Cyclization and rearrangement products from coupling reactions between terminal o-alkynylphenols or o-ethynyl(hydroxymethyl)benzene and 6-halopurines

Article abstract of DOI:10.1016/j.tet.2006.03.112

Cyclization reactions on 6-[(2-hydroxyphenyl)ethynyl]purines, 6-[(2-hydroxymethylphenyl)ethynyl]purines and 6-[(2-hydroxyphenyl)propyn-1-yl]purines have been studied. 6-(2-Benzofuryl)purines are readily available via a one-pot Sonogashira coupling-cyclization between 6-iodopurine and 2-ethynylphenol. When the same reaction was performed with o-(hydroxymethyl)ethynylbenzene, 6-[isobenzofuran-1(3H)-ylidenemethyl]purine was formed, mainly as the (E)-isomer. Acid catalyzed isomerization of the (E)-compound afforded the (Z)-isomer. The latter compound was also formed from a two-step reaction; Sonogashira coupling with O-silylated alkyne followed by deprotection and subsequent 5-exo cyclization. Sonogashira coupling between 6-halopurines and 2-propynylphenol gave only the alkyne coupling product and no cyclization took place. However, the Sonogashira product was unexpectedly rearranged to 6-(3-phenoxypropa-1,2-dienyl)purines under basic conditions. Theoretical calculations demonstrated that the allenes are more stable than their alkyne isomers.

Full text of DOI:10.1016/j.tet.2006.03.112

Tetrahedron 62 (2006) 6121–6131
Cyclization and rearrangement products from coupling
reactions between terminal o-alkynylphenols or
o-ethynyl(hydroxymethyl)benzene and 6-halopurines
*
Tom Christian Berg, Vebjørn Bakken, Lise-Lotte Gundersen and Dirk Petersen
Department of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315 Oslo, Norway
Received 15 December 2005; revised 22 February 2006; accepted 9 March 2006
Available online 27 April 2006
Abstract—Cyclization reactions on 6-[(2-hydroxyphenyl)ethynyl]purines, 6-[(2-hydroxymethylphenyl)ethynyl]purines and 6-[(2-hydroxy-
phenyl)propyn-1-yl]purines have been studied. 6-(2-Benzofuryl)purines are readily available via a one-pot Sonogashira coupling–cyclization
between 6-iodopurine and 2-ethynylphenol. When the same reaction was performed with o-(hydroxymethyl)ethynylbenzene, 6-[isobenzo-
furan-1(3H)-ylidenemethyl]purine was formed, mainly as the (E)-isomer. Acid catalyzed isomerization of the (E)-compound afforded the
(Z)-isomer. The latter compound was also formed from a two-step reaction; Sonogashira coupling with O-silylated alkyne followed by
deprotection and subsequent 5-exo cyclization. Sonogashira coupling between 6-halopurines and 2-propynylphenol gave only the alkyne
coupling product and no cyclization took place. However, the Sonogashira product was unexpectedly rearranged to 6-(3-phenoxypropa-
1
,2-dienyl)purines under basic conditions. Theoretical calculations demonstrated that the allenes are more stable than their alkyne isomers.
Ó 2006 Elsevier Ltd. All rights reserved.
3
4
1
. Introduction
like antimycobacterial activity, cytotoxic effects, a(nta)-
gonist activity toward adenosine receptors, inhibition of
5
6
7,4f
During our synthetic studies toward potential plant growth
hormone analogs, we found that 6-(hydroxyalkynyl)purines
ring close by an exo-dig attack from the hydroxy group on
the triple bond. The electron deficient purine activates
the alkyne function for nucleophilic attack. We have previ-
ously studied addition of nucleophiles to alkenylpurines.
15-lipoxygenase, and antiviral activity
in addition to
1
1
the above-mentioned ability to stimulate plant growth. In
order to increase the synthetic methodologies for construct-
ing 6-substituted purines, we decided to study the cycliza-
tions of alkynylpurines with the general structure I and to
explore the possibility of forming benzofuryl derivatives
II, III, and V by 5-exo cyclization, or isomeric 6-endo prod-
ucts IV and VI (Scheme 1).
1
d
2
Purines carrying different carbon substituents in the 6-posi-
tion are associated with a wide variety of biological effects,
x
y
O
O
5-exo
5-exo
O
O
OH
Ar
Ar
Ar
Ar
x=0
y=1
x=1
y=0
IIIb
IIIa
N
Va
Vb
N
N
R
N
Ar:
I
N
N
6
-endo
6-endo
x=y=0
N
R
O
O
N
Ar
IV
Ar
VI
O
Ar II
Scheme 1. Cyclization reactions studied herein.
*
0
Corresponding author. Tel.: +47 22857019; fax: +47 22855507; e-mail: l.l.gundersen@kjemi.uio.no
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.112

6122
T. C. Berg et al. / Tetrahedron 62 (2006) 6121–6131
2
. Results and discussion
2-alkylbenzo[c]furans have shown that equilibria like
IIIa–IIIb (Scheme 1) lies in favor of the benzenoid tautomer
IIIa.
1
0
Benzo[b]furans and indoles may be formed by Pd(0) and/or
Cu(I)-mediated reactions of 2-alkynylphenols. 2-Aryl- or
8
2
-vinylbenzo[b]furans have been prepared by a one-pot So-
Structure elucidation of compound 5 was initially based on
NOESY correlation between H-2 in the purine ring and
one of the hydrogens in the benzofuryl substituent (Scheme
3). The distance between the H-2 and the benzene ring would
have been much larger in the (Z)-isomer 7 or in the 6-endo
cyclized isomer (comp. IV, Scheme 1).
nogashira coupling–cyclization when ethynylphenol 2 was
reacted with aryl- or vinyl iodides under solventless micro-
wave-enhanced Sonogashira coupling conditions, but only
moderate yields were achieved due to polymerization reac-
tions. The 6-(2-benzofuryl)purine 3 (Scheme 2) exhibits
antimycobacterial activity and has previously been prepared
by Stille coupling on 6-halopurine. 6-(2-Benzofuryl)purine
riboside has been prepared by Suzuki coupling in quite mod-
est yield. We have determined that 6-iodopurine 1a reacts
with ethynylphenol 2 under standard Sonogashira conditions
to give 2-benzofurylpurine 3 in a yield almost identical to
what have been obtained previously, but the reaction
described herein takes place under more environmentally
benign conditions and utilizes less expensive starting mate-
rials, since the use of an organotin compound in stoichio-
metric amounts is avoided (Scheme 2).
9
3
d
It was interesting to note that the chemical shift for the benzo-
furyl proton correlating to H-2 in the NOESY spectrum
was shifted significantly downfield (d 9.84 ppm). This might
be explained by the close proximity to N-1 in the purine. The
4
f
1
15
only difference found in the H– N HMBC spectra of com-
pound 5 and isomer 7 (Scheme 3) discussed below was a cor-
relation between N-1 and the proton shifted downfield in the
benzofuran ring of compound 5. This confirms the close
proximity of those two atoms and a hydrogen bond between
them forming a pseudo 7-membered ring (Fig. 1). Not only is
the hydrogen shifted downfield, also a 5.8 ppm up-field shift
was observed for N-1 in compound 5 relative to the N-1 shift
in the isomer 7. The chemical shift values found for N-3,
N-7, and N-9 in the two isomers were virtually identical.
To the best of our knowledge, a persistent C–H/N bond in
3
d
I
O
N
N
OH
i
+
N
N
6
5%
N
1
15
N
N
solution, detected by H– N HMBC spectroscopy, has not
been reported before, but it is now established that scalar
N
Ph
1
1
1a
2
3
Ph
2
, CuI, (i-Pr) NH,
couplings can be observed across H-bonds. The correla-
tion between N-1 and the benzofuryl signal at 9.84 ppm,
Scheme 2. Reagents and conditions: (i) (Ph
ꢀ
3
P)
2
PdCl
2
DMF, 60 C.
O
SCH
3
6
-Iodopurine 1a was reacted with terminal alkynes 4. When
β
the acetylene carried a free hydroxy group (4a), cyclization
took place under Sonogashira conditions and the (E)-5-exo
product 5 was formed together with minor amounts of the
α
N
N
6
H
N
N
1
N
N
N
H
N
(
Z)-isomer 7 (Scheme 3). NMR spectroscopic analyses indi-
5
Ph
cated that compound 5 exists as an enol ether with the CH2-
group inside the newly formed ring, and the presence of an
aromatic benzo[c]furyl substituent (product type IIIb,
Scheme 1) could easily be excluded. Also other studies of
Figure 1. Structure of compound 5 with an intramolecular C–H/N bond
and the more flexible 6-styrylpurine where no intramolecular H-bond
was observed.
13
O
N
H N
R=H
nOe
61% (5:7; 88:12)
N
I
H
N
N
N
5
Ph
N
i
+
iv
OR
N
Ph
1a
4a, R=H
b, R=TBS
R=TBS
4
Correlations from sel.
1D INADEQUATE
TBSO
O
ii or iii
N
N
N
N
N
N
N
7
N
Ph
6
Ph
9
3
0% (HCl)
9% (TBAF)
9
6%
quant. according to NMR (TFA-d )
1
ꢀ
2 2 1 3
PdCl , CuI, (i-Pr) NH, DMF, 60 C; (ii) HCl (aq), EtOH; (iii) TBAF, THF; (iv) TFA-d , CDCl .
Scheme 3. Reagents and conditions: (i) (Ph
3
P)
2

T. C. Berg et al. / Tetrahedron 62 (2006) 6121–6131
6123
1
15
seen in the H– N HMBC spectrum of compound 5, is
a strong indication of a C–H/N bond, which may be the
reason for the high chemical shift value for the benzofuryl
proton.
cyclized isochromene (type IV product; Scheme 1) was
not formed. Selective 1D INADEQUATE (SELINQUATE)
NMR, optimized for J(C,C) proved unambiguously the 5-
membered ring structure of compound 7. When the CH]
in the side chain was irradiated, correlations to the two
neighboring carbons, C-6 in the purine and the ]C–O, in
the newly formed ring was observed (Scheme 3).
1
The (E)-benzofurylalkylidene compound 5 readily isomer-
izes to the corresponding (Z)-isomer 7 (see below) and the
intramolecular H-bond appears to be a consequence of the
rigidity of compound 5. No abnormalities in the H NMR
spectra indicating a C–H/N bond could be seen in spectra
1
Based on the mechanism proposed for cycloisomerization of
2-alkynylbenzyl alcohols
1
6,17
and the isomerization experi-
1
2
reported for a series of 6-styrylpurines where there is free
rotation between the phenyl and double bond. In the 6-styryl-
purine shown in Fig. 1, the torsion angle N1–C-6–Ca–Cb
ments described below, it seems reasonable that compound
5 is formed by cyclization followed by cross-coupling
(Scheme 4, route A) rather than the alternative route B.
The latter route may explain the formation of the by-product
7 (Scheme 4), but compound 7 is also available from iso-
merization of the (E)-isomer 5. CuI was present in the syn-
thesis of compound 5. The copper salt is of course
required in the Sonogashira coupling in route B, and may
replace Pd(II) in the cyclization in route B, but the possible
role of CuI in route A is not clarified.
ꢀ
was only 6.7 in the crystal structures, but the angle between
ꢀ
13
the phenyl and purine ring was 117 .
When the TBS-protected alcohol 4b was employed in the
Sonogashira reaction, the alkyne 6 was isolated in nearly
quantitative yield (Scheme 3). Cyclization took place during
deprotection. Both acidic and TBAF mediated cleavage of
the silyl ether gave the (Z)-5-exo cyclized product 7. The
regioselectivity in cyclizations of compounds related to the
general structure I (x¼0, y¼1, Scheme 1) is difficult to
predict. Under basic conditions the alkoxy anion generally
attacks the triple bond in related non-purine compounds to
Complete isomerization of compound 5 to isomer 7 was ob-
served in less than 5 min by NMR spectroscopy, when a drop
of TFA-d was added to a CDCl solution of pure (E)-isomer
1
3
5. The isomerization of pure (E)-5 also took place, although
slowly, in pure CDCl . After one day 8% of the (Z)-isomer 7
1
4
form 5-exo products, but there are examples of rearrange-
3
1
4a
ment to the 6-endo isomer during work-up. Ring forma-
tion in the presence of TBAF appears to be sensitive to
sterical hindrance; with relatively bulky alkyls on the alkyne
the 6-endo product is formed, otherwise 5-exo cyclization is
was formed and after 26 days 87% of compound 7 was pres-
ent in the mixture as judged by H NMR. In CD Cl and
1
2
2
CD OD, the conversion of compound 5 to isomer 7 was 53
3
and 62%, respectively, after 26 days. The (Z)-compound 7
was completely stable under acidic conditions. The elusive
o-quinonoid tautomer of compounds 5 and 7 shown in
Scheme 4, could not be observed in the NMR spectra from
the isomerization studies, and related o-quinonoid isobenzo-
1
5
favored. PdI also promotes cyclization of alkynes related
2
to I (x¼0, y¼1, Scheme 1). In these reactions the regio-
1
6
chemical outcome is sensitive to the solvent used.
1
15
2
3
10
The H– N HMBC spectrum, optimized for 10 Hz J/ J
couplings of compound 7 was, with exception of the intra-
molecular H-bond in compound 5, identical with the
furans are reported to be highly unstable.
Compounds 5 and 7 were tested as antimycobacterials and
both isomers exhibited MIC values of 6.25 mg/mL against
Mycobacterium tuberculosis. Compound 5 may have isomer-
ized to isomer 7 during determination of antibacterial effect.
The activity against M. tuberculosis found for compound 7 is
1
15
H– N HMBC spectrum of the (E)-isomer 5. In both spectra
correlation between the CH] in the side chain and N-1
was easily seen, an indication that both compounds were 5-
membered rings, and that the theoretically possible 6-endo
Route A (see ref. 16)
Ar-I, Pd(0)
Ar-Pd-I
OH
O
Base
Ar
- Pd(0)
O
Pd
Ar
4
a
5
"Sonogashira"
O
Ar
Pd(II)
H+
OH
O
O
XPd
Route B (see ref. 17)
Scheme 4. Possible mechanisms for the formation of the isomers 5 and 7.
Ar
7
Ar
Ar

6124
T. C. Berg et al. / Tetrahedron 62 (2006) 6121–6131
X
N
OH
O
N
i
ii
N
•
+
OH
N
R
N
N
N
N
8
N
R
N
R
N
N
1
1
1
a, X=I, R=Bn
b, X=Cl, R=CH -C H -p-Cl
9a 30%
9b 27%
2
6
4
10a 41% from 1a
0b 20%
10c 39%
c, X=Cl, R=THP
1
9
c 44%
ꢀ
Scheme 5. Reagents and conditions: (i) (Ph
3
P)
2
PdCl , CuI, (i-Pr)
2
2
NR, DMF, 60–80 C; (ii) CuI, Et
3
N, D.
comparable with that reported for the benzofuryl derivative
and purinyl moieties were separated by a CH–C–CH linkage.
Furthermore, the direct coupling constants between C and H
in this fragment were found to be ca. 175 Hz, a strong indica-
3
d
3
promising antimycobacterial purines.
,
but none of these compounds are as active as our most
3
2
tion that both CH carbons are sp hybridized and that the
phenyl- and purine rings were separated by the allenyloxy
The alkyne 8 (Scheme 5) is reported to react with aryl
iodides in the presence of BuLi and a Pd(II) precatalyst to
give 5-exo products (type V, Scheme 1), a reaction somewhat
1
3
fragment. It is worth mentioning that ‘unusual’ C NMR
shifts were observed especially for the central allene carbon
and C-2, C-4, and C-6 in the purine ring, all these C reso-
1
7
13
like route B in Scheme 3. However, the application of these
conditions in reaction between halopurine 1c and the acetyl-
ene derivative 8 was not successful. Compound 9c was pre-
pared in moderate yield by standard Sonogashira conditions
and several unsuccessful attempts were made to cyclize this
nances were shifted considerably up-field (Fig. 2). Up-field
shifts for central allene carbons have been observed before
when the allene carries alkoxy group(s) acting as p-donors.
1
8
However, the low up-field shifts found for several purine
carbon resonances indicate that the purine ring behaves as
a p-acceptor, which should lead to a deshielding of the
central allene carbon. In ‘push–pull’ substituted allenes
described before, the effects from the donors and acceptors
compound. When refluxed in Et N in the presence of cata-
3
lytic amounts of CuI and (Ph P) PdCl , still no cyclization
2
3
2
occurred, but an unexpected rearrangement to the allene
0c took place. We found that the reaction took place in
Et N without any additives, but the yield of compound 10c
1
1
3
often cancel each other with respect to the C NMR shift
of the central allene carbon.
3
1
8
was somewhat higher when the reaction was carried out in
the presence of CuI. Addition of a Pd-catalyst [generated
from Pd(II) or Pd(0)] actually had a negative effect on the
yield of allene. Compound 10c was isolated in 39% when
1
00 (60-130)
1
34 (185-216)
3 (60-130)
22 (140-155)
Ph
O
9
c was refluxed in Et N in the presence of catalytic CuI.
3
9
Allenes 10a and 10b were formed by the same reaction
sequence. Compound 10a could also be isolated directly
from the Sonogashira coupling after prolonged reaction
time. Allenes 10 decomposed when exposed to light in
•
1
125 (ca. 130)
N
N
133 (150-155)
136 (140-45)
N
N
CHCl solution and the low stability of the allenes may
3
THP
explain the only moderate isolated yields. The allenes 10
carry both an electron withdrawing and an electron donating
group and high reactivity has also been previously reported
132 (ca. 152)
13
Figure 2. Structure of the phenoxy allene 10c. Selected C NMR shifts
for compound 10c are shown, typical shift ranges for purine ring carbons
1
8
1
,2,6
18
and allene carbons are shown in
for ‘push–pull’ substituted allenes.
in 6-alkenyl or alkynylpurines,
brackets.
NMR spectroscopy as well as synthesis by a different route
see Scheme 7 below) confirmed the unexpected allene struc-
ture of compounds 10. Compound 10c possesses a mono
(
A tentative mechanism for allene formation without CuI, is
detailed in Scheme 6. The presence of a 4-membered ring
intermediate seems reasonable given that the carbon–oxygen
bond is formed by attack from the phenolate anion on an
allene isomer of 9, even though allenes are normally attacked
1
13
substituted benzene ring and the H and C NMR signals
see Section 4) for the benzene ring indicated that an RO–
substituent was connected to the phenyl ring. The phenoxy-
(
OH
O
•
•
O
•
O
N
Base
N
N
N
N
N
N
H
N
N
R
N
R
N
N
R
N
N
R
N
N
9
10
Scheme 6. Tentative mechanism for the formation of compounds 10.

T. C. Berg et al. / Tetrahedron 62 (2006) 6121–6131
6125
X
X
•
I
N
N
N
N
N
N
X
i
N
N
+
+
N
N
N
N
Ph
Ph
Ph
1a
11a, X=O
12
X=O 12a : 10a : 13 : 87
X=CH only 12b formed
10
1
1b, C=CH2
2
ꢀ
3 2 2 2
Scheme 7. Reagents and conditions: (i) (Ph P) PdCl , CuI, (i-Pr) NR, DMF, 60 C.
by nucleophiles at the central carbon. The favorable influ-
ence of CuI on the rearrangement is currently not under-
stood.
and 11a were optimized individually before assembling
the two products 12a and 10a from these fragments. As
both the resulting compounds are highly flexible, a thorough
search of the conformational space was necessary. The equi-
librium structures and the gas-phase molecular energies
were determined by locating the global minimum of the
potential energy surface (PES) of each isolated product. A
large number of starting geometries were generated, and
subsequently optimized, by systematically rotating key dihe-
dral angles in the two product structures. For compound 12a
nine conformers were found, whereas a total of 15 different
conformers were found for compound 10a. Frequency calcu-
lations were then carried out for the handful of conformers of
each system possessing the lowest energy, serving both to
verify that the geometries indeed corresponded to stable
structures and to estimate the zero-point vibrational energy
of each system. The two equilibrium structures are shown
in Figure 3, and it was found that the molecular energy of
the allene 10a is 27 kJ/mol lower than the expected Sonoga-
shira alkynylation product 12a. By adding the zero-point
vibrational energy, the energy difference increases very
In order to further confirm the structure of the allenes 10,
purine 1a was reacted with the alkyne 11a and the allene
1
chromatography (Scheme 7). Theoretical calculations have
0a was isolated together with the alkyne 13a (13%) after
1
9
shown that an alkoxy group will stabilize an allene, and
propargyl ethers can be isomerized to alkoxyallenes under
basic conditions, but generally strong bases like Bu OK or
t
2
0
RLi, are employed. Formation of the allene 10a under
moderately basic Sonogashira conditions indicates that the
6
-purinyl moiety facilitate allene formation. When the 3-
phenoxypropyn-1-yl functionality was introduced in the
less electron deficient purine 2-position, the expected alkyne
was formed.
2
1
Electronic structure calculations were carried out to further
investigate the formation of the allene 10a, rather than the
expected alkyne 12a, in Scheme 7. First, the reactants 1a
Figure 3. The gas-phase equilibrium structure of the expected Sonogashira product 12a and the observed product 10a as calculated at the B3LYP/6-31G(d,p)
level of theory. Carbon, hydrogen, nitrogen, and oxygen atoms are shown in black, in white, with grids, and with lines, respectively.

6126
T. C. Berg et al. / Tetrahedron 62 (2006) 6121–6131
i
ii
OH
OH
O
•
8
Ar
Ar
9
9
9
9
d, Ar = 2-Cl-pyrimidin-4-yl
10d, Ar = 2-Cl-pyrimidin-4-yl: 39%
10e, Ar = pyridin-2-yl
e, Ar = pyridin-2-yl
f, Ar = p-NO -C H
10f, Ar = p-NO -C H
not formed
2
6
4
2
6
4
g, Ar = Ph
10g, Ar = Ph
ꢀ
Scheme 8. Reagents and conditions: (i) ArX, (Ph
P)
3 2
PdCl
2
, CuI, (i-Pr) NR, DMF, 60 C; (ii) CuI, Et
2
3
N, D.
slightly to 28 kJ/mol. One may also estimate the standard
enthalpy of formation for the two compounds, and the allene
is again found to be 28 kJ/mol more stable than the alkyne.
While not yielding a huge energy difference, the theoretical
calculations clearly indicate that of the two compounds, the
allene is energetically favorable. The theoretical results are
thus in very good agreement with the experimental findings.
with o-(hydroxymethyl)ethynylbenzene, 6-(isobenzofuryl-
idenemethyl)purine was formed, mainly as the (E)-isomer.
The pure (Z)-isomer was available from a two-step reaction;
Sonogashira coupling with O-silylated alkyne followed by
acidic or TBAF mediated deprotection and subsequent 5-
exo cyclization. The less stable o-quinonoid tautomer 6-(iso-
benzofurylmethyl)purine could not be detected, neither
could formation of a 6-endo cyclized isochromene product.
In the (E)-isomer of the 6-(isobenzofurylidenemethyl)-
purine, NMR spectroscopy indicates the presence of an
intramolecular C–H/N bond between N-1 in the purine
and H-7 in the isobenzofurane.
The rearrangement of compounds 9 to the allenes 10
(
Scheme 5 above) was highly unexpected and we decided
to look into the scopes and limitations of the reaction. Even
though allenes often has been regarded as chemical curio-
2
2,23
sities, they may be useful synthetic intermediates
there are quite a few examples of pharmacologically active
and
Sonogashira coupling between 6-halopurines and 2-propy-
nylphenol gave only the alkyne coupling product and no cy-
clization took place. However, the Sonogashira product was
unexpectedly rearranged to 6-(3-phenoxypropa-1,2-dienyl)-
2
4
allenes including allene natural products. Our hypothesis
was that the allene formation is especially favorable when
the allene carries both powerful electron withdrawing and
electron donating groups. Coupling between purine 1a and
alkyne 11b gave only the alkyne 12b (Scheme 7). The alkyne
purines, when refluxed in Et N. The yields were somewhat
3
improved in the presence of CuI. Only allenes with both
a powerful electron withdrawing and electron releasing sub-
stituent on the allene fragment was formed by this novel
rearrangement.
8
was reacted with different aryl halides or heteroaryl halides
to give compounds 9d–9g. Only the alkyne 9d rearranged to
the allene under basic conditions confirming that a highly
electron withdrawing group is required for the reaction to
take place (Scheme 8).
4
. Experimental
Finally, we reacted alkyne 11a with the same aryl- or hetero-
aryl halides as used in the reactions described in Scheme 9.
In all cases examined the ‘normal’ Sonogashira product 12
was formed and no allenes 10 could be detected, not even
in the synthesis of pyrimidine 12d even though the allene
4
.1. General
1
The H NMR spectra were acquired on a Bruker Avance AV
00 spectrometer, a Bruker Avance DRX 500 spectrometer,
a Bruker Avance DPX 300 spectrometer or a Bruker Avance
DPX 200 spectrometer at 600, 500, 300 or 200 MHz, respec-
tively. The H decoupled C NMR spectra were recorded
at 150, 125, 75 or 50 MHz using the above-mentioned
spectrometers. Assignments of H and C resonances are
inferred from 1D H NMR, 1D C NMR, APT, DEPT
and/or from 2D NMR (gs-COSY, gs-HMQC, gs-HMBC,
NOESY) spectral data. N NMR data were acquired at
0 MHz on the Bruker Avance DRX 500 with a 5 mm TXI
H/ C, N– H) Triple Resonance Inverse probe, equipped
with Z-gradient coil, by applying 2D NMR experiments
based on gradient pulse selection and inverse detection
methods: gs-[ H, N] HMBC, optimized for J/ J N/ H-
couplings of 10 Hz (Bruker pulse program: inv4gplplrndqf,
6
1
0d could be formed by rearrangement (Scheme 8).
1
13
1
13
O
O
1
13
O
i
•
+
Ar
10
15
Ar 12
11a
5
12 : 10; > 95 : 5
1
13
15
2
(
Ar = 2-Cl-pyrimidin-4-yl, pyridin-2-yl, p-NO -C H , Ph
2
6 4
Scheme 9. Reagents and conditions: (i) ArX, (Ph
ꢀ
3
P)
2
PdCl
2
, CuI, (i-Pr)
2
NR,
1
15
2
3
15
1
DMF, 60 C.
1
5
N-pulses via F2-channel, relaxation delay, d1: 1.5 s, ac-
quisition time, aq: 0.17 s, delay for evolution of long range
couplings, d6: 0.1 s). N chemical shifts are reported relative
3. Conclusions
1
5
1
5
6
-(2-Benzofuryl)purines are readily available by one-pot
to external Me NO at 0 ppm (MeNO dissolved in the re-
2 2
Sonogashira coupling–cyclization between 6-iodopurine
and 2-ethynylphenol. When the same reaction is performed
spective deuterated solvent in ratio 9:1). The selective 1D IN-
ADEQUATE (SELINQUATE) spectrum for verification of

T. C. Berg et al. / Tetrahedron 62 (2006) 6121–6131
6127
the 5-membered ring structure of product 7 was acquired on
the Bruker Avance AV 600 with a 5 mm CP–TCI ( H/ C,
(1 mL) was added dropwise over 1 h. The resulting mixture
ꢀ
1
13
was stirred at 60 C for 4 h before evaporation. The product
1
5
2
13
N– H) Triple Resonance Inverse Cryo probe (cold
coil and preamplifier). In order to decrease the relaxation
C
was isolated by flash chromatography on silica gel eluting
with EtOAc–hexane (2:1); yield 206 mg (61%, E/Z ratio:
88:12), 100 mg of the isomeric mixture was purified by flash
1
3
times especially for the quaternary C atoms and thereby
to reduce the experiment time, 130 mg of product 7 was dis-
solved in 0.6 mL nonafluoro-tert-butyl alcohol (perfluoroter-
chromatography silica gel eluting with CHCl –EtOAc (2:1);
3
yield 79 mg pure (E)-isomer, yellow crystals, mp 170–
ꢀ
2
5
1
tiarybutanol, ‘artificial blood’). 5% DMSO-d was added
6
173 C. H NMR (600 MHz, DMSO-d ): d 9.84 (d,
6
for the lock and the solution was saturated with oxygen at
room temperature. Bruker pulse program: selina. AGaussian
shape cascade with 1024 data points (SPNAM1: Q5.1000) of
J 7.9 Hz, 1H, benzofuran), 8.88 (s, 1H, H-2), 8.59 (s, 1H,
H-8), 7.59–7.53 (m, 3H, benzofuran), 7.34–7.27 (m, 5H, Ph),
6.82 (s, 1H, CH]), 5.53 (s, 2H, OCH ), 5.48 (s, 2H, NCH );
2
2
1
3
1
calibrated for our specific spectrometer probe), correspond-
0 ms length (p11) and 32 dB attenuation (sp1, which was
C NMR (150 MHz, DMSO-d ): d 166.0 (benzofuran),
6
153.3 (C-6), 151.5 (C-2), 150.2 (C-4), 144.5 (benzofuran),
144.4 (C-8), 136.7 (Ph), 131.4 (benzofuran), 130.0 (benzo-
furan), 129.6 (C-5), 128.7 (Ph), 127.86 (benzofuran),
127.85 (benzofuran), 127.8 (Ph), 127.6 (Ph), 121.4 (benzo-
ꢀ
pulse. The acquisition was optimized for J(C,C) couplings
13
ing to 90 excitation was used as the C transmitter soft
1
of 60 Hz (CNST3), corresponding to d4¼4.17 ms. Relaxa-
tion delay (d1): 4 s, acquisition time (aq): 0.3 s. The experi-
mental time was 62 h with 50,000 scans applied. IR spectra
were recorded at a Perkin–Elmer Spectrum One instrument.
MS spectra under electron impact conditions were recorded
with a VG Prospec instrument at 70 eV ionizing voltage
1
5
furan), 94.3 (CH]), 73.7 (OCH ), 46.3 (NCH ); N NMR
2
2
1
3
(50 MHz, Me NO ): d ꢁ217.0 (N-9), ꢁ137.4 (br, N-3 and
2
N-7), ꢁ114.9 (N-1); IR (KBr) n
1621 (s), 1578 (s), 1469
(m), 1444 (m), 1401 (m), 1088 (m), 982 (m) cm ; EIMS
max
ꢁ
1
+
m/z (rel %): 340 (96, M ), 240 (100), 91 (71); HRMS (EI)
found 340.1327, calcd for C H N O 340.1324.
and are presented as m/z (% rel int.). CH was employed as
4
21 16 4
the ionization gas for chemical ionization (CI). Electrospray
MS spectra were recorded with a Bruker Apex 47e FT-ICR
mass spectrometer. Elemental analyses were performed by
Ilse Beetz Mikroanalytisches Laboratorium, Kronach, Ger-
many. Melting points are uncorrected. DMF, CH Cl , tri-
4.1.3. 9-Benzyl-6-{[2-({[(1,1-Dimethylethyl)dimethylsilyl]
oxy}methyl)phenyl]ethynyl}-9H-purine (6). 9-Benzyl-6-
iodo-9H-purine 1a (168 mg, 0.500 mmol) was added to
a stirred solution of (PPh ) PdCl (18 mg, 0.025 mmol),
2
2
3 2
2
ethylamine, and diisopropylamine were distilled from
CaH . The following compounds were prepared by literature
CuI (9 mg, 0.05 mmol), and diisopropylamine (427 mL,
3.00 mmol) in DMF (5 mL) under N -atm. The reaction
mixture was heated to 60 C and compound 4b (148 mg,
2
2
2
6
3c
27
9
28 29
ꢀ
0.60 mmol) in DMF (1 mL) was added dropwise over 1.5 h.
methods: 1a, 1b, 1c, 2, 4b, 8. All other reagents
were commercially available and used as received. All quan-
tum chemical calculations were performed using Gaussian
ꢀ
evaporation. The product was isolated by flash chromato-
The resulting mixture was stirred at 60 C for 22 h before
3
0
0
3. Both geometry optimizations and frequency calcula-
tions were carried out at the DFT level of theory, employing
the B3LYP-functional in conjunction with the 6-31G(d,p)
basis set and the ‘ultrafine’ grid. The chosen computational
method is well established and it gives sufficiently accurate
results for this study at a reasonable computational cost.
Antimycobacterial activities were determined as described
graphy on silica gel eluting with CHCl –EtOAc (1:1); yield
3
1
219 mg (96%), pale brownish oil. H NMR (300 MHz,
CDCl ): d 8.97 (s, 1H, H-2), 8.07 (s, 1H, H-8), 7.64–7.61
3
(m, 3H, Ph), 7.43–7.21 (m, 6H, Ph), 5.44 (s, 2H, OCH2),
5.12 (s, 2H, NCH ), 0.94 (s, 9H, t-Bu), 0.12 [s, 6H,
2
1
3
Si(CH ) ]; C NMR (75 MHz, CDCl ): d 152.6 (C-2),
3
2
3
3
before.
151.6 (C-4), 145.0 (C-8), 144.9 (Ph), 142.0 (C-6), 134.9
C-5), 134.4 (Ph), 132.6 (Ph), 130.1 (Ph), 129.2 (Ph), 128.7
(Ph), 127.8 (Ph), 126.4 (Ph), 125.7 (Ph), 117.9 (Ph), 95.0
(
4
.1.1. 6-(2-Benzo[b]furyl)-9-benzyl-9H-purine (3). Diiso-
propylamine (848 mL, 6.00 mmol) was added to a stirred
solution of 9-benzyl-6-iodo-9H-purine (336 mg, 1.00 mmol),
(C^), 88.9 (C^), 63.2 (OCH ), 47.4 (NCH ), 26.0 (CH in
2
2
3
t-Bu), 18.4 (C in t-Bu), ꢁ5.3 [Si(CH ) ]; IR (CCl ) n
3
2
4
max
(
PPh ) PdCl (35 mg, 0.05 mmol), and CuI (19 mg,
3
3069 (w), 304 (w), 2956 (m), 2930 (m), 2886 (m), 2857
2
2
ꢁ
1
0
6
.10 mmol) in DMF (5 mL). The mixture was heated at
ꢀ
(m), 2213 (m), 1748 (w), 1579 (s) cm ; CIMS m/z (rel %):
455 (76, M+1), 397 (100), 91 (34); HRMS (ESI) found
455.2250, calcd for C H N OSi+H 455.2261.
0 C, and 2-ethynylphenol (142 mg, 1.20 mmol) in DMF
(
1 mL) was added over 2 h and the reaction mixture was
2
7 30 4
stirred for additional 3 h before evaporation. The product
was isolated by flash chromatography on silica gel eluting
with EtOAc–CHCl (1:9); yield 211 mg (65%) off-white
4.1.4. (Z)-9-Benzyl-6-[isobenzofuran-1(3H)-ylidene-
methyl]-9H-purine (7). Method A: The TBS-protected
alcohol 6 (200 mg, 0.44 mmol) was dissolved in EtOH
(10 mL) and aq HCl (5 mL, 1 M) was added dropwise. The
resulting mixture was stirred at ambient temperature for 6 h
3
ꢀ
3d
ꢀ
1
crystalline solid, mp 200–202 C (lit. 202–203 C). H
NMR (300 MHz, CDCl ): d 9.08 (s, 1H, H-2), 8.29 (s, 1H,
3
H-3 in benzofuryl), 8.13 (s, 1H, H-8), 7.70–7.72 (m, 2H in
Ar), 7.28–7.40 (m, 7H, Ar), 5.48 (s, 2H, CH2).
and quenched by addition of NaHCO to neutral pH before
3
evaporation. The product was isolated by flash chromato-
graphy on silica gel eluting with EtOAc–EtOH (9:1); yield
99 mg (90%), pale yellow crystals, mp 207–208 C. H
4
.1.2. (E)-9-Benzyl-6-[isobenzofuran-1(3H)-ylidene-
methyl]-9H-purine (5). 9-Benzyl-6-iodo-9H-purine 1a
336 mg, 1.00 mmol) was added to a stirred solution
of (PPh ) PdCl (35 mg, 0.05 mmol), CuI (19 mg,
ꢀ
NMR (200 MHz, CDCl ): d 9.03 (s, 1H, H-2), 7.94 (s, 1H,
1
(
3
H-8), 7.85–7.81 (m, 1H, benzofuran), 7.48–7.26 (m, 8H, Ph
and benzofuran), 6.84 (s, 1H, CH]), 5.73 (s, 2H, OCH ),
3
2
2
0.10 mmol), and diisopropylamine (854 mL, 6.00 mmol) in
DMF (5 mL) under N -atm. The reaction mixture was heated
to 60 C and compound 4a (159 mg, 1.20 mmol) in DMF
2
1
3
5.41 (s, 2H, NCH2); C NMR (75 MHz, CDCl ): d 163.5
3
2
ꢀ
(C-2 in benzofuran), 153.3 (C-6), 152.1 (C-2), 150.3 (C-4),

6128
T. C. Berg et al. / Tetrahedron 62 (2006) 6121–6131
1
1
44.2 (C-8), 141.5 (C in benzofuran), 136.8 (C-1 in Ph),
33.4 (C in benzofuran), 130.9 (C in benzofuran), 129.5
(96); HRMS (EI) found 374.0946, calcd for C H N OCl
21 15 4
374.0934.
(
1
C-5), 128.7 (C in benzofuran), 128.6 (C in benzofuran),
27.9 (C in benzofuran), 127.6 (C in Ph), 120.0 (C in benzo-
furan), 121.4 (C in benzofuran), 88.0 (CH]), 76.2 (CH in
4.1.7. 2-[3-(9-Tetrahydropyran-2-yl-9H-purin-6-yl)-2-
propynyl]phenol (9c). A mixture of 6-chloro-9-(tetrahy-
dro-2H-pyran-2-yl)-9H-purine 1c (476 mg, 2.00 mmol), di-
isopropyl(ethyl)amine (2.08 mL, 12.0 mmol), (PPh ) PdCl
2
1
5
13
benzofuran), 46.3 (NCH2); N NMR (50 MHz, Me NO ):
2
d ꢁ217.6 (N-9), ꢁ137.3 (br, N-3 and N-7), ꢁ109.1 (N-1);
3
2
2
IR (KBr) n
(
1635 (s), 1577 (s), 1452 (m), 1398 (m), 1296
m), 1052 (m), 975 (m) cm ; EIMS m/z (rel %): 340 (97,
(140 mg, 0.20 mmol), and CuI (76 mg, 0.40 mmol) in
ꢀ
max
ꢁ
1
DMF (8 mL) was heated to 60 C under N -atm. 2-(Prop-2-
2
+
M ), 249 (100), 91 (34); HRMS (EI) found 340.1321, calcd
for C H N O 340.1324.
ynyl)phenol 8 (344 mg, 2.40 mmol) in DMF (4 mL) was
added dropwise over 5.5 h, and the resulting mixture was
stirred for another 0.5 h. The product was isolated by flash
2
1 16 4
Method B: The TBS-protected alcohol 6 (153 mg, 0.34
mmol) was dissolved in THF (5 mL), a solution of tetra-
butylammonium fluoride (440 mL, 0.1 mM in THF) was
added and the resulting mixture was stirred for 4 h at ambi-
chromatography on silica gel eluting with EtOAc–CHCl
(1:1); yield 294 mg (44%), yellow oil. H NMR (300 MHz,
CDCl ): d 8.89 (s, 1H, H-2), 8.31 (s, 1H, H-8), 7.29–7.24
3
3
1
(m, 2H, Ph), 7.02–6.92 (m, 2H, Ph), 5.75 (dd, J 9.8 and
2.6 Hz, 1H, H-2 in THP), 5.02 (s, 2H, CH ), 4.13 (dd, J
ent temperature under N -atm. The reaction mixture was
2
2
evaporated on silica gel and the product was isolated by flash
chromatography on silica gel eluting with EtOAc–EtOH
11.5 and 3.8 Hz, 1H, H-6 in THP), 3.74 (dt, J 11.5 and
a
2.6 Hz, 1H, H-6 in THP), 2.09–2.02 (m, 3H, THP), 1.75–
b
1
3
(
9:1); yield 44 mg (39%); data, see above.
1.63 (m, 3H, THP); C NMR (75 MHz, CDCl ): d 157.5
3
(Ph), 152.4 (C-2), 150.7 (C-4), 143.3 (C-8), 140.6 (C-6),
4
(
0
(
0
6
.1.5. 2-[3-(9-Benzyl-9H-purin-6-yl)-2-propynyl]phenol
9a). A mixture of 9-benzyl-6-iodo-9H-purine 1a (169 mg,
.50 mmol), diisopropylamine (427 mL, 3.00 mmol),
PPh ) PdCl (35 mg, 0.05 mmol), and CuI (19 mg,
134.5 (C-5), 129.4 (Ph), 121.5 (Ph), 114.8 (Ph), 93.1 (C^),
82.0 (C-2 in THP), 81.4 (C^), 68.6 (C-6 in THP), 56.2
(CH ), 31.6 (THP), 24.7 (THP), 22.6 (THP); IR (neat) n
2
max
3446 (br), 3102 (m), 3060 (m), 2947 (s), 2859 (s), 2240
(m), 1735 (w), 1583 (s), 1494 (s), 1441 (s), 1403 (s) cm ;
3
2
2
ꢁ1
.10 mmol) in DMF (5 mL) under N -atm was heated to
2
ꢀ
0 C. 2-(Prop-2-ynyl)phenol 8 (82 mg, 0.60 mmol) in
CIMS (CH ) m/z (rel %): 335 (14, M+1), 251 (100); HRMS
4
DMF (1 mL) was added dropwise over 3 h, and the resulting
mixture was stirred for 2 h. The product was isolated by flash
chromatography on silica gel eluting with EtOAc–EtOH
(CI) found 335.1510, calcd for C H N O +H 335.1508.
19 19 4 2
4.1.8. 2-[3-(2-Chloropyrimidin-4-yl)-2-propynyl]phenol
(9d). A mixture of 2,4-dichloropyrimidine (149 mg,
1.00 mmol), diisopropyl(ethyl)amine (1.02 mL, 6.00 mmol),
(PPh ) PdCl (35 mg, 0.05 mmol), and CuI (19 mg,
1
(
CD OD): d 8.96 (s, 1H, H-2), 8.11 (s, 1H, H-8), 7.38–7.24
1:1); yield 50 mg (30%), yellow oil. H NMR (300 MHz,
3
(
5
m, 6H, Ph), 7.07–6.96 (m, 3H, Ph), 5.44 (s, 2H, CH ),
2
.06 (s, 2H, CH2); C NMR (75 MHz, CD OD): d 157.6
3
3 2
2
1
3
ꢀ
0.10 mmol) in DMF (5 mL) was heated to 60 C under N -
2
(
C-6), 152.7 (C-2), 151.7 (C-4), 145.3 (C-8), 140.8 (Ph),
atm. 2-(Prop-2-ynyl)phenol 8 (163 mg, 1.20 mmol) in DMF
(1 mL) was added dropwise over 3 h, and the resulting mix-
ture was stirred for another 2 h. The product was isolated by
flash chromatography on silica gel eluting with hexane–
1
1
9
34.7 (Ph), 134.3 (C-5), 129.5 (Ph), 129.2 (2ꢂC in Ph),
28.7 (Ph), 127.8 (Ph), 121.6 (Ph), 114.9 (2ꢂC in Ph),
3.2 (C^), 81.4 (C^), 56.3 (CH ), 47.4 (NCH ); IR
2
2
1
(
(
neat) n
s) cm ; EIMS m/z (rel %): 340 (81, M ), 247 (54), 91
3063 (m), 2987 (m), 1593 (s), 1494 (s), 1403
EtOAc (4:1); yield 44 mg (18%), brownish oil. H NMR
(300 MHz, CDCl ): d 8.53 (d, J 5.1 Hz, 1H, H-6), 7.29–7.21
max
1
ꢁ
+
3
(
3
100); HRMS (EI) found 340.1313, calcd for C H N O
4
40.1324.
(m, 3H, Ph H-5), 6.99–6.93 (m, 2H, Ph), 4.89 (s, 2H, CH );
2
C NMR (75 MHz, CDCl ): d 161.2 (C-2), 159.6 (C-6),
3
2
1
16
1
3
1
57.3 (Ph), 152.3 (C-4), 129.6 (2ꢂC in Ph), 121.9 (Ph),
4
.1.6. 2-{3-[9-(4-Chlorobenzyl)-9H-purin-6-yl]-2-pro-
121.8 (C-5), 114.8 (2ꢂC in Ph), 91.1 (C^), 83.2 (C^),
pynyl}phenol (9b). A mixture of 6-chloro-9-[(4-chlorophe-
nyl)methyl]-9H-purine 1b (140 mg, 0.500 mmol), diiso-
propyl(ethyl)amine (424 mL, 3.00 mmol), (PPh ) PdCl
2
56.0 (CH ); IR (neat) n 3043 (w), 2917 (w), 2237 (w),
1561 (s), 1495 (m) cm ; EIMS m/z (rel %): 246/244
2 max
ꢁ1
+
(42/100, M ), 215/217 (71/26), 151 (47); HRMS (EI) found
244.0394, calcd for C H N OCl 244.0403.
3
2
(
(
35 mg, 0.05 mmol), and CuI (19 mg, 0.10 mmol) in DMF
ꢀ
1
3 9 2
5 mL) was heated to 80 C under N -atm. 2-(Prop-2-ynyl)-
2
phenol 8 (82 mg, 0.60 mmol) in DMF (1 mL) was added
dropwise over 3 h, and the resulting mixture was stirred for
another 3.5 h. The product was isolated by flash chromato-
4.1.9. 2-[3-(Pyridin-2-yl)-2-propynyl]phenol (9e). 2-Bro-
mopyridine (158 mg, 1.00 mmol), (PPh ) PdCl (70 mg,
0.10 mmol), CuI (38 mg, 0.20 mmol) diisopropyl(ethyl)-
amine (1.04 mL, 6.00 mmol), and 2-(prop-2-ynyl)phenol 6
(163 mg, 1.20 mmol) was reacted as described for 9b above.
The product was isolated by flash chromatography on silica
3
2
2
graphy on silica gel eluting with EtOAc–CHCl (1:1); yield
3
1
5
d 8.92 (s, 1H, H-2), 8.07 (s, 1H, H-8), 7.32–7.20 (m, 5H,
0 mg (27%), yellow oil. H NMR (300 MHz, CDCl ):
3
Ph), 7.03 (m, 3H, Ph), 5.38 (s, 2H, CH ), 5.03 (s, 2H,
2
CH2); C NMR (75 MHz, CDCl ): d 157.6 (C-6), 152.8
3
gel eluting with hexane–EtOAc (1:1); yield 123 mg (59%),
brownish oil. H NMR (300 MHz, CDCl ): d 8.55 (d, J
1
3
1
3
(
1
(
4
C-2), 151.6 (C-4), 145.1 (C-8), 141.0 (Ph), 134.8 (Ph),
34.4 (C-5), 133.2 (Ph), 129.5 (Ph), 129.2 (Ph), 121.7
Ph), 115.0 (Ph), 93.5 (C^), 81.4 (C^), 56.4 (CH2),
6.8 (CH ); IR (neat) n 3420 (br), 3063 (m), 2239
4.5 Hz, 1H, Ar), 7.60–7.57 (m, 1H, Ar), 7.41–7.38 (m, 1H,
Ar), 7.32–7.27 (m, 2H, Ar), 7.24–7.21 (m, 1H, Ar), 7.03–
6.95 (m, 2H, Ar), 4.91 (s, 2H, CH2); C NMR (75 MHz,
1
3
CDCl ): d 157.7 (Ar), 150.0 (Ar), 142.5 (Ar), 136.1 (Ar),
3
2
max
ꢁ
1
(
EIMS m/z (rel %): 376/374 (26/87, M ), 249 (100), 125
w), 1897 (w), 1593 (s), 1495 (s), 1437 (s), 1403 (s) cm
;
129.5 (Ar), 127.3 (Ar), 123.2 (Ar), 121.5 (Ar), 114.9 (Ar),
86.2 (C^), 83.9 (C^), 56.3 (CH ); IR (CCl ) n
+
3066
max
2
4

T. C. Berg et al. / Tetrahedron 62 (2006) 6121–6131
6129
ꢁ
1
(
2
w), 1599 (m), 1583 (s), 1495 (s) cm ; EIMS m/z (rel %):
263 (42), 91 (100); HRMS (EI) found 340.1320, calcd for
C H N O 340.1324.
+
09 (74, M ), 116 (100); HRMS (EI) found 209.0839, calcd
for C H NO 209.0841; Anal. found: C, 80.16; H, 5.60; N,
2
1 16 4
14 11
7
.00. C H NO requires C, 80.36; H, 5.30; N, 6.69%.
14 11
4.1.13. 9-(4-Chlorobenzyl)-6-(3-phenoxypropa-1,2-
dienyl)-9H-purine (10b). A mixture of compound 9b
4.1.10. 2-[3-(p-Nitrophenyl)-2-propynyl]phenol (9f). 1-
Bromo-4-nitrobenzene (202 mg, 1.00 mmol), (PPh ) PdCl
(50 mg, 0.14 mmol) and CuI (3 mg, 0.014 mmol) in Et N
3
(5 mL) was refluxed under N -atm for 24 h. The product
2
3
2
2
(
(
70 mg, 0.10 mmol), CuI (38 mg, 0.20 mmol), diisopropyl-
ethyl)amine (1.04 mL, 6.00 mmol), and 2-(prop-2-ynyl)-
was isolated by flash chromatography on silica gel eluting
with EtOAc–hexane (2:1); yield 10 mg (20%), brownish
oil. H NMR (600 MHz, CD OD): d 8.40 (s, 1H, H-2), 7.73
3
1
phenol 8 (163 mg, 1.20 mmol) was reacted as described
for 9b above. The product was isolated by flash chromato-
graphy on silica gel eluting with hexane–EtOAc (95:5);
yield 166 mg (66%), mp 83–85 C, off-white crystals. H
NMR (300 MHz, CDCl ): d 8.17–8.14 (m, 2H, Ph), 7.58–
(s, 1H, H-8), 7.32–7.27 (m, 4H, Ph), 7.20 (m, 2H, Ph), 7.10
(m, 1H, Ph), 7.00 (m, 2H, Ph), 6.65 (dd, J 3.9 and 0.7 Hz,
1H, ]CH), 6.35 (d, J 3.9 Hz, 1H, ]CH), 5.41 (s, 2H,
ꢀ
1
1
3
NCH2); C NMR (150 MHz, CD OD): d 157.7 (Ph), 137.9
3
3
7
2
.54 (m, 2H, Ph), 7.35–7.29 (m, 2H, Ph), 7.03–6.98 (m,
H, Ph), 4.92 (s, 2H, CH2); C NMR (75 MHz, CDCl3):
(C-8), 134.5 (Ph), 133.8 (Ph), 133.6 (C-4), 134.2 (]C]),
132.2 (C-2), 129.9 (Ph), 129.3 (Ph), 128.2 (Ph), 125.3 (C-
5), 123.7 (Ph), 122.8 (C-6), 115.8 (Ph), 100.7 (]CH in
1
3
d 157.5 (Ph), 147.3 (Ph), 132.5 (Ph), 129.5 (Ph), 129.1
(
Ph), 123.5 (Ph), 121.7 (Ph), 114.9 (Ph), 89.3 (C^), 85.1
C^), 56.3 (CH ); IR (KBr) nmax 3415 (br), 3107 (w),
allene), 93.1 (]CH in allene), 46.9 (NCH ); EIMS m/z
2
+
(
(rel %): 376/374 (37/100, M ), 299/297 (15/45), 127/125
(21/65); HRMS (EI) found 374.0930, calcd for
C H N OCl 374.0934.
2
ꢁ1
2
(
856 (w), 1592 (s), 1519 (s), 1490 (s) cm ; EIMS m/z
rel %): 253 (63, M ), 160 (100), 130 (99); HRMS (EI) found
+
2
1 15 4
2
7
53.0737, calcd for C H NO 253.0738; Anal. found: C,
15 11 3
1.11; H, 4.38. C H NO requires C, 71.14; H, 4.38%.
3
4.1.14. 6-(3-Phenoxypropa-1,2-dienyl)-9-(tetrahydro-
pyran-2-yl)-9H-purine (10c). A mixture of compound 9c
1
5
11
4
(
.1.11. 2-(3-Phenyl-2-propynyl)phenol (9g). Iodobenzene
114 mL, 1.00 mmol), (PPh ) PdCl (71 mg, 0.100 mmol),
(140 mg, 0.42 mmol) and CuI (8 mg, 0.042 mmol) in Et N
3
(5 mL) was refluxed under N -atm for 16 h. The product
2
3
2
2
CuI (38 mg, 0.20 mmol), diisopropylamine (0.84 mL,
.0 mmol), and2-(prop-2-ynyl)phenol8(163 mg, 1.20 mmol)
was isolated by flash chromatography on silica gel eluting
with EtOAc–EtOH (99:1); yield 54 mg (39%), yellow oil.
H NMR (500 MHz, CDCl ): d 8.39 (s, 1H, H-2), 7.96 (s,
3
1H, H-8), 7.31–7.28 (m, 2H, Ph), 7.09–7.06 (m, 1H, Ph),
6.99–6.97 (m, 2H, Ph), 6.64 (dd, J 3.9 and 0.8 Hz, 1H,
CH]), 6.35 (d, J 3.9 Hz, 1H, CH]), 5.68–5.66 (m, 1H,
6
1
was reacted as described for 9b above. The product was
isolated by flash chromatography on silica gel eluting with
hexane–acetone (199:1); yield 169 mg (81%), mp 44–
ꢀ
5 C, pale yellow crystals. H NMR (300 MHz, CDCl ):
3
1
4
d 7.46–7.42 (m, 2H, Ph), 7.34–7.28 (m, 4H, Ph), 7.05–6.97
(m, 3H, Ph), 4.91 (s, 2H, CH2); C NMR (75 MHz, CDCl3):
d 158.2 (Ph), 132.2 (Ph), 129.9 (Ph), 129.1 (Ph), 128.7 (Ph),
H-2 in THP), 4.15 (dd, J 11.7 and 2.3 Hz, 1H, H-6 in
a
1
3
THP), 3.74 (dt, J 11.7 and 2.3 Hz, 1H, H-6 in THP), 2.11–
b
1
3
2.02 (m, 3H, THP), 1.76–1.62 (m, 3H, THP); C NMR
(75 MHz, CDCl ): d 157.7 (Ph), 136.2 (C-8), 133.6
1
5
2
22.7 (Ph), 121.6 (Ph), 115.4 (Ph), 87.6 (C^), 84.4 (C^),
7.1 (CH ); IR (KBr) n 3436 (br), 3050 (w), 2964 (w),
3
(]C]), 132.6 (C-2), 132.0 (C-4), 129.9 (Ph), 125.1 (C-5),
122.0 (C-6), 123.6 (Ph), 115.7 (Ph), 100.8 (]CH in allene),
93.1 (]CH in allene), 82.1 (C-2 in THP), 68.7 (THP), 31.7
(THP), 24.9 (THP), 22.9 (THP); IR (neat) nmax 2947 (m),
2
max
ꢁ
1
930 (w), 2196 (w), 1598 (m), 1586 (m), 1489 (s) cm
;
+
EIMS m/z (rel %): 208 (19, M ), 115 (100); HRMS (EI)
found 208.0886, calcd for C H O 208.0888; Anal. found:
1
5 12
ꢁ1
C, 86.30; H, 5.72. C H O requires C, 86.51; H, 5.81%.
15 12
2858 (m), 1641 (m), 1579 (m), 1552 (s), 1490 (s) cm ;
EIMS m/z (rel %): 334 (24, M ), 250 (100), 173 (89);
+
4
.1.12. 9-Benzyl-6-(3-phenoxypropa-1,2-dienyl)-9H-
purine (10a). A mixture of 9-benzyl-6-iodo-9H-purine 1a
336 mg, 1.00 mmol), (PPh ) PdCl (35 mg, 0.05 mmol),
HRMS (EI) found 334.1432, calcd for C H N O
9 19 4 2
334.1430.
1
(
3
2
2
CuI (19 mg, 0.10 mmol), and diisopropylamine (854 mL,
.00 mmol) in DMF (5 mL) was stirred under N -atm at
4.1.15. 2-Chloro-4-(3-phenoxypropa-1,2-dienyl)-pyrimi-
dine (10d). mixture of compound 9d (44 mg,
0.18 mmol) and CuI (4 mg, 0.018 mmol) in Et N (5 mL)
6
A
2
ꢀ
in DMF (1 mL) was added dropwise over 3 h. The mixture
6
0 C, and 2-(prop-2-ynyl)phenol 8 (163 mg, 1.20 mmol)
3
was refluxed under N -atm for 26 h. The compound was iso-
2
ꢀ
lated by flash chromatography on silica gel eluting with
was stirred for another 24 h at 60 C. The product was iso-
lated by flash chromatography on a silica gel eluting with
hexane–EtOAc (4:1); yield 17 mg, (39%), pale yellow oil.
ꢀ
yellow crystals. H NMR (500 MHz, CD OD): d 8.43 (s,
1
EtOAc–hexane (3:2); yield 139 mg (41%), mp 83–85 C,
H NMR (500 MHz, CD OD): d 8.56 (d, J 1.3 Hz, 1H, H-
3
1
6), 7.37–7.34 (m, 3H, H-5 and 2H in Ph), 7.15–7.12 (m,
1H, Ph), 7.04–7.02 (m, 2H, Ph), 6.43 (s, 2H, 2ꢂCH] in
3
1
7
3
2
1
2
H, H-2), 8.04 (s, 1H, H-8), 7.32–7.28 (m, 7H, Ph), 7.08–
.00 (m, 1H, Ph), 6.99–6.98 (m, 2H, Ph), 6.59 (d, J
.9 Hz, 1H, ]CH), 6.33 (d, J 3.9 Hz, 1H, ]CH), 5.41 (s,
H, NCH2); C NMR (125 MHz, CD OD): d 159.1 (Ph),
3
40.0 (C-8), 137.9 (Ph), 135.6 (Ph), 134.6 (C-4), 133.6 (C-
), 131.1 (Ph), 129.9 (Ph), 129.1 (Ph and ]C]), 128.8
1
3
allene); C NMR (125 MHz, CD OD): d 158.6 (Ph),
3
136.1 (C-6), 135.2 (]C]), 134.5 (C-2), 131.2 (Ph), 127.2
(C-4), 125.2 (Ph), 117.2 (Ph), 113.0 (C-5), 103.8 (CH] in
allene), 98.7 (CH] in allene); EIMS m/z (rel %): 246/244
1
3
+
(25/72, M ), 169/167 (36/100); HRMS (EI) found
244.0402, calcd for C H N OCl 244.0403.
(
1
(
1
Ph), 125.5 (Ph), 124.8 (C-5), 123.4 (C-6), 116.9 (Ph),
01.4 (CH] in allene), 94.1 (CH] in allene), 49.0
NCH ); IR (neat) n 3108 (w), 2943 (w), 1639 (m),
1
3 9 2
4.1.16. 9-Benzyl-6-(3-phenoxy-1-propynyl)-9H-purine
(12a). A mixture of 9-benzyl-6-iodo-9H-purine 1a (336 mg,
2
max
ꢁ
1
+
556 (s), 1490 (s) cm ; EIMS m/z (rel %): 340 (88, M ),

6130
T. C. Berg et al. / Tetrahedron 62 (2006) 6121–6131
1
.00 mmol), (PPh ) PdCl (35 mg, 0.05 mmol), CuI (19 mg,
3
silica gel eluting with hexane–EtOAc (2:1), yield 79 mg
(38%), brownish oil. H NMR (300 MHz, CDCl ): d 8.55
2
2
1
0
DMF (5 mL) was heated to 60 C. Phenyl propargyl ether
.10 mmol), and diisopropylamine (854 mL, 6.00 mmol) in
ꢀ
154 mL, 1.20 mmol) in DMF (1 mL) was added dropwise
3
(d, J 4.4 Hz, 1H, H-6), 7.61–7.58 (m, 1H, H-3), 7.41–7.39
(m, 1H, H-4), 7.32–7.27 (m, 2H, Ph), 7.24–7.22 (m, 1H,
(
1
3
over 2 h, and the resulting mixture was stirred for 7 h. The
product was isolated by flash chromatography on silica gel
eluting with EtOAc–hexane (3:1); yield 145 mg (43%) as
H-5), 7.03–6.95 (m, 3H, Ph), 4.92 (s, 2H, CH2); C NMR
(75 MHz, CDCl ): d 157.7 (C in Ph), 150.6 (C-6), 142.5
3
(C-2), 136.1 (C-3), 129.5 (CH in Ph), 127.3 (C-4), 123.2
(C-5), 121.5 (CH in Ph), 114.9 (CH in Ph), 86.2 (C^),
a 13:87 mixture of 12a and 10a, NMR data for 12a:
H NMR (500 MHz, CDCl ): d 8.93 (s, 1H, H-2), 8.06
1
84.0 (C^), 56.3 (CH ); IR (CCl ) n
2
3065 (w), 2918
max
3
4
ꢁ1
(
5
s, 1H, H-8), 7.33–7.00 (m, 10H, Ph), 5.47 (s, 2H, NCH2),
.03 (s, 2H, OCH2).
(w), 2862 (w), 1599 (s), 1583 (s), 1495 (s), 1464 (s) cm ;
EIMS m/z (rel %): 209 (96, M ), 116 (100); HRMS (EI)
+
found 209.0831, calcd for C H NO 209.0841; Anal.
1
4 11
4.1.17. 9 Benzyl-6-(4-phenyl-1-butynyl)-9H-purine (12b).
A mixture of 9-benzyl-6-iodo-9H-purine 1a (336 mg,
Found: C, 80.35; H, 5.41; N, 6.62. C H NO requires C,
14 11
80.36; H, 5.30; N 6.69%.
1
.00 mmol), (PPh ) PdCl (35 mg, 0.05 mmol), CuI (19 mg,
3 2 2
0
mmol) in DMF (5 mL) was heated to 60 C under N -atm.
4
.10 mmol), and diisopropyl(ethyl)amine (1.02 mL, 6.00
ꢀ
-Phenyl-1-butyne (169 mL, 1.20 mmol) in DMF (1 mL)
4.1.20. 1-Nitro-4-(3-phenoxy-1-propynyl)benzene (12e).
A mixture of 1-bromo-4-nitrobenzene (202 mg, 1.00
mmol), (PPh ) PdCl (35 mg, 0.05 mmol), CuI (19 mg,
2
3
2
2
was added dropwise over 2 h, and the resulting mixture was
stirred for 4 h. The product was isolated by flash chromato-
graphy on silica gel eluting with hexane–EtOAc (1:1); yield
0.10 mmol), and diisopropyl(ethyl)amine (1.02 mL,
ꢀ
6.00 mmol) in DMF (5 mL) was heated to 60 C under N -
2
atm. Phenyl propargyl ether (158 mL, 1.20 mmol) in DMF
(1 mL) was added dropwise over 2.5 h, and the resulting mix-
ture was stirred for 2.5 h. The product was isolated by flash
chromatography on silica gel eluting with hexane–EtOAc
1
2
89 (86%), pale brownish oil. H NMR (300 MHz,
CD OD): d 8.81 (s, 1H, H-2), 8.55 (s, 1H, H-8), 7.35–7.15
3
(
m, 10H, Ph), 5.50 (s, 2H, NCH ), 3.02–2.98 (m, 2H, CH ),
2 2
1
3
ꢀ
2
d 153.3 (C-2), 152.8 (C-4), 148.2 (C-8), 142.6 (Ph), 141.6
.90–2.84 (m, 2H, CH2); C NMR (75 MHz, CD OD):
(9:1); yield 175 mg (69%), off-white crystals, mp 87–89 C
(lit. 76–77 C). H NMR (300 MHz, CDCl ): d 8.18–8.14
3
3
1
ꢀ
(m, 2H, Ph), 7.57–7.54 (m, 2H, Ph), 7.34–7.24 (m, 2H, Ph),
1
3
(
(
(
C-6), 137.0 (Ph), 135.1 (C-5), 130.0 (Ph), 129.5 (Ph), 129.4
Ph), 129.0 (Ph), 127.5 (Ph), 102.5 (C^), 76.9 (C^), 48.3
NCH ), 35.3 (CH ), 22.7 (CH ), one C in Ph was hidden;
13
7.02–6.98 (m, 3H, Ph), 4.93 (s, 2H, CH2); C NMR
(75 MHz, CDCl ): d 158.0 (C in Ph), 147.8 (C in Ph),
2
2
2
3
IR (neat) nmax 3088 (m), 2930 (m), 2862 (m), 2233 (s), 1734
(
3
133.0 (CH in Ph), 130.0 (CH in Ph), 129.5 (C in Ph), 124.0
(CH in Ph), 122.2 (CH in Ph), 115.3 (CH in Ph), 89.7
(C^), 85.6 (C^), 56.8 (CH ); EIMS m/z (rel %): 253 (97,
ꢁ
1
w), 1710 (w), 1582 (s), 1497 (s) cm ; EIMS m/z (rel %):
38 (72, M ), 247 (51), 91 (100); HRMS (EI) found
38.1529, calcd for C H N 338.1531.
+
2
+
3
M ), 160 (100); HRMS (EI) found 253.0733, calcd for
C H NO 253.0738.
2
2 18 4
1
5
11
3
4
(
.1.18. 2-Chloro-4-(3-phenoxy-1-propynyl)pyrimidine
12c). A mixture of 2,4-dichloropyrimidine (149 mg,
4.1.21. (3-Phenoxy-1-propynyl)benzene (12f). A mixture
of iodobenzene (112 mL, 1.00 mmol), (PPh ) PdCl
2
1
0
6
.00 mmol), (PPh ) PdCl (35 mg, 0.05 mmol), CuI (19 mg,
3 2 2
3 2
.10 mmol), and diisopropyl(ethyl)amine (1.02 mL,
ꢀ
(35 mg, 0.05 mmol), CuI (19 mg, 0.10 mmol), and diisopro-
pyl(ethyl)amine (1.02 mL, 6.00 mmol) in DMF (5 mL) was
.00 mmol) in DMF (5 mL) was heated to 60 C under
ꢀ
N -atm. Phenyl propargyl ether (158 mL, 1.20 mmol) in
2
heated to 60 C under N -atm. Phenyl propargyl ether
2
DMF (1 mL) was added dropwise over 2 h, and the resulting
mixture was stirred for 3 h. The product was isolated by flash
chromatography on silica gel eluting with hexane–EtOAc
(158 mL, 1.20 mmol) in DMF (1 mL) was added dropwise
over 2 h, and the resulting mixture was stirred for 3 h. The
product was isolated by flash chromatography on silica gel
eluting with hexane–EtOAc (9:1); yield 208 mg (quant.),
1
(
(
4:1); yield 74 mg (30%), brownish oil. H NMR
300 MHz, CDCl ): d 8.57 (d, J 5.0 Hz, 1H, H-6), 7.33 (m,
ꢀ
31
ꢀ
1
off-white crystals, mp 44–45 C (lit. 44 C). H NMR
(300 MHz, CDCl ): d 7.44–7.41 (m, 2H, Ph), 7.33–7.24
3
3
CH2); C NMR (75 MHz, CDCl ): d 161.6 (C-2), 159.6
H, Ph and H-5), 7.03–6.96 (m, 3H, Ph), 4.92 (s, 2H,
3
1
3
13
(m, 5H, Ph), 7.04–6.96 (m, 3H, Ph), 4.91 (CH2); C NMR
(75 MHz, CDCl ): d 157.8 (Ph), 131.8 (Ph), 129.5 (Ph),
3
(
1
(
C-6), 157.4 (C in Ph), 152.3 (C-4), 129.6 (CH in Ph),
22.0 (C-5), 121.8 (CH in Ph), 114.8 (CH in Ph), 91.1
C^), 83.2 (C^), 56.0 (CH ); IR (CCl ) n 3043 (w),
3
128.6 (Ph), 128.3 (Ph), 122.3 (Ph), 121.4 (Ph), 115.0 (Ph),
87.1 (C^), 83.9 (C^), 56.6 (CH ); EIMS m/z (rel %):
2
4
max
2
+
2
(
959 (w), 2926 (w), 2860 (w), 2237 (w), 1599 (s), 1590
s), 1495 (s) cm ; EIMS m/z (rel %): 246/244 (33/100,
208 (40, M ), 115 (100); HRMS (EI) found 208.0885, calcd
for C H O 208.0888.
ꢁ
1
1
5 12
+
M ), 151 (11); HRMS (EI) found 244.0402, calcd for
C H N OCl 244.0403.
1
3 9 2
Acknowledgements
4
.1.19. 2-(3-Phenoxy-1-propynyl)pyridine (12d). A mix-
ture of 2-bromopyridine (96 mL, 1.0 mmol), (PPh ) PdCl
2
This work has received support through a grant of computer
time from the Research Council of Norway (NFR) (Grant
No. NN1118K). NFR is also greatly acknowledged for
a scholarship to TCB (KOSK program, grant 139080/431)
as well as for partial financing of the Bruker Avance instru-
ments used in this study. Antimycobacterial data were pro-
vided by the Tuberculosis Antimicrobial Acquisition and
3
2
(
pyl(ethyl)amine (1.02 mL, 6.00 mmol) in DMF (5 mL) was
35 mg, 0.05 mmol), CuI (19 mg, 0.10 mmol), and diisopro-
ꢀ
heated to 60 C under N -atm. Phenyl propargyl ether
2
(
158 mL, 1.20 mmol) in DMF (1 mL) was added dropwise
over 3 h, and the resulting mixture was stirred for another
h. The product was isolated by flash chromatography on
3

T. C. Berg et al. / Tetrahedron 62 (2006) 6121–6131
6131
Coordinating Facility (TAACF) through a research and de-
velopment contract with the US National Institute of Allergy
and Infectious Diseases.
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