Palladium-catalysed Claisen rearrangement of 6-allyloxypurines

Article abstract of DOI:10.2478/s11696-012-0239-y

6-Allyloxypurines readily undergo palladium-catalysed Claisen rearrangement under mild conditions affording N ¹-substituted hypoxanthines. In contrast with the previously reported protocol, the Claisen rearrangement can be performed using Pd(PP

Full text of DOI:10.2478/s11696-012-0239-y

Chemical Papers 67 (1) 3–8 (2013)
DOI: 10.2478/s11696-012-0239-y
ORIGINAL PAPER
Palladium-catalysed Claisen rearrangement of 6-allyloxypurines
Petr Koukal, Hana Dvořáková, Dalimil Dvořák, Tomáš Tobrman*
Department of Organic Chemistry, Institute of Chemical Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic
Received 4 April 2012; Revised 25 June 2012; Accepted 27 June 2012
Dedicated to Professor Štefan Toma on the occasion of his 75th birthday
6-Allyloxypurines readily undergo palladium-catalysed Claisen rearrangement under mild condi-
tions affording N 1-substituted hypoxanthines. In contrast with the previously reported protocol,
the Claisen rearrangement can be performed using Pd(PPh3)4 or Pd(dba)2/dppf in dry THF at
60◦C. The reaction can accommodate variously substituted allyl fragments to position N 1 of the
hypoxanthine skeleton with high yields. Retention of the double bond configuration during rear-
rangement was observed.
c
ꢀ 2012 Institute of Chemistry, Slovak Academy of Sciences
Keywords: Claisen rearrangement, purine, allyloxypurines, palladium, hypoxanthine
Introduction
Experimental
Purine derivatives occur extensively in biologi-
cal systems as the components of nucleic acids. It
is not surprising, therefore, that many substituted
purines are biologically active compounds displaying,
for example, antiviral (Simons et al., 2005; De Clercq
& Neyts, 2004), anti-fungal (Miura & Izuta, 2004;
Szafraniec et al., 2004), or anti-neoplastic (Lagoja,
2005; Kimura & Bugg, 2003; Rachakonda & Cartee,
2004) properties. Recent reports of artificially mod-
ified nucleosides make possible the investigation of
the structure and function of RNAs (Phelps et al.,
2012). The introduction of alkyne chain into RNA is
frequently used for further functionalisation of RNAs
by azide/alkyne cycloaddition (Yamada et al., 2011).
Even very simple naturally occurring substituted
purines are biologically active. Thus, theophylline and
theobromine are used as anti-asthma drugs (Wieland
& Bauer, 1951), 1,3-dimethylisoguanine shows activity
against human ovarian cancer (Mitchell et al., 1997),
and 1-methylherbipoline acts as an inhibitor of col-
lagenase (Yagi et al., 1994). In addition, purine acts
as a copper corrosion inhibitor in both alkaline and
neutral sulfate solutions (Petrovi´c et al., 2012).
All reactions were performed in an argon atmo-
sphere. 1H (300.07 MHz or 600.13 MHz) and 13C
(75.45 MHz or 150.90 MHz) NMR spectra were mea-
sured on Varian Gemini 300 or Bruker Avance III 600
instruments, respectively. IR spectra (neat samples)
were recorded on a Nicolet 6700 with continuum mi-
croscope. Mass spectra (HRMS-ESI) were recorded on
a LTQ Orbitrap Velos spectrometer (Thermo Scien-
tific). The solvents were dried and degassed by stan-
dard procedures; silica gel (Merck, Silica Gel 60, 40–
63 µm) was used for column chromatography. The
stereochemical purity of commercially available crotyl
alcohol was 95 % E. Other compounds were com-
mercially available products and alkenes were used as
≥ 98 % E isomers. Preparation of compounds: Ia, Ig,
IIa, and IIg was reported previously (Ranganathan et
al., 1986).
General method for preparation of starting 6-
allyloxypurines I
Corresponding alcohol (2 mmol) was added to a
suspension of NaH (2 mmol, 80 mg, 60 % suspen-
*Corresponding author, e-mail: Tomas.Tobrman@vscht.cz

4
P. Koukal et al./Chemical Papers 67 (1) 3–8 (2013)
Fig. 1. Claisen rearrangement of various 6-allyloxy-9-benzyl-9H-purines (Ia–If ) and 9-benzyl-6-(prop-2-ynyloxy)-9H-purine (Ig) to
corresponding 1-allyl-9-benzylhypoxanthines (IIa–IIf ) and 9-benzyl-1-(prop-2-ynyl)hypoxanthine (IIg), respectively. Reac-
tion conditions: i) see Table 1 for optimised reaction conditions for rearrangement of 6-allyloxy-9-benzyl-9H-purine (I, R
= allyloxy) to 1-allyl-9-benzylhypoxanthine (IIa); ii) for rearrangement of Ib–Ig to corresponding IIb–IIg: Pd(PPh3)4 or
Pd(dba)2/dppf, THF, 60◦C, 16 h.
Table 1. Optimisation of transition metal catalysed rearrangement of 6-allyloxy-9-benzyl-9H-purine (Ia) to 1-allyl-9-benzylhypoxanthine
(IIa)
Entry
Catalysta
Solvent
Temperature/◦C
Yieldb/%
1
2
3
4
5
6
7
8
9
Hoveyda–Grubbs 2
Cu(acac)2
Ru(PPh3)2Cl2
Rh(PPh3)2Cl
Pd(PPh3)2Cl2
Pd(PPh3)4
toluene
toluene
toluene
toluene
toluene
toluene
DCM
THF
THF
THF
110
110
110
110
100
rt
rt
rt
rt
rt
60
65
55
45
64
58
77
91
96
77
Pd(PPh3)4
Pd(PPh3)4
Pd(dba)2/dppfc
Pd(dba)2/TFPd
10
a) 5 mole % of catalyst was used; b) isolated yield of IIa; c) 5 mole % of dppf was used; d) 10 mole % of TFP was used; rt –
ambient temperature.
sion in mineral oil) in dry THF (5 mL) and the
mixture was stirred for 30 min at ambient tempera-
ture, followed by the addition of 9-benzyl-6-chloro-9H-
purine (1 mmol, 245 mg) or 9-benzyl-6-chloro-2-iodo-
9H-purine (1 mmol, 371 mg), or 9-benzyl-6-methoxy-
8-iodo-9H-purine (1 mmol, 366 mg). The mixture was
stirred at 60◦C for 16 h, pre-concentrated at reduced
pressure and the crude products were purified by col-
umn chromatography (silica gel, hexane/EtOAc, ϕr =
1 : 2) to give the final products Ia–Ii.
selective synthesis of biologically active purines (To-
brman & Dvořák, 2003, 2008; Kotek et al., 2010,
2012), we focused on the cross-metathesis of alkenyl
purines. This area of purine chemistry remains al-
most untouched (Vik & Gundersen, 2007). However,
to our surprise, when 6-allyloxypurine Ia was heated
to 110◦C in dry toluene in the presence of second
generation Hoveyda–Grubbs catalyst, formal prod-
uct of Claisen rearrangement IIa was isolated with
60 % yield instead of the anticipated product of self-
metathesis (Fig. 1, Table 1, entry 1). The thermal
Claisen rearrangement of Ia has already been de-
scribed as proceeding at 190◦C to afford 30 % yield
(Ranganathan et al., 1986). As many transition met-
als are known to catalyse this kind of rearrangement
(Schenck & Bosnich, 1985; Castro, 2004), we tested
several of them. While Ni(acac)2, Co(acac)2, and
Cr(acac)3 were inactive, Cu(acac)2, Ru(PPh3)2Cl2,
Rh(PPh3)2Cl, and all Pd complexes catalysed this
reaction (Table 1, entries 1–5). None of these com-
plexes with the exception of Pd(PPh3)4 (Table 1, en-
try 6) worked below 100◦C. Running the same re-
action in dry dichloromethane (DCM) increased the
yield of IIa to 77 % (Table 1, entry 7) and the
best result (91 % yield) was obtained when THF
was used as a solvent (Table 1, entry 8). A some-
General method for Claisen rearrangement of
Ia–Ii
A solution of allyloxypurine I (1 mmol) and
Pd(PPh3)4 (5 mole %, 0.05 mmol, 58 mg) or Pd(dba)2
(5 mole %, 0.05 mmol, 29 mg), or dppf (5 mole %,
0.05 mmol, 28 mg) in dry THF (5 mL) was stirred
at 60◦C for 16 h. The solvent was evaporated at re-
duced pressure and the crude product was purified by
flash chromatography (silica gel, EtOAc/MeOH, ϕr =
20 : 1) to afford the corresponding hypoxanthine II.
Results and discussion
As a part of our on-going effort to develop a new

P. Koukal et al./Chemical Papers 67 (1) 3–8 (2013)
5
Table 2. Palladium-catalysed Claisen rearrangement of various 6-allyloxy-9-benzyl-9H-purines (Ia–If) and 9-benzyl-6-(prop-2-
ynyloxy)-9H-purine (Ig)
Purine I
Hypoxanthine II
Entry
Series
Yielda/%
R
R
—
—
1
2
3
4
a
b
c
CH2—CHCH2
CH2—CHCH2
96b
82b
Cyclohex-2-enyl
—
(E)-PhCH CHCH2
—
Cyclohex-2-enyl
—
(E)-PhCH CHCH2
—
98c
d
Geranyl
Geranyl
84b (39d, 61e)c
f
2
g
2
89h
—
—
—
—
5
6
7
e
f
g
(E)-CH3CH CHCH
(E)-CH3CH CHCH
—
CH2—CHCHCH3
—
CH2—
—
CH2—CHCHCH3
–
65i,j , 25i
—
—
CH
—
CH—CCH2
C
—
a) Isolated yield of II (product of rearrangement); b) using 5 mole % of Pd(dba)2/dppf as catalyst; c) using 5 mole % of Pd(PPh3)4
as catalyst; d) yield of stereoisomers of IId; e) yield of 9-benzyl-6-hypoxanthine; f ) 95 % of E-isomer (determined by 1H NMR); g)
80 % of E-isomer (determined by 1H NMR); h) overall isolated yield of the mixture of IIe and IIf in the ratio of 58 : 42; i) using 5
mole % of PdCl2(PPh3)2 as catalyst; j) the yield determined by 1H NMR of crude reaction mixture (durene was used as internal
standard).
Fig. 2. Claisen rearrangement of bisallyloxypurines Ih and Ii. Reaction conditions: i) Ih, 5 mole % of Pd(dba)2/dppf, THF, 60◦C,
16 h, 93 % yield of IIh; ii) Ii, 5 mole % of Pd(dba)2/dppf, THF, 60◦C, 16 h, 87 % yield of IIi.
what higher yield was obtained using Pd(dba)2/dppf
in THF, while Pd(dba)2/TFP gave a yield comparable
with Pd(PPh3)4 (Table 1, entries 9, 10).
entry 4). In the case of the isomeric purines Ie and If
bearing (E)-6-(but-2-enyloxy) or 6-(1-methylallyloxy)
moieties, both conditions including Pd(PPh3)4, or
Pd(dba)2/dppf afforded inseparable mixture of iso-
meric products IIe and IIf at the same 58 : 42 ratio and
89 % overall isolated yield (Table 2, entries 5 and 6).
In all the cases reported in Table 2, the formation of
small amounts (< 5 %) of 9-benzylhypoxanthine was
observed. The only exception was the rearrangement
of IId in the presence of Pd(PPh3)4 referred to above,
where 9-benzylhypoxanthine was the main product.
We also tested the ability of the readily avail-
able 6,8- and 2,6-bisallyloxy-9-benzylpurines Ih and
Ii, respectively to undergo the above isomerisation.
The starting compounds Ih and Ii are available by
double nucleophilic displacement of 9-benzyl-8-iodo-6-
methoxy-9H-purine and 9-benzyl-6-chloro-2-iodo-9H-
purine with allyl alcohol in the presence of NaH in
dry THF. In the first case, not only iodine but also
the methoxy group in position 6 is substituted. Subse-
quent isomerisation of Ih, and Ii using Pd(dba)2/dppf
in dry THF at 60◦C readily afforded the products
of the double Claisen rearrangement with high yields
(Fig. 2).
The optimised reaction conditions (Table 1, entries
8 or 9) were applied to the rearrangement of vari-
ous 6-allyloxypurines Ib–If and also 9-benzyl-6-(prop-
2-ynyloxy)-9H-purine (Ig) (Fig. 1, Table 2). In con-
trast with the rearrangement of Ia, heating of the re-
action mixtures to 60◦C was needed to achieve a com-
plete conversion of the starting purines Ib–Ig. Thus,
6-(cyclohex-3-enyloxy)purine Ib was smoothly con-
verted to the hypoxanthine IIb using Pd(dba)2/dppf
and the cinnamyloxypurine Ic was transformed ex-
clusively to the corresponding (E)-1-(3-phenylprop-2-
enyl)hypoxanthine (IIc) affording a 98 % yield in the
presence of Pd(PPh3)4 (Table 2, entries 2 and 3). The
outcome of the isomerisation of the geranyloxy deriva-
tive Id was dependent on the phosphine ligand used.
With Pd(dba)2/dppf, clean conversion to only (E)-
1-geranylhypoxanthine (IId) with 84 % yield was ob-
served. By contrast, isomerisation of Id performed in
the presence of Pd(PPh3)4 afforded a mixture of the
rearranged product IId with 39 % isolated yield along
with 9-benzylhypoxanthine with 61 % yield (Table 2,

6
P. Koukal et al./Chemical Papers 67 (1) 3–8 (2013)
Table 3. Physical and spectral data of 6-allyloxypurines I and hypoxanthines II
Compound
Physical and spectral dataa
Ib
M.p. 82–85◦C
1H NMR (300 MHz, CDCl3), δ: 1.8–2.1 (m, 6H, CH2), 5.40 (s, 2H, CH2), 5.90 (m, 1H, CH), 5.98 (s, 2H, CH), 7.30
(m, 5H, CHꢀꢀ), 7.86 (s, 1H, CHꢀ), 8.54 (s, 1H, CHꢀ)
13C NMR (75.5 MHz, CDCl3), δ: 18.9, 25.0, 28.3, 47.3, 70.6, 121.5, 125.7, 127.7, 128.4, 129.0, 132.8, 135.4, 141.7,
152.20, 152.25, 160.6
HRMS (ESI), m/z (found/calc.): 329.13742/329.13728 (C18H18N4ONa)
Ic
Id
M.p. 124–127◦C
1H NMR (300 MHz, CDCl3), δ: 5.29 (d, J = 6.0 Hz, 2H, CH2), 5.42 (sꢀ,ꢀ 1H, CH2), 6.54 (td, J = 6.0 Hz, J = 15.8 Hz,
ꢀ
ꢀ
—
—
—
1H, CH), 6.81 (d, J = 15.8 Hz, 1H, CH), 7.26–7.40 (m, 10H, CH ), 7.90 (s, 1H, CH ), 8.59 (s, 1H, CH )
—
13C NMR (75.5 MHz, CDCl3), δ: 47.4, 67.4, 123.5, 126.6, 127.7, 127.9, 128.3, 128.4, 128.5, 129.0, 134.2, 135.2, 136.3,
142.0, 152.1, 152.2, 160.4.
HRMS (ESI), m/z (found/calc.): 365.13741/365.13728 (C21H18N4ONa)
M.p. 67–72◦C
1H NMR (300 MHz, CDCl3), δ: 1.59 (s, 3H, CH3), 1.65 (s, 3H, CH3), 1.79 (s, 3H, CH3), 2.10 (m, 4H, CH2), 5.08
(t, J = 6.6 Hz, 1H, CH), 5.14 (d, J = 7.2 Hz, 2H, CH2), 5.41 (s, 2H, CH2), 5.62 (t, J = 6.3 Hz, 1H, CH), 7.27–7.37
(m, 5H, CHꢀꢀ), 7.87 (s, 1H, CHꢀ), 8.56 (s, 1H, CHꢀ)
13C NMR (75.5 MHz, CDCl3), δ: 16.6, 17.5, 25.5, 26.1, 39.4, 47.2, 63.8, 118.5, 121.3, 123.7, 127.6, 128.3, 128.9,
131.6, 135.3, 141.7, 142.0, 152.0, 152.1, 160.7
HRMS (ESI), m/z (found/calc.): 385.20007/385.19988 (C22H26N4ONa)
Ieb
1H NMR (300 MHz, CDCl3), δ: 1.72 (d, J = 5.7 Hz, 3H, CH3), 5.03 (d, J = 5.4 Hz, 2H, CH2), 5.39 (s, 2H, CH2),
5.90 (m, 2H, CH), 7.24–7.34 (m, 5H, CHꢀꢀ), 7.87 (s, 1H, CHꢀ), 8.54 (s, 1H, CHꢀ)
13C NMR (75.5 MHz, CDCl3), δ: 17.7, 47.3, 67.6, 121.4, 125.3, 127.7, 128.4, 129.0, 131.5, 135.3, 152.16, 152.18,
160.6
HRMS (ESI), m/z (found/calc.): 303.12169/303.12163 (C16H16N4ONa)
If
1H NMR (300 MHz, CDCl3), δ: 1.52 (d, J = 5.7 Hz, 3H, CH3), 5.14 (d, J = 9.6 Hz, 2H, CH2), 5.33 (m, 3H, CH2
and CH), 6.00 (m, 2H, CH), 7.25 (m, 5H, CHꢀꢀ), 7.86 (s, 1H, CHꢀ), 8.51 (s, 1H, CHꢀ)
13C NMR (75.5 MHz, CDCl3), δ: 20.1, 47.2, 73.3, 115.9, 121.4, 127.6, 128.3, 128.9, 135.2, 137.7, 152.17, 152.28,
160.2
HRMS (ESI), m/z (found/calc.): 303.12177/303.12163 (C16H16N4ONa)
Ih
Ii
1H NMR (300 MHz, CDCl3), δ: 4.91 (d, J = 5.7 Hz, 2H, CH2), 5.07 (d, J = 6.6 Hz, 2H, CH2), 5.30 (m, 4H), 5.40
ꢀꢀ
ꢀ
—
(m, 2H, CH), 6.20 (m, 2H, CH), 7.30 (m, 5H, CH ), 7.71 (s, 1H, CH )
—
HRMS (ESI), m/z (found/calc.): 345.13235/345.13220 (C18H18N4O2Na)
1
—
—
—
H NMR (300 MHz, CDCl3), δ: 5.09 (m, 4H, CH2), 5.24 (s, 2H, CH2), 5.35 (m, 4H, CH2), 6.10 (m, 2H, CH),
—
7.30 (m, 5H, CHꢀꢀ), 8.41 (s, 1H, CHꢀ)
HRMS (ESI), m/z (found/calc.): 345.13241/345.13220 (C18H18N4O2Na)
IIb
M.p. 129–136◦C
1H NMR (300 MHz, CDCl3), δ: 1.60 (m, 2H, CH2), 2.05 (m, 4H, CH2), 5.25 (s, 2H, CH2), 5.55 (m, 2H, CH), 6.10
(m, 1H, CH), 7.25 (m, 5H, CHꢀꢀ), 7.72 (s, 1H, CHꢀ), 8.03 (s, 1H, CHꢀ)
13C NMR (75.5 MHz, CDCl3), δ: 19.1, 24.3, 30.0, 47.1, 49.3, 123.7, 125.3, 127.4, 128.1, 128.7, 134.1, 135.2, 139.6,
145.3, 147.3, 156.2
IR (neat), ν˜/cm−1: 3099, 3035, 2929, 1679, 1570, 1544, 1507, 1496, 1449, 1424, 1358, 1229, 1204, 1184, 1130, 1064,
960, 929, 873, 787, 737, 717, 696, 677, 656
HRMS (ESI), m/z (found/calc.): 329.13727/329.13728 (C18H18N4ONa)
IIc
M.p. 197–205◦C
1H NMR (300 MHz, CDCl3), δ: 4.84 (d, J = 6.9 Hz, 2H, CH2), 5.31 (sꢀ,ꢀ 2H, CH2), 6.35 (td, J = 6.6 Hz, J = 15.8 Hz,
ꢀ
ꢀ
—
—
—
1H, CH), 6.62 (d, J = 15.8 Hz, 1H, CH), 7.25–7.37 (m, 10H, CH ), 7.75 (s, 1H, CH ), 8.05 (s, 1H, CH )
—
13C NMR (75.5 MHz, CDCl3), δ: 47.4, 47.9, 123.3, 126.5, 127.6, 128.2, 128.5, 128.6, 129.0, 134.4, 135.2, 135.7, 139.8,
146.8, 155.8.
IR, ν˜/cm−1: 3100, 3035, 2993, 2927, 2853, 1680, 1606, 1573, 1543, 1508, 1494, 1454, 1439, 1429, 1351, 1305, 1269,
1223, 1200, 1178, 1140, 1080, 1051, 1028, 978, 960, 861, 847, 789, 740, 723, 688, 669, 653
HRMS (ESI), m/z (found/calc.): 365.13745/365.13728 (C21H18N4ONa)
IId
M.p. 140–144◦C
1H NMR (300 MHz, CDCl3), δ: 1.56 (s, 3H, CH3), 1.64 (s, 3H, CH3), 1.78 (s, 3H, CH3), 2.05 (m 4H, CH2), 4.66
ꢀꢀ
—
—
—
(d, J = 7.2 Hz, 2H, CH2), 5.03 (m, 1H, CH), 5.29 (s, 2H, CH2), 5.32 (m, 1H, CH), 7.20–7.35 (m, 5H, CH ),
—
7.72 (s, 1H, CHꢀ), 7.96 (s, 1H, CHꢀ)
13C NMR (75.5 MHz, CDCl3), δ: 16.4, 17.6, 25.6, 26.1, 39.4, 43.3, 47.3, 118.3, 123.4, 124.2, 127.6, 128.4, 129.0,
132.0, 135.3, 139.7, 142.3, 146.6, 147.6, 156.6
IR, ν˜/cm−1: 3101, 3040, 2971, 2917, 2850, 1674, 1571, 1545, 1509, 1495, 1453, 1438, 1376, 1361, 1345, 1306, 1280,
1226, 1199, 1172, 1135, 1078, 1052, 1028, 970, 941, 875, 860, 847, 802, 790, 761, 723, 694, 652
HRMS (ESI), m/z (found/calc.): 385.19998/385.19988 (C22H26N4ONa)

P. Koukal et al./Chemical Papers 67 (1) 3–8 (2013)
7
Table 3. (continued)
Compound
Physical and spectral dataa
IIe, IIfc 1H NMR (600 MHz, CDCl3), δ: 1.54 (d, J = 6.0 Hz, CH3), 1.72 (d, J = 6.0 Hz, CH3), 1.83 (d, J = 6.0 Hz, CH3),
4.63 (d, J = 6.0 Hz, CH2), 4.74 (d, J = 6.0 Hz, CH2), 5.31 (s, CH2), 5.35 (m, CH), 5.55 (m, CH), 5.65 (m, CH),
5.75–5.85 (m, CH), 6.05 (m, CH), 7.25 (m, CHꢀꢀ), 7.74 (s, CHꢀ), 7.96, 7.98, 7.99 (s, CHꢀ)
13C NMR (75.5 MHz, CDCl3), δ: 12.7, 17.3, 18.7, 41.9, 47.2, 49.6, 49.9, 117.4, 123.6, 123.8, 123.9, 124.9, 127.3,
127.9, 128.5, 129.4, 130.4, 135.1, 136.9, 139.5, 139.6, 144.7, 146.4, 146.6, 147.0, 147.3, 155.8, 156.0
HRMS (ESI), m/z (found/calc.): 303.12164/303.12163 (C16H16N4ONa)
IIh
IIi
1H NMR (600 MHz, CDCl3), δ: 4.63 (d, J = 5.9 Hz, 2H, CH2), 4.7ꢀ4ꢀ (d, J = 5.7 Hz, 2H, CH2), 5.09 (s, 2H, CH2),
ꢀꢀ
—
5.20–5.35 (m, 4H, CH2), 6.0 (m, 2H, CH), 7.29–7.36 (m, 3H, CH ), 7.47 (d, J = 7.8 Hz, 2H, CH ), 7.87 (s, 1H,
—
CHꢀ)
13C NMR (150.9 MHz, CDCl3), δ: 43.9, 44.5, 48.4, 108.1, 117.6, 119.4, 128.0, 128.4, 128.7, 131.9, 133.0, 136.2, 143.8,
145.7, 150.8, 152.1
HRMS (ESI), m/z (found/calc.): 345.13228/345.13220 (C18H18N4O2Na)
1H NMR (600 MHz, CDCl3), δ: 4.55 (m, 2H, CH2), 4.70 (m, 2H, CH2), 5.08 (td, J = 1.8 Hz, J = 17.3 Hz, 1H,
—
—
—
CH2), 5.20 (dd, J = 1.1 Hz, J = 10.2 Hz, 1H, CH2), 5.30 (m, 2H, CH2), 5.36 (m, 2H, CH2), 7.03 (d, J =
—
—
—
7.2 Hz, 2H, CHꢀꢀ), 7.45 (m, 3H, CHꢀꢀ), 7.46 (s, 1H, CHꢀ)
13C NMR (150.9 MHz, CDCl3), δ: 44.0, 45.7, 49.8, 116.6, 117.9, 125.3, 129.0, 129.7, 129.8, 132.0, 132.3, 135.3, 138.6,
138.7, 150.7, 156.8
IR, ν˜/cm−1: 3089, 3033, 2930, 2854, 1680, 1572, 1543, 1509, 1496, 1454, 1436, 1425, 1348, 1271, 1203, 1185, 1139,
1107, 1077, 1045, 968, 787, 717, 697, 651
HRMS (ESI), m/z (found/calc.): 281.13967/281.13974 (C18H18N4O2 – C2H2O + H)
a) Methine protons of purine moiety are identified by prime and those of phenyl moiety by double prime; b) 95 % E-isomer
(determined by 1H NMR); c) spectral data given for inseparable mixture of IIe and IIf; IIe was determined (by 1H NMR) as 80 %
E-isomer.
benzylmethylamine – a product of the nucleophilic
addition of N-methylbenzylamine to C with 59 % iso-
lated yield. The formation of two isomeric products
IIe and IIf with the same yield and ratio starting ei-
ther from Ie or from If (Table 2, entries 5 and 6) also
is considered to be the common π-allyl intermediate.
Alternatively, the formation of 9-benzylhypoxanthine
during the rearrangement of Id in the presence of
Pd(PPh3)4 can be explained by β-elimination of inter-
mediate π-allyl complex of type A followed by reduc-
tive elimination. This was supported by the detection
of the trienes myrcene and (Z)-ocimene by 1H and 13
C
NMR spectroscopy in the crude reaction mixture.
Unlike Pd(0), other metals do not catalyse the re-
arrangement of Ia to IIa below 100◦C. This, together
with the finding that the rearrangement of Ie and
If does not, unlike Ia, proceed at 110◦C, show that
these metals operate in accordance with the report of
Schenck and Bosnich (1985) by different mechanism.
Fig. 3. Proposed mechanism for Pd-catalysed rearrangement
of allyloxypurines I.
Physical and spectral data of 6-allyloxypurines I
and hypoxanthines II are given in Table 3.
The Claisen rearrangement catalysed by zero-
valent palladium (Pd(0)) was reported to proceed via
π-allyl intermediate (Schenck & Bosnich, 1985). Our
experimental results also accord with this mechanism.
We assumed that, in the first step, the π-allyl palla-
dium complex A was formed through the oxidative
addition of Pd(0) (Fig. 3). Complex A is in equi-
librium with its dissociated form – π-allyl palladium
cation C and hypoxanthine anion B. Subsequently, an-
ion B acts as nucleophile and adds to the π-allyl lig-
and of C giving the final product IIa (Fig. 3). The
presence of π-allyl intermediate A was proved by the
rearrangement of Ia in the presence of Pd(PPh3)4
and N-methylbenzylamine which afforded N-allyl-N-
Conclusions
Pd(0) catalyses the Claisen rearrangement of 6-, 2-,
and 8-allyloxypurines to the corresponding N-allyl-6-
oxopurines (N-allylhypoxanthines). The reaction pro-
ceeds via π-allyl intermediate and can be useful for
the synthesis of new purine derivatives with potential
biological activity. Other metals such as Cu, Rh or Ru
are less active catalysts and most probably operate by
different mechanisms.
Acknowledgements. This project was supported by the
Grant Agency of the Czech Republic (grant no. 203/09/1552).

8
P. Koukal et al./Chemical Papers 67 (1) 3–8 (2013)
References
Ranganathan, D., Rathi, R., Keshavan, K., & Pal Singh, W.
(1986). The demonstration of normal O→N Claisen rear-
rangement in purines. Tetrahedron, 42, 4873–4878. DOI:
10.1016/s0040-4020(01)82069-x.
Schenck, T. G., & Bosnich B. (1985). Homegeneous catalysis.
Transition-metal-catalyzed Claisen rearrangements. Journal
of the American Chemical Society, 107, 2058–2066. DOI:
10.1021/ja00293a041.
Simons, C., Wu, Q., & Htar, T. T. (2005). Recent advances
in antiviral nucleoside and nucleotide therapeutics. Current
Topics in Medicinal Chemistry, 5, 1191–1203.
Szafraniec, S. I., Stachnik, K. J., & Skierski, J. S. (2004). New
nucleoside analogs in the treatment of hematological disor-
ders. Acta Poloniae Pharmaceutica – Drug Research, 61,
223–232.
Tobrman, T., & Dvořák, D. (2003). 6-Magnesiated purines:
Preparation and reaction with aldehydes. Organic Letters,
5, 4289–4291. DOI: 10.1021/ol0355027.
Tobrman, T., & Dvořák, D. (2008). Heck reactions of 6- and 2-
halopurines. European Journal of Organic Chemistry, 2008,
2923–2928. DOI: 10.1002/ejoc.200800091.
Vik, A., & Gundersen, L. L. (2007). Synthetic studies di-
rected towards asmarines; construction of the tetrahydrodi-
azepinopurine moiety by ring closing metathesis. Tetrahedron
Letters, 48, 1931–1934. DOI: 10.1016/j.tetlet.2007.01.090.
Castro, A. M. M. (2004). Claisen rearrangement over the
past nine decades. Chemical Reviews, 104, 2939–3002. DOI:
10.1021/cr020703u.
De Clercq, E.,
& Neyts, J. (2004). Therapeutic potential
of nucleoside/nucleotide analogues against poxvirus infec-
tions. Reviews in Medical Virology, 14, 289–300. DOI:
10.1002/rmv.439.
Kimura, K.,
& Bugg, T. D. H. (2003). Recent advances
in antimicrobial nucleoside antibiotics targeting cell wall
biosynthesis. Natural Product Reports, 20, 252–273. DOI:
10.1039/b202149h.
Kotek, V., Chudíková, N., Tobrman, T., & Dvořák, D. (2010).
Selective synthesis of 7-substituted purines via 7,8-dihydro-
purines. Organic Letters, 12, 5724–5727. DOI: 10.1021/
ol1025525.
Kotek, V., Tobrman, T., & Dvořák, D. (2012). Highly efficient
and broad-scope protocol for the preparation of 7-substituted
6-halopurines via N9-Boc-protected 7,8-dihydropurines Syn-
thesis, 2012, 610–618. DOI: 10.1055/s-0031-1290068.
Lagoja, I. M. (2005). Pyrimidine as constituent of natural bio-
logically active compounds. Chemistry &Biodiversity, 2, 1–
50. DOI: 10.1002/cbdv.200490173.
Mitchell, S. S., Whitehill, A. B., Trapido-Rosenthal, H. G., &
Ireland, C. M. (1997). Isolation and characterization of 1,3-
dimethylisoguanine from the Bermudian sponge Amphime-
don viridis. Journal of Natural Products, 60, 727–728. DOI:
10.1021/np970015j.
Wieland, T.,
& Bauer, L. (1951). Weitere Versuche zur
Stofftrennung durch Papierchromatographie und Ionophroe-
se. Purine und Aminosäuren. Angewandte Chemie, 63, 511–
513. DOI: 10.1002/ange.19510632104.
Yagi, H., Matsunaga, S., & Fusetani, N. (1994). Isolation of
1-methylherbipoline, a purine base, from a marine sponge,
Jaspis sp. Journal of Natural Products, 57, 837–838. DOI:
10.1021/np50108a025.
Yamada, T., Peng, C. G., Matsuda, S., Addepalli, H., Jayapra-
kash, K. N., Alam, M. R., Mills, K., Maier, M. A., Charisse,
K., Sekine, M., Manoharan, M., & Rajeev, K. G. (2011). Ver-
satile site-specific conjugation of small molecules to siRNA
using click chemistry. The Journal of Organic Chemistry, 76,
1198–1211. DOI: 10.1021/jo101761g.
Miura, S., & Izuta, S. (2004). DNA polymerases as targets of
anticancer nucleosides. Current Drug Targets, 5, 191–195.
DOI: 10.2174/1389450043490578.
Petrovi´c, M., B., Simonovi´c, A. T., Radovanovi´c, M. B., Mili´c, S.
M., & Antonijevi´c, M. M. (2012). Influence of purine on cop-
per behavior in neutral and alkaline sulfate solutions. Chem-
ical Papers, 66, 664–676. DOI: 10.2478/s11696-012-0174-y.
Phelps, K., Morris, A., & Beal, P. A. (2012). Novel modifi-
cations in RNA. ACS Chemical Biology, 7, 100–109. DOI:
10.1021/cb200422t.
Rachakonda, S., & Cartee, L. (2004). Challenges in antimi-
crobial drug discovery and the potential of nucleoside an-
tibiotics. Current Medicinal Chemistry, 11, 775–793. DOI:
10.2174/0929867043455774.