-
THP), 5.89 (dd, J = 10.4, 2.3 Hz, 1 H, CHO-THP), 7.58 (t, J4Ј,5Ј
= 0.8 Hz, 1 H, 4Ј-H), 7.65 (m, 2 H, m-C6H4CF3-H), 8.09 (m, 2 H,
o-C6H4CF3-H), 8.34 (s, 1 H, 8-H), 9.10 (s, 1 H, 2-H) ppm. 13C
NMR (125.7 MHz, CDCl3): δ = 21.98 and 22.59 (CH2-6Ј and CH2-
7Ј), 22.77 and 24.86 (CH2-THP), 25.90 (CH2-8Ј), 29.66 (CH2-5Ј),
31.88 (CH2-THP), 68.91 (CH2O-THP), 82.06 (CHO-THP), 122.00
(CH-4Ј), 124.27 (q, JC,F = 272 Hz, CF3), 125.44 (q, JC,F = 4 Hz,
4), 152.35 (CH-2), 153.41 (C-1Ј), 157.02 (C-6) ppm. IR (CHCl ): ν
˜
3
= 2983, 2949, 1594, 1580, 1496, 1441, 1332, 1326, 1086, 1045 cm–1.
MS (FAB): m/z (%) = 413 (38) [M + H]+, 356 (31), 329 (100).
HRMS (FAB): calcd. for C24H25N6O [M + H]+ 413.2090; found
413.2084.
6-(3-Methyl-5,6,7,8-tetrahydroisoquinolin-1-yl)-9-(tetrahydropyran-
2-yl)-9H-purine (4bh) (Method C2): Column chromatography on
silica gel (EtOAc/MeOH/CHCl3, 20:2:1) afforded a yellowish oil,
which after co-evaporation with CHCl3 formed 85 mg (61%) of a
1
white foam. Rf (EtOAc/MeOH, 5:1) = 0.34. H NMR (500 MHz,
CDCl3): δ = 1.65–1.88 (m, 7 H, 7Ј,6Ј-H and CH2-THP), 2.04–2.20
(m, 3 H, CH2-THP), 2.54 (s, 3 H, CH3), 2.60 and 2.66 (2 dt, Jgem
CH-m-C6H4CF3), 127.32 (CH-o-C6H4CF3), 130.20 (q, JC,F
=
32 Hz, C-p-C6H4CF3), 132.04 (C-8Јa), 132.40 (C-5), 142.81 (C-i-
C6H4CF3), 143.04 (CH-8), 148.41 (C-4Јa), 151.52 (C-4), 152.38
(CH-2), 152.66 (C-3Ј), 153.20 (C-1Ј), 157.27 (C-6) ppm. 19F NMR
= 17.1, J8Ј,7Ј = 6.3 Hz, 2 H, 8Ј-H), 2.81 (td, J5Ј,6Ј = 6.3, J5Ј,4Ј
=
0.8 Hz, 2 H, 5Ј-H), 3.82 (td, J = 11.8, 2.6 Hz, 1 H, CHaHbO-THP),
4.21 (ddt, J = 11.8, 4.5, 1.8 Hz, 1 H, CHaHbO-THP), 5.86 (dd, J
= 10.3, 2.6 Hz, 1 H, CHO-THP), 6.99 (s, 1 H, 4Ј-H), 8.30 (s, 1 H,
8-H), 9.07 (s, 1 H, 2-H) ppm. 13C NMR (125.7 MHz, CDCl3): δ =
22.04 and 22.70 (CH2-6Ј and CH2-7Ј), 22.73 (CH2-THP), 23.97
(CH3), 24.84 (CH2-THP), 25.60 (CH2-8Ј), 29.23 (CH2-5Ј), 31.89
(CH2-THP), 68.86 (CH2O-THP), 82.01 (CHO-THP), 124.38 (CH-
4Ј), 129.17 (C-8Јa), 132.22 (C-5), 142.87 (CH-8), 147.58 (C-4Јa),
151.33 (C-4), 152.23 (C-1Ј), 152.48 (CH-2), 154.70 (C-3Ј), 157.60
(470.3 MHz, CDCl ): δ = –62.96 ppm. IR (CHCl ): ν = 2986, 2948,
˜
3
3
1590, 1580, 1496, 1434, 1379, 1326, 1168, 1130, 1085, 1069,
1045 cm–1. MS (FAB): m/z (%) = 480 (7) [M + H]+, 396 (100).
HRMS (FAB): calcd. for C26H25N5OF3 [M + H]+ 480.2011; found
480.1997.
6-[3-(Furan-2-yl)-5,6,7,8-tetrahydroisoquinolin-1-yl]-9-(tetrahydro-
pyran-2-yl)-9H-purine (4be) (Method C1): Column chromatography
on silica gel (CHCl3/diethyl ether, 5:1) afforded 68 mg (42%) of a
yellowish oil, which after co-evaporation with CHCl3 formed a
white foam. Crystallization from CH2Cl2/heptane gave greyish
crystals, m.p. 193–194 °C (CH2Cl2/heptane). Rf (EtOAc) = 0.50. 1H
NMR (500 MHz, CDCl3): δ = 1.66–1.89 (m, 7 H, 7Ј,6Ј-H and CH2-
(C-6) ppm. IR (CHCl ): ν = 2982, 2948, 1594, 1579, 1497, 1441,
˜
3
1331, 1326, 1086, 1045 cm–1. MS (FAB): m/z (%) = 350 (27) [M +
H]+, 266 (100). HRMS (FAB): calcd. for C20H24N5O [M + H]+
350.1981; found 350.1975.
General Procedure for the [CpCo(CO)2]-Mediated Cyclotrimeri-
zation of Bis(purinyl)diynes 2 with Nitriles 3 Under Microwave Irra-
diation. Method D: Procedure with THF as Solvent (Method D1):
Bis(purinyl)diyne 2 (0.4 mmol) was placed in a vial filled with ar-
gon. Then nitrile 3 (2 mmol), THF (4 mL), and the cobalt catalyst
[CpCo(CO)2] (52 µL, 0.4 mmol) were added to the starting material
under argon. The vial was placed in the microwave reactor and
irradiated for 10 min. Then the solvent was evaporated under re-
duced pressure and the residue was purified by chromatography on
silica gel to give the corresponding product 5.
THP), 2.05–2.21 (m, 3 H, CH2-THP), 2.65 and 2.70 (2 dt, Jgem
=
17.2, J8Ј,7Ј = 6.4 Hz, 2 H, 8Ј-H), 2.89 (td, J5Ј,6Ј = 6.3, J5Ј,4Ј = 0.9 Hz,
2 H, 5Ј-H), 3.83 (td, J = 11.8, 2.6 Hz, 1 H, CHaHbO-THP), 4.21
(ddt, J = 11.8, 4.3, 2.0 Hz, 1 H, CHaHbO-THP), 5.87 (dd, J = 10.4,
2.8 Hz, 1 H, CHO-THP), 6.45 (dd, J4,3 = 3.4, J4,5 = 1.8 Hz, 1 H,
4-furyl-H), 6.95 (dd, J3,4 = 3.4, J3,5 = 0.9 Hz, 1 H, 3-furyl-H), 7.47
(dd, J5,4 = 1.8, J5,3 = 0.9 Hz, 1 H, 5-furyl-H), 7.52 (t, J4Ј,5Ј = 0.9 Hz,
1 H, 4Ј-H), 8.31 (s, 1 H, 8-H), 9.09 (s, 1 H, 2-H) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 21.99 and 22.62 (CH2-6Ј and CH2-7Ј),
22.76 and 24.85 (CH2-THP), 25.94 (CH2-8Ј), 29.51 (CH2-5Ј), 31.88
(CH2-THP), 68.87 (CH2O-THP), 82.02 (CHO-THP), 108.25 (CH- Procedure with Nitrile 3 as Solvent (Method D2): Bis(purinyl)diyne
3-furyl), 111.69 (CH-4-furyl), 119.64 (CH-4Ј), 130.89 (C-8Јa), 2 (0.4 mmol) was placed in a vial filled with argon. Then nitrile 3
132.40 (C-5), 142.76 (CH-5-furyl), 142.88 (CH-8), 146.32 (C-3Ј), (4 mL) and the cobalt catalyst [CpCo(CO)2] (52 µL, 0.4 mmol)
Eur. J. Org. Chem. 2008, 3335–3343
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3341

P. Turek, M. Hocek, R. Pohl, B. Klepetárˇová, M. Kotora
FULL PAPER
were added to the starting material under argon. The vial was
placed in the microwave reactor and irradiated for 10 min. Then
the solvent was evaporated under reduced pressure and the residue
purified by chromatography on silica gel to give the corresponding
product 5.
5Ј), 27.64 (CH2-8Ј), 31.32, 31.33, 31.74, 31.76, and 31.83 (CH2-
THP), 68.81 and 68.84 (CH2O-THP), 81.62, 81.93, and 82.07
(CHO-THP), 127.15, 127.27, 127.43, 127.53, and 127.54 (CH-m,p-
Ph), 129.23, 129.26, 129.28, and 129.31 (CH-o-Ph), 130.23, 130.25,
and 130.27 (C-4Ј), 130.82, 130.84, 130.93, and 130.95 (C-8Јa),
132.52, 133.21, 133.23, 133.28, and 133.31 (C-5), 140.17 and 140.27
(C-i-Ph), 142.38, 142.41, 142.54, 142.57, and 142.85 (CH-8),
146.56, 146.57, 146.69, and 146.70 (C-4Јa), 150.54, 150.58, 150.67,
150.72, 151.48, 151.49, and 151.52 (C-4), 152.27, 152.33, and
152.35 (CH-2), 153.26 and 153.28 (C-1Ј), 154.66, 154.68, 154.80,
and 154.81 (C-3Ј), 157.28, 157.30, 157.31, 157.62, 157.67, and
1,4-Bis(9-benzyl-9H-purin-6-yl)-3-phenyl-5,6,7,8-tetrahydroisoquin-
oline (5aa) (Method D2): Column chromatography on silica gel
(EtOAc/MeOH/CHCl3, 10:1:1) afforded a brownish oil, which after
co-evaporation with CHCl3 formed 78 mg (31 %) of a brownish
foam. Rf (EtOAc/MeOH, 5:1) = 0.59. 1H NMR (600 MHz,
CDCl3): δ = 1.70–1.80 (m, 4 H, 6Ј,7Ј-H), 2.45 and 2.80 (2 m, 2 H,
8Ј-H), 2.86 (m, 2 H, 5Ј-H), 5.40 and 5.49 (2 s, 2ϫ2 H, CH2-Ph),
6.96–7.03 (m, 3 H, m,p-Ph-H), 7.17 (m, 2 H, o-Bn-H), 7.27 (m, 2
H, o-Ph-H), 7.32–7.40 (m, 8 H, 2ϫm,p-Bn-H and o-Bn-H), 7.88
and 8.09 (2 s, 2ϫ1 H, 8-H), 9.00 and 9.14 (2 s, 2ϫ1 H, 2-H) ppm.
157.68 (C-6) ppm. IR (CHCl ): ν = 2979, 2950, 2931, 1590, 1581,
˜
3
1497, 1406, 1332, 1326, 1207, 1085, 1045 cm–1. MS (FAB): m/z (%)
= 614 (23) [M + H]+, 530 (15), 446 (36), 57 (100). HRMS (FAB):
calcd. for C35H36N9O2 [M + H]+ 614.2992; found 614.2999.
13C NMR (151 MHz, CDCl3): δ = 21.91 and 22.99 (CH2-6Ј and 1,4-Bis[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]-3-[4-(trifluorometh-
CH2-7Ј), 26.38 (CH2-5Ј), 27.68 (CH2-8Ј), 47.14 and 47.31 (CH2- yl)phenyl]-5,6,7,8-tetrahydroisoquinoline (5bd) (Method D1): Col-
Ph), 127.10 (CH-p-Ph), 127.36 (CH-o-Ph), 127.59 and 127.98 (CH- umn chromatography on silica gel (EtOAc/acetone/CHCl3, 10:1:1)
o-Bn), 128.54 and 128.60 (CH-p-Bn), 129.10 and 129.14 (CH-m-
Bn), 129.25 (CH-m-Ph), 130.30 (C-8Јa), 130.97 (C-4Ј), 132.35 and
133.04 (C-5), 134.98 and 135.03 (C-i-Bn), 140.28 (C-i-Ph), 144.54
and 144.87 (CH-8), 146.58 (C-4Јa), 151.51 and 152.35 (C-4), 152.44
afforded 76 mg (28%) of a yellowish foam (mixture of four dia-
stereoisomers). Rf (EtOAc/acetone, 5:2) = 0.31. 1H NMR
(600 MHz, CDCl3): δ = 1.65–1.88 (m, 40 H, 7Ј,6Ј-H and CH2-
THP), 2.02–2.23 (m, 24 H, CH2-THP), 2.40–2.50 and 2.60–2.74 (2
and 152.50 (CH-2), 153.32 (C-1Ј), 154.87 (C-3Ј), 157.24 and 157.60 m, 8 H, 8Ј-H), 2.79–2.93 (m, 8 H, 5Ј-H), 3.77–3.86 (m, 4 H,
(C-6) ppm. IR (CHCl ): ν = 2988, 2944, 1589, 1579, 1500, CHaHbO-THP), 4.15–4.24 (m, 4 H, CHaHbO-THP), 5.77–5.82 and
˜
3
1330 cm–1. MS (FAB): m/z (%) = 626 (40) [M + H]+, 91 (100).
HRMS (FAB): calcd. for C39H32N9 [M + H]+ 626.2781; found
626.2764.
5.86–5.90 (2 m, 4 H, CHO-THP), 7.26–7.31 (m, 8 H, m-C6H4CF3-
H), 7.41–7.46 (m, 8 H, o-C6H4CF3-H), 8.17, 8.19, 8.20, 8.21, 8.349,
8.353, and 8.355 (7s, 8 H, 8-H), 8.95, 8.97, 8.98, 8.99, 9.110, 9.111,
and 9.114 (7s, 8 H, 2-H) ppm. 13C NMR (151 MHz, CDCl3): δ =
21.77, 21.81, and 21.87 (CH2-6Ј and CH2-7Ј), 22.69, 22.74, 22.76,
24.78, and 24.85 (CH2-THP), 26.38, 26.40, and 26.42 (CH2-5Ј),
27.66 and 27.67 (CH2-8Ј), 31.33, 31.34, 31.71, 31.74, and 31.84
(CH2-THP), 68.80, 68.81, 68.83, 68.84, and 68.87 (CH2O-THP),
1,4-Bis(9-benzyl-9H-purin-6-yl)-3-methyl-5,6,7,8-tetrahydroisoquin-
oline (5ah) (Method D2): Column chromatography on silica gel
(EtOAc/MeOH/CHCl3, 10:1:1) afforded a brownish oil, which after
co-evaporation with CHCl3 formed 75 mg (33 %) of a brownish
foam. Rf (EtOAc/MeOH, 5:1) = 0.28. 1H NMR (600 MHz,
CDCl3): δ = 1.66–1.73 (m, 4 H, 6Ј,7Ј-H), 2.30 (s, 3 H, CH3), 2.40
81.68, 81.69, 81.98, and 82.16 (CHO-THP), 124.08 (q, JC,F
=
272 Hz, CF3), 124.40, 124.42, 124.57, and 124.58 (q, JC,F = 4 Hz,
CH-m-C6H4CF3), 129.11 and 129.23 (q, JC,F = 32 Hz, C-p-
C6H4CF3), 129.60, 129.62, 129.65, and 129.68 (CH-o-C6H4CF3),
130.38, 130.39, and 130.41 (C-4Ј), 131.72, 131.74, 131.85, and
131.89 (C-8Јa), 132.47, 132.48, 133.12, 133.18, 133.21, and 133.27
(C-5), 142.64, 142.66, 142.88, 142.89, and 143.01 (CH-8), 143.77
and 143.86 (C-i-C6H4CF3), 147.01, 147.02, 147.15, and 147.16 (C-
4Јa), 150.68, 150.73, 150.79, 150.83, 151.54, 151.55, and 151.58 (C-
4), 152.36, 152.40, and 152.43 (CH-2), 153.23, 153.25, 153.32, and
153.33 (C-3Ј), 153.50 and 153.54 (C-1Ј), 156.88, 156.89, 156.90,
156.92, 156.93, 156.94, and 156.95 (C-6) ppm. 19F NMR
and 2.57 (2 m, 2 H, 8Ј-H), 2.77 (m, 2 H, 5Ј-H), 5.486 (d, Jgem
14.9 Hz, 1 H, CHaHb-Ph), 5.494 (s, 2 H, CH2-Ph), 5.51 (d, Jgem
=
=
14.9 Hz, 1 H, CHaHb-Ph), 7.33–7.44 (m, 10 H, Ph), 8.06 and 8.09
(2 s, 2ϫ1 H, 8-H), 9.14 and 9.15 (2 s, 2ϫ1 H, 2-H) ppm. 13C
NMR (151 MHz, CDCl3): δ = 21.86 and 22.01 (CH2-6Ј and CH2-
7Ј), 23.03 (CH3), 26.22 (CH2-5Ј), 27.50 (CH2-8Ј), 47.31 and 47.48
(CH2-Ph), 127.96 and 128.19 (CH-o-Ph), 128.60 and 128.75 (CH-
p-Ph), 129.13 and 129.23 (CH-m-Ph), 129.75 (C-8Јa), 130.79 (C-
4Ј), 132.13 and 132.63 (C-5), 134.80 and 135.04 (C-i-Ph), 144.67
and 144.85 (CH-8), 145.87 (C-4Јa), 151.79 and 152.30 (C-4), 152.63
(CH-2), 152.65 (C-1Ј), 152.84 (CH-2), 152.92 (C-3Ј), 157.29 and
(470.3 MHz, CDCl ): δ = –63.17, –63.16 ppm. IR (CHCl ): ν =
˜
3
3
157.51 (C-6) ppm. IR (CHCl ): ν = 2990, 2944, 1588, 1579, 1500,
˜
3
2983, 2950, 1590, 1580, 1497, 1408, 1325, 1168, 1129, 1086, 1066,
1045 cm–1. MS (FAB): m/z (%) = 682 (27) [M + H]+, 598 (28), 514
(100). HRMS (FAB): calcd. for C36H35N9O2F2 [M + H]+ 682.2866;
found 682.2863.
1329 cm–1. MS (FAB): m/z (%) = 564 (100) [M + H]+, 91 (58).
HRMS (FAB): calcd. for C34H30N9 [M + H]+ 564.2624; found
564.2618.
1,4-Bis[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]-3-phenyl-5,6,7,8-te-
trahydroisoquinoline (5ba) (Method D2): Column chromatography
on silica gel (EtOAc/acetone/CHCl3, 10:1:1) afforded 104 mg (42%)
of a yellowish foam (mixture of four diastereoisomers). Rf (EtOAc/
General Procedure for Deprotection of the 9-THP-6-pyridylpurines:
A reaction mixture composed of 9-THP-6-pyridylpurine 4by
(0.5 mmol) and Dowex D-50 (100 mg) in EtOH (10 mL) was heated
at reflux for 1 h or until the starting material had been consumed
(followed by TLC). The reaction mixture was filtered through a frit
and the residue was washed with hot EtOH (3ϫ10 mL). Finally,
the combined organic fractions were concentrated under reduced
pressure.
1
acetone, 5:2) = 0.18. H NMR (600 MHz, CDCl3): δ = 1.64–1.94
(m, 40 H, 7Ј,6Ј-H and CH2-THP), 2.02–2.20 (m, 24 H, CH2-THP),
2.38–2.48 and 2.59–2.70 (2 m, 8 H, 8Ј-H), 2.77–2.91 (m, 8 H, 5Ј-
H), 3.76–3.86 (m, 4 H, CHaHbO-THP), 4.15–4.23 (m, 4 H,
CHaHbO-THP), 5.75–5.81 and 5.86–5.89 (2 m, 4 H, CHO-THP),
6.98–7.04 (m, 12 H, m,p-Ph-H), 7.28–7.31 (m, 8 H, o-Ph-H), 8.167, 6-(3-Phenyl-5,6,7,8-tetrahydroisoquinolin-1-yl)-9H-purine (6a): The
8.176, 8.184, 8.195, 8.341, 8.345 and 8.346 (7s, 8 H, 8-H), 8.94,
8.959, 8.960, 8.976, 9.106, 9.107, and 9.109 (7s, 8 H, 2-H) ppm. 13
NMR (151 MHz, CDCl3): δ = 21.85, 21.89, and 21.94 (CH2-6Ј and
deprotection of 4ba (218 mg, 0.53 mmol) afforded 121 mg (70%) of
the title compound as a white solid. Recrystallization from EtOH/
toluene gave white crystals, m.p. 239–240 °C (EtOH/toluene). 1H
C
CH2-7Ј), 22.71, 22.76, 24.79, and 24.85 (CH2-THP), 26.33 (CH2- NMR (500 MHz, [D6]DMSO + DCl): δ = 1.71 (m, 2 H, 6Ј-H), 1.80
3342
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3335–3343

Cobalt-Induced Synthesis of 6-(Pyridin-2-yl)purines
[3] K. P. C. Vollhardt, R. G. Bergman, J. Am. Chem. Soc. 1974,
96, 4996–4998.
(m, 2 H, 7Ј-H), 2.87 (t, Jvic = 6.2 Hz, 2 H, 8Ј-H), 3.00 (t, Jvic
=
6.2 Hz, 2 H, 5Ј-H), 7.44–7.52 (m, 3 H, m,p-Ph-H), 8.05 (s, 1 H, 4Ј-
H), 8.09 (m, 2 H, o-Ph-H), 9.31 (s, 1 H, 2-H), 9.40 (s, 1 H, 8-
H) ppm. 13C NMR (125.7 MHz, [D6]DMSO + DCl): δ = 21.65
(CH2-7Ј), 22.20 (CH2-6Ј), 25.83 (CH2-8Ј), 29.59 (CH2-5Ј), 123.86
(CH-4Ј), 126.24 (C-5), 127.60 (CH-o-Ph), 129.23 (CH-m-Ph),
130.15 (CH-p-Ph), 133.63 (C-8Јa), 136.75 (C-i-Ph), 148.02 (C-1Ј),
148.53 (CH-8), 149.98 (C-4), 151.19 (CH-2), 152.04 (C-4Јa), 152.62
[4] For reviews, see: a) H. Bönnemann, W. Brijoux, Adv. Hetero-
cycl. Chem. 1990, 48, 177–222; b) J. A. Varela, C. Saá, Chem.
Rev. 2003, 103, 3787–3801; c) J. A. Varela, L. Castedo, C. Saá,
J. Org. Chem. 1997, 62, 4189–4192; d) for a new cobalt-based
catalytic system, see: K. Kase, A. Goswami, K. Ohtaki, E. Tan-
abe, N. Saino, S. Okamoto, Org. Lett. 2007, 9, 931–934; e) A.
Goswami, K. Ohtaki, K. Kase, T. Ito, S. Okamoto, Adv. Synth.
Catal. 2008, 350, 143–152.
(C-3Ј), 154.95 (C-6) ppm. IR (KBr): ν = 2940, 2918, 1601, 1588,
˜
[5] a) C. A. Parnell, K. P. C. Vollhardt, Tetrahedron 1985, 41,
5791–5796; b) R. E. Geiger, M. Lalonde, H. Stoller, K. Schle-
ich, Helv. Chim. Acta 1984, 67, 1274–1282; c) C. Saá, D. D.
Crotts, G. Hsu, K. P. C. Vollhardt, Synlett 1994, 487–489.
[6] a) A. J. Cocuzza, D. R. Chidester, S. Culp, L. Fitzgerald, P.
Gilligan, Bioorg. Med. Chem. Lett. 1999, 9, 1063–1066; b)
L. C. W. Chang, R. F. Spanjersberg, J. K. von Frijtag Drabbe
Künzel, T. Mulder-Krieger, J. Brussee, A. P. IJzerman, J. Med.
Chem. 2006, 49, 2861–2867; c) A. K. Bakkestuen, L.-L. Gund-
ersen, G. Langli, F. Liu, J. M. J. Nolsøe, Bioorg. Med. Chem.
Lett. 2000, 10, 1207–1210; d) L.-L. Gundersen, J. Nissen-
Meyer, B. Spilsberg, J. Med. Chem. 2002, 45, 1383–1386; e)
A. K. Bakkestuen, L.-L. Gundersen, B. T. Utenova, J. Med.
Chem. 2005, 48, 2710–2723; f) A. Brathe, L.-L. Gundersen, J.
Nissen-Meyer, F. Rise, B. Spilsberg, Bioorg. Med. Chem. Lett.
2003, 13, 877–880; g) M. Brændvang, L.-L. Gundersen, Bioorg.
Med. Chem. 2005, 13, 6360–6373; h) M. Hocek, A. Holý, I.
Votruba, H. Dvorˇáková, J. Med. Chem. 2000, 43, 1817–1825; i)
M. Hocek, A. Holý, I. Votruba, H. Dvorˇáková, Collect. Czech.
Chem. Commun. 2001, 66, 483–499.
1583, 1562, 1547, 1482, 1465, 1435, 1427, 1397, 1384, 1322, 1266,
1250, 1230, 1125 cm–1. MS (FAB): m/z (%) = 328 (100) [M +
H]+. HRMS (FAB): calcd. for C20H18N5 [M + H]+ 328.1562; found
328.1563.
6-{3-[4-(Trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-1-yl}-
9H-purine (6d): The deprotection of 4bd (240 mg, 0.5 mmol) af-
forded 133 mg (67%) of the title compound as a white solid.
Recrystallization from EtOH/toluene gave white crystals, m.p. 208–
1
210 °C (EtOH/toluene). H NMR (600 MHz, [D6]DMSO + DCl):
δ = 1.67 (m, 2 H, 6Ј-H), 1.76 (m, 2 H, 7Ј-H), 2.87 (t, Jvic = 6.3 Hz,
2 H, 8Ј-H), 2.95 (t, Jvic = 6.3 Hz, 2 H, 5Ј-H), 7.79 (m, 2 H, m-
C6H4CF3-H), 8.07 (s, 1 H, 4Ј-H), 8.30 (m, 2 H, o-C6H4CF3-H),
9.33 (s, 1 H, 2-H), 9.55 (s, 1 H, 8-H) ppm. 13C NMR (151 MHz,
[D6]DMSO + DCl): δ = 21.94 (CH2-7Ј), 22.50 (CH2-6Ј), 26.24
(CH2-8Ј), 29.70 (CH2-5Ј), 124.40 (CH-4Ј), 124.93 (q, JC,F = 272 Hz,
CF3), 125.60 (C-5), 126.26 (q, JC,F = 3 Hz, CH-m-C6H4CF3),
128.43 (CH-o-C6H4CF3), 130.03 (q, JC,F = 32 Hz, C-p-C6H4CF3),
134.76 (C-8Јa), 141.84 (C-i-C6H4CF3), 148.74 (C-1Ј), 148.80 (CH-
8), 150.72 (C-4), 151.31 (C-4Јa), 151.33 (CH-2), 151.95 (C-3Ј),
154.63 (C-6) ppm. 19F NMR (470.3 MHz, [D6]DMSO + DCl): δ =
[7] M. Hocek, P. Nausˇ, R. Pohl, I. Votruba, P. A. Furman, P. M.
Tharnish, M. J. Otto, J. Med. Chem. 2005, 48, 5869–5873.
[8] a) P. Turek, M. Kotora, M. Hocek, I. Císarová, Tetrahedron
ˇ
–61.55 ppm. IR (KBr): ν = 2936, 1613, 1591, 1562, 1476, 1427,
˜
Lett. 2003, 44, 785–788; b) P. Turek, M. Kotora, I. Tisˇlerová,
M. Hocek, I. Votruba, I. Císarˇová, J. Org. Chem. 2004, 69,
9224–9233; c) P. Turek, P. Novák, R. Pohl, M. Hocek, M. Ko-
tora, J. Org. Chem. 2006, 71, 8978–8981; d) for Ni-mediated
reactions of 6-alkynylpurines with zirconacyclopentadienes,
see: P. Turek, M. Kotora, M. Hocek, I. Votruba, Collect.
Czech. Chem. Commun. 2005, 70, 339–349.
1379, 1335, 1326, 1163, 1127, 1108, 1070 cm–1. MS (FAB): m/z (%)
= 396 (100) [M + H]+. HRMS (FAB): calcd. for C21H17N5F3 [M
+ H]+ 396.1436; found 396.1420.
Supporting Information (see also the footnote on the first page of
this article): Details of all experimental procedures for the cyclo-
trimerization reactions, X-ray data, and spectral characteristics of
the prepared compounds.
[9] L.-L. Gundersen, Acta Chem. Scand. 1996, 50, 58–63.
[10] a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
1975, 16, 4467–4470; b) S. Takahashi, Y. Kuroyama, K. Sono-
gashira, N. Hagihara, Synthesis 1980, 627–630; c) S. Thorand,
S. N. Krause, J. Org. Chem. 1998, 63, 8851–8853.
[11] For a review, see: M. Hocek, Eur. J. Org. Chem. 2003, 245–254.
[12] O. C. Kappe, A. Stadler, Microwaves in Organic and medicinal
Chemistry, Wiley-VCH, Weinheim, 2005.
[13] a) R. Hrdina, A. Kadlcˇíková, I. Valterová, J. Hodacˇová, M.
Kotora, Tetrahedron: Asymmetry 2006, 17, 3185–3191; b) R.
Hrdina, I. Valterová, J. Hodacˇová, M. Kotora, Adv. Synth. Ca-
tal. 2007, 349, 822–826.
Acknowledgments
This work was supported by the Centre for New Antivirals and
Antineoplastics of the Ministry of Education of the Czech Repub-
lic (project no. 1M0508) and is a part of the research projects
Z40550506 and MSM0021620857 and Gilead Sciences, Inc.
[14] a) Y. Zhou, J. A. Porco, J. K. Snyder, Org. Lett. 2007, 9, 393–
396; b) D. D. Young, A. Deiters, Angew. Chem. Int. Ed. 2007,
47, 5178–5190.
[15] a) Y. Yamamoto, R. Ogawa, K. Itoh, Chem. Commun. 2001,
123, 1102–1103; b) Y. Yamamoto, R. Ogawa, K. Itoh, J. Am.
Chem. Soc. 2001, 123, 6189–6190; c) Y. Yamamoto, K. Kin-
para, T. Saigoku, H. Takagishi, S. Okuda, H. Nishiyama, K.
Itoh, J. Am. Chem. Soc. 2005, 127, 605–613; d) Y. Yamamoto,
K. Kinpara, R. Ogawa, H. Nishiyama, K. Itoh, Chem. Eur. J.
2006, 12, 5618–5631.
[1] For reviews, see: a) K. P. C. Vollhardt, Angew. Chem. Int. Ed.
Engl. 1984, 23, 539–556; b) N. E. Schore, Chem. Rev. 1988, 88,
1081–1119; c) M. Lautens, W. Klute, W. Tam, Chem. Rev. 1996,
96, 49–92; d) H.-H. Frühauf, Chem. Rev. 1997, 97, 523–596; e)
C. P. Dell, J. Chem. Soc. Perkin Trans. 1 1998, 3873–3905; f) S.
Saito, Y. Yamamoto, Chem. Rev. 2000, 100, 2901–2916; g) S.
Kotha, E. Brachmachary, K. Lahiri, Eur. J. Org. Chem. 2005,
4741–4761.
[2] a) Y. Wakatsuki, H. Yamazaki, J. Chem. Soc., Chem. Commun.
1973, 280; b) Y. Wakatsuki, H. Yamazaki, Tetrahedron Lett.
1973, 14, 3383–3384.
Received: February 22, 2008
Published Online: May 21, 2008
Eur. J. Org. Chem. 2008, 3335–3343
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3343