The optimized microwave-assisted decomposition of formamides and its synthetic utility in the amination reactions of purines

Article abstract of DOI:10.1016/j.tet.2010.12.040

The microwave-assisted decomposition of DMF was thoroughly studied and the reaction conditions (temperature, solvent effect, and effect of additives, such as acids, bases, and salts) were optimized for its use in amination reactions. The applicability of this expedient methodology in purine chemistry and with various formamides is demonstrated.

Full text of DOI:10.1016/j.tet.2010.12.040

Tetrahedron 67 (2011) 866e871
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The optimized microwave-assisted decomposition of formamides
and its synthetic utility in the amination reactions of purines
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*
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Lucie Cechova, Petr Jansa, Michal Sala, Martin Dracínsky, Antonín Holy, Zlatko Janeba
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Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, CZ-166 10 Prague 6, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2010
Received in revised form 23 November 2010
Accepted 13 December 2010
Available online 17 December 2010
The microwave-assisted decomposition of DMF was thoroughly studied and the reaction conditions
(temperature, solvent effect, and effect of additives, such as acids, bases, and salts) were optimized for its
use in amination reactions. The applicability of this expedient methodology in purine chemistry and with
various formamides is demonstrated.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Microwave-assisted synthesis
DMF
Formamides
Dehalogenative amination
Purines
1. Introduction
route to N6-substituted adenines involves regioselective alkylation
of the adenine exocyclic nitrogen by the Mitsunobu reaction.12
N,N-Dimethylformamide (DMF) is one of the most common
protic polar solvents in organic synthetic chemistry and is the
solvent of choice for a wide range of organic reactions. Nonetheless,
DMF is much more than a solvent since it is quite a reactive mol-
ecule. DMF can react either as a nucleophilic or an electrophilic
agent and also has interesting coordination properties. Depending
on the reaction conditions, DMF can be the source of various key
intermediates in organic synthesis, such as carbon monoxide,
dimethylamine, the formyl group, and formate.1
Many biologically active compounds possess either a N-methyl-
amino or N,N-dimethylamino motif within their molecules, which is
also true in the chemistry of nucleic acids components.2e4 The
synthesis of adenosine nucleosides substituted at the N-6 position
has usually been carried out by a condensation of protected sugars
(e.g., ribosides) with mercuric chloride salts of N6-substituted ade-
nines.5 These procedures often suffer from low yields and the for-
mation of undesired regioisomers. A more expedient method is the
nucleophilic displacement of the halogen atom at the C-6 position of
a purine by amines.6e10 The nucleophilic displacement of a 6-(1,2,4-
triazol-4-yl) moiety with dimethylamine also gives the corre-
sponding N6,N6-dimethylaminopurine derivatives of nucleosides
and 20-deoxynucleosides quantitatively.11 Another novel synthetic
As early as in 1954 Coppinger13 reported an efficient method
(yields >90%) for the preparation of N,N-dimethylamides by simple
heating of the corresponding acid chloride or anhydride with N,N-
dimethylformamide (DMF). Since then, reactions of activated aro-
matic or heteroaromatic halides with DMF at elevated temperature
for the preparation of N,N-dimethylamino substituted compounds
have occasionally been reported.14ꢀ21
Microwave-assisted (MW-assisted) organic synthesis has be-
come a very rapidly developing area of chemistry and provides
a number of advantages over the standard heating techniques, such
as clean reactions, improved reaction yields, shorter reaction times,
easy work-ups, and solvent-free reaction conditions. Diverse or-
ganic reactions have recently been reported to proceed under mi-
crowave irradiation.22
Also several examples of reactions using a MW-assisted de-
composition of formamides have recently been described. The
MW-assisted decomposition of formamide to generate ammonia in
situ has been used as a tool for the synthesis of nitrogen containing
heterocyclic compounds.23 Sharma et al.24 have described a novel
MW-assisted procedure for the desulfitative dimethylamination of
5-chloro-3-(phenylsulfanyl)pyrazin-2(1H)-ones using a DMF/H2O
mixture in the presence of sodium carbonate. The N,N-dimethyla-
minated products were obtained in high yields (63e96%) in rela-
tively short reaction times (20e60 min) when compared to the
reactions under the conventional heating (usually in hours). To the
* Corresponding author. Tel.: þ420 220183143; fax: þ420 220183560; e-mail
address: janeba@uochb.cas.cz (Z. Janeba).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.040

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L. Cechova et al. / Tetrahedron 67 (2011) 866e871
867
Table 2
best of our knowledge, this is the first report on a MW-assisted
dimethylamination reaction using DMF as a reagent.24
Effect of various additives (0.5 mmol in 5 mL DMF) on the microwave-assisted de-
composition of DMF (180 ꢁC, 1 min reaction time) as indicated by change in pressure
The aim of this study was to develop and optimize dehaloge-
native amination (nucleophilic aromatic substitution, SNAr) using
the MW-assisted decomposition of formamides and apply the
methodology for the modification of purine derivatives, i.e., com-
pounds of pharmaceutical interest. Such a procedure would offer an
alternative method for the amination of heterocyclic compounds.
Entry
1
2
3
4
5
6
7
Additives
Pressure (bar) 0.8
BF3$Et2O FeCl3 1þFeCl3 CuSO4 Zn(OAc)2 HCl 1þHCl
1.8 2.3 0.3 1.2 5.4 10
HCl in the reaction mixture dramatically accelerates the process
(entries 6 and 7, Table 2). This finding offers an explanation for the
dramatic difference of the decomposition rate of neat DMF when
compared to the mixture of compound 1 in DMF. In the latter case,
dimethylamine formed during the decomposition of DMF reacts
immediately with the chloro derivative 1. In the course of the nu-
cleophilic aromatic substitution, HCl is generated, which sub-
sequently catalyzes the further decomposition of DMF. This
reaction under the described conditions is autocatalytic.
Increasing the quantity of concentrated aqueous HCl evidently
accelerates the reaction (Fig. 2, blue dots). Since water does not
facilitate the decomposition of DMF (entry 6, Table 1), we switched
to the anhydrous 5.7 M solution of HCl in DMF. The results show
that the successive addition of anhydrous HCl markedly increases
the decomposition rate of DMF (Fig. 2, violet dots).
2. Results and discussion
2.1. Optimization of the microwave-assisted decomposition
of DMF
The microwave-assisted decomposition of DMF was studied in
a sealed vessel and monitored automatically by the increase of
pressure. Such a sealed vessel system was also used for the sub-
sequent amination reactions under microwave irradiation.
Initially, a solution of 9-benzyl-6-chloropurine (1, 0.5 mmol) in
DMF (5 mL) was being irradiated at various temperatures (Fig. 1).
DMF starts to decompose at 170 ꢁC (Fig. 1). At 190 ꢁC marked de-
composition of DMF was observed and this temperature was cho-
sen for further optimizations.
20
18
16
14
12
10
8
9
8
7
6
5
4
3
2
1
0
6
HCl (11 M in water)
4
HCl (5.7 M in DMF)
2
0
140
150
160
170
180
190
200
210
220
0
20
40
60
80
100
120
Temperature (°C)
Quantity of the HCl solution (mg) in DMF (5 mL)
Fig. 1. Effect of temperature on the microwave-assisted decomposition of DMF in
a mixture of DMF and compound 1 (1 min reaction time) as indicated by change in
pressure.
Fig. 2. Effect of the amount of HCl on the microwave-assisted decomposition (180 ꢁC,
1 min reaction time) of DMF (5 mL) as indicated by change in pressure.
This compelling data encouraged us to reoptimize the reaction
temperature further. We have speculated that the amination re-
actions with addition of HCl could proceed at lower temperatures
and thus under milder reaction conditions, providing that the
starting compounds are stable in acids.
A mixture of DMF (5 mL) and anhydrous HCl (60 mg of 5.7 M DMF
solution) was irradiated at varioustemperatures for 1 min (Fig. 3). The
rate of the decomposition of DMF in the presence of HCl at 180 ꢁC is
considerably increased (9.3 bar, Fig. 3) as compared to the
For the use of alternative or more expensive formamides, the
reaction may need to be conducted in a suitable solvent. Thus, the
solvent effect on the decomposition of DMF was studied. Irradiation
(190 ꢁC, 1 min) of DMF (1 mL) in a wide range of solvents (5 mL)
indicated the accelerated decomposition of DMF in toluene, THF,
and acetic acid (entries 4, 7, and 9, respectively, Table 1). On the
other hand, solvents like EtOH, MeOH, and water did not facilitate
the decomposition of DMF (entries 2, 3, and 6, respectively, Table 1).
Table 1
Effect of solvents on the microwave-assisted decomposition of DMF (190 ꢁC, 1 min
reaction time, solvent/DMF ratio 5:1) as indicated by change in pressure
10
9
8
7
6
5
4
3
2
1
0
Entry
1
2
3
4
5
6
7
8
9
Solvent
Pressure (bar) 0.2
DMF EtOH MeOH Toluene Dioxane Water THF MeCN AcOH
0.6 0.3 0.6 2.3
0
0
0
0
Surprisingly, irradiation of neat DMF resulted in a much lower
pressure (0.2 bar, entry 1, Table 1) and thus a much slower de-
composition rate, as compared to the pressure (6.2 bar, Fig. 1) of the
irradiated mixture of DMF with compound 1 under otherwise
identical conditions (190 ꢁC,1 min). This interesting finding led us to
investigate further the effect of some other chemicals (Lewis acids,
inorganic salts, and HCl) on the decomposition rate of DMF (Table 2).
The data clearly showed that in general, additives facilitate the
MW-assisted decomposition of DMF and especially the presence of
90
110
130
150
170
190
Temperature (°C)
Fig. 3. Effect of temperature on the microwave-assisted decomposition of DMF (5 mL)
in the presence of anhydrous HCl (60 mg of 5.7 M DMF solution) as indicated by
change in pressure (1 min reaction time).

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L. Cechova et al. / Tetrahedron 67 (2011) 866e871
decomposition of neat DMF at 190 ꢁC (0.2 bar, entry 1, Table 1).
Moreover, the significant decompositionrateof DMF(3.9bar, Fig. 3)in
the presence of HCl can be reached at a temperature as low as 110 ꢁC.
The MW-assisted amination with DMF was reported in the
presence of various bases.24,25 We have irradiated (180 ꢁC, 1 min)
mixtures of DMF (5 mL) with several commonly used bases
(0.5 mmol, Table 3). The highest decomposition rate of DMF was
observed with t-BuOK (entry 1, Table 3), but the reaction mixture
turned dark brown.
Table 4
MW-assisted dimethylamination of 6-chloropurines 1e9 with DMF
Entry
Substrate
Time (min)
Product
Yielda (%)
92
N
Cl
N
1
1
N
N
N
N
N
N
N
2
3
4
25
7
2
50b
62c
96d
1
10
Table 3
N
N
Effect of various bases (0.5 mmol in 5 mL DMF) on the microwave-assisted de-
composition of DMF (180 ꢁC, 1 min) as indicated by change in pressure
Cl
N
N
N
N
N
5
6
3
3
70
81
Entry
1
2
3
4
N
N
Base
Pressure (bar)
t-BuOK
3.0
K2CO3
0.2
DMAP
2.4
Et3N
0
2
Cl
11
N
N
N
N
N
N
N
When a mixture of 9-benzyl-6-chloropurine (0.5 mmol) and
t-BuOK (0.5 mmol) in DMF (5 mL) was irradiated at 180 ꢁC, a col-
orful and complex reaction mixture with a moderate yield (50%) of
the N6,N6-dimethyladenine analog 10 was obtained (entry 2, Table
4). A cleaner reaction mixture and better yield (62%) of derivative 10
was obtained from the reaction using DMAP (4-dimethylamino-
pyridine, entry 3, Table 4). Nevertheless, an analogous reaction of
the compound 1 in DMF with the addition of anhydrous HCl proved
to be superior since it provided a clean reaction mixture and a high
yield of the derivative 10 (96%, entry 4, Table 4) but even analogous
reaction in neat DMF at 210 ꢁC gave 92% yield of 10 (entry 1, Table 4).
H2N
N
H2N
N
12
3
N
Cl
N
N
N
N
N
N
N
7
8
9
57
82
N
H2N
N
H2N
13
N
4
Cl
N
N
N
2.2. Application of the microwave-assisted decomposition of
formamides in purine chemistry
10
N
H
N
H
N
N
5
14
The encouraging results of the optimized conditions for the
MW-assisted decomposition of DMF prompted us to apply this
method to amination reactions, namely for the derivatization of
various 6-chloropurine derivatives, including N9- and N7-benzy-
lated purines 1e4, free purine bases 5e7, riboside 8, and acyclic
nucleoside phosphonate 9 (Table 4).
The DMF solutions of the 6-chloropurines 1e9 were irradiated
(180e210 ꢁC) for the given period of time (Table 4). Their reactivity
and the yields of the obtained products correspond to their elec-
tronic and steric properties. The yields of the N6,N6-dimethylamino
products 10e18 are generally high (48e96%) and only the reaction
of 2,6-dichloropurine 6 gave the bis substituted purine base 15 in
35% yield (entry 9, Table 4). Owing to the lability of the nucleosidic
bond of the riboside 8, the desired amination product 17 was iso-
lated in very low yield (15%) while the free base 14 was obtained as
the main product (63%, entry 11, Table 4).
The yields of the described MW-assisted amination of 6-chlor-
opurines with DMF are comparable to the yields of the classical
nucleophilic aromatic substitution of 6-chloropurines with dimet
hylamine, but reaction times are markedly shorter. Thus, the
reported yields of 9-benzyl purine derivatives 10 and 12 are 87%
(15 h at ambient temperature)26 and 92% (20 h at 60 ꢁC),27 re-
spectively, whereas we have obtained compound 10 in 92% yield
(1 min at 210 ꢁC, entry 1, Table 4) and compound 12 in 81% yield
(3 min at 180 ꢁC, entry 6, Table 4). The reported yields of 6-
(dimethylamino)purine 14 are 81% (12 h at 150 ꢁC),28 84.5% (14 h at
110 ꢁC),29 and 95% (24 h at ambient temperature),30 compared to
our 82% yield of product 14 (10 min at 180 ꢁC, entry 8, Table 4).
Finally, we have prepared compound 16 in 83% yield in 50 min
(180 ꢁC, entry 10, Table 4), whereas the yield of the derivative 16
prepared by nucleophilic aromatic substitution was reported as 97%
in 16 h at 110 ꢁC.29 Moreover, no need to use solvents is another
advantage of our new methodology.
Cl
N
N
N
N
N
N
9
21
50
35
83
N
H
N
H
Cl
N
N
N
6
Cl
15
N
N
N
N
10
N
H
H2N
N
N
H
H2N
N
16
7
Cl
N
N
N
N
N
N
N
N
N
HO
HO
11
4
15
63
O
O
H
H
H
H
H
H
H
H
OH
OH
OH OH
17
þ14
8
N
Cl
N
N
N
N
N
N
H2N
N
H2N
N
12
3
48
O
P
O
O
O
O
O
P
O
O
9
18
Reaction conditions: MW irradiation in DMF at 180e210 ꢁC.
a
Isolated yields.
t-BuOK added.
b
c
DMAP added.
d
HCl added.

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L. Cechova et al. / Tetrahedron 67 (2011) 866e871
869
In order to establish the universal applicability of the described
MW-assisted methodology in synthetic organic chemistry, a series of
N6-substituted 9-benzyl-2,6-diaminopurine derivatives 19 was pre-
pared using various formamides (Table 5). All reactions were carried
out in toluene since this solvent had previously been shown to be the
solvent of choice for the described procedure (entry 4, Table 1).
Treatment of compound 3 with N-methylformamide, N-ethyl-
formamide, and N,N-diethylformamide under the MW-assisted con-
ditions (180e190 ꢁC) afforded the corresponding N6-methyladenine
19a (66%), N6-ethyladenine 19b (59%), and N6,N6-diethyladenine 19c
(60%) derivatives, respectively (entries 1e3, Table 5). A similar ami-
nation of the compound 3 with N-tert-butylformamide (190 ꢁC,
330min) proceeded veryslowlyand only 30% of the expected product
19d was obtained after a prolong period of time (entry 4, Table 5). The
obtained data indicate that the yields of these amination reactions
depend both on the nucleophilicity and bulkiness of the corre-
sponding amine released during the MW-assisted decomposition of
formamides. The lowest yield gave the reaction with N-tert-butyl-
formamide (entry 4, Table 5), which under the microwave conditions
releases relatively bulky tert-butylamine. Moreover, there is clear
evidence that aminations carried out in solvent require prolonged
irradiation (over 30 min, Table 5) compared to the analogous pro-
cedure in neat formamide (DMF, 3 min, entry 6, Table 4).
reactions and with various formamides. In total,13 compounds were
prepared with this expedient methodology, six of which (13, 18,
19aed) for the first time. The procedure proved to be the method of
choice for the introduction of substituted amino functions into or-
ganic molecules and for the facile and convenient modification of
compounds of biological interest.
4. Experimental section
4.1. General methods
Unless otherwise stated, solvents were evaporated at 40 ꢁC/
2 kPa, and compounds were dried at 2 kPa over P2O5. Melting
points were determined on a Stuart SMP3 melting point apparatus.
TLC was performed on TLC aluminum sheetsdsilica gel 60 F254
(MERCK KGaA, Germany) in chloroformemethanol. 1H and 13C
NMR spectra were recorded in CDCl3 or DMSO-d6 at 27 ꢁC with
a Bruker Avance II 600 and/or Bruker Avance II 500 spectrometers
operating at 600.0 or 500.0 MHz in 1H and 150.9 or 125.7 MHz in
13C. Hydrogen and carbon spectra were referenced to TMS or to
residual solvent signals (d 2.50 and 39.7 for DMSO and 77.0 for
CDCl3). The ESI mass spectra were measured with an LCQ Fleet
spectrometer (Thermo Fisher Scientific). The standard 70 eV mass
spectra were recorded in the mass range of 25e800 using a 4 min
solvent delay. The temperatures of the transfer line, ion source, and
quadrupole were 280, 230, and 150 ꢁC, respectively. Elemental
microanalysis was performed using a PE 2400 Series II CHNS/O
Analyzer (PerkineElmer, USA). IR spectra were recorded on an FTIR
spectrometer Bruker IFS 55 (Equinox) in CHCl3.
Table 5
MW-assisted amination reactions of 2-amino-6-chloropurine derivative 3
R1
R2
O
Cl
N
N
N
N
N
N
N
N
H
NR1R2
N
toluene
microwave
180-190 °C
H2N
H2N
4.2. General microwave-assisted procedure
3
19
All reactions were carried out in CEM Discover (Explorer) mi-
crowave apparatus, 24-position system for 10-mL vessels sealed
with Teflon septum. It was operated at a frequency of 2.45 GHz with
continuous irradiation power from 0 to 300 W. The solutions were
steadily stirred during the reaction. The temperature was measured
with an IR sensor on the outer of the process vessel. The vials were
cooled to ambient temperature with gas jet cooling system. The
pressure was measured with an inboard CEM Explorer pressure
control system (0e21 bar).
Entry
t (min)
Formamide
Product
Yielda (%)
1
2
3
4
30
62
56
N-Methylformamide
N-Ethylformamide
N,N-Diethylformamide
N-tert-Butylformamide
19a R1¼H, R2¼Me
19b R1¼H, R2¼Et
19c R1¼R2¼Et
66
59
60
30
330
19d R1¼H, R2¼t-Bu
a
Isolated yield.
Although the recently described MW-assisted nucleophilic dis-
placement reactions of 6-chloropurines with amines give the cor-
responding products in high yields (86e95%) and short reaction
times (>6 min),9 our new amination method affords an alternative
and convenient route of efficient synthesis of N6-substituted ade-
nine derivatives.
Compounds and/or additives were dissolved in appropriate
formamide or formamide/solvent mixture and added into a 10-mL
reaction vessel containing a stirring bar. The vessel was sealed with
a Teflon septum and heated under MW irradiation for the set time
and temperature using maximum power (300 W).
3. Conclusions
4.3. Synthesis of compound 10 in the presence of additives
A convenient microwave-assisted procedure for the dimethyla-
minations (and generally alkyl- and dialkyl-aminations) of various
compounds was elaborated. The present study proved that MW-
assisted decomposition of formamides is an extremely useful tool in
modern synthetic organic chemistry, which can be used as a conve-
nient alternative to the classical nucleophilic aromatic substitutions
using amines. The main advantages of the described MW-assisted
amination procedure as compared to the reactions using conven-
tional heating are short reaction times, high yields, and simple work-
ups. Furthermore, an important safety issue may lie in the elimina-
tion of the handling of dangerous and volatile amines. The optimum
temperature for the described MW-assisted amination procedure
with DMF was found to be 180e190 ꢁC but under the acid catalysis it
can be as low as 110 ꢁC. The aminations can be carried out either in
neat formamide or in suitable solvents, e.g., toluene. The reaction
conditions of the MW-assisted formamide decompositions were
thoroughly optimized and were used in nucleophilic substitution
Mixtures of 1 (122 mg, 0.5 mmol) and t-BuOK (56 mg,
0.5 mmol), DMAP (62 mg, 0.5 mmol), or HCl (53 mg of 5.7 M HCl/
DMF) in DMF (6 mL) were heated under microwave irradiation at
180 ꢁC for 25 min, 7 min, and 2 min, respectively. Each reaction
mixture was evaporated in vacuo and the residue applied onto
a silica gel column and flash chromatographed (chloroform/MeOH,
19:1) to afford 10 as white solid in 50% (63 mg), 62% (7 mg), and 96%
(122 mg) yield, respectively. The 1H and 13C NMR spectra were
identical with compound 10 prepared by General procedure 4.3.
4.4. General procedure for the preparation of compounds
10e16
A solution of 1 (1.10 g, 4.5 mmol), 2 (244 mg,1 mmol), 3 (649 mg,
2.5 mmol), 4 (518 mg, 2 mmol), 5 (310 mg, 2 mmol), 6 (190 mg,
1 mmol) or 7 (340 mg, 2 mmol) in DMF (6 mL for 0.5 mmol of
starting compound) was divided into several vials. Each vial

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L. Cechova et al. / Tetrahedron 67 (2011) 866e871
870
contained starting compound (0.5 mmol) and DMF (6 mL). The
solutions were heated under microwave irradiation. Reaction
mixtures were collected and evaporated in vacuo. For 10, 11, 12, 13,
and 16 the residue was applied on silica gel column and flash
chromatographed. For 14 and 15 the residue was partitioned be-
tween water (60 mL) and EtOAc (50 mL). The water layer was
extracted with EtOAc (3ꢂ40 mL), dried over anhydrous MgSO4,
filtered, and evaporated.
(5% MeOH/CHCl3) 0.42; nmax (liquid film) 2815 and 1424 (CH3), 3455,
3113, and 3073 (NH), 1607, 1582, 1539, 1512, 1388, and 1339 cmꢀ1
(purine); 1H NMR (DMSO-d6): 12.27 (1H, br s, NH), 7.67 (1H, s, H-8),
3.38 (6H, br s, CH3), 3.05 (6H, s, CH3). 13C NMR (DMSO-d6): 159.0,
154.2, 153.7, 134.7, 113.0, 37.7, and 37.2. HRMS (ESI) m/z C9H15N6
[MþH]þ calcd: 207.1353. Found: 207.1352.
4.4.7. 2-Amino-6-(dimethylamino)purine (16)29. The reaction mix-
ture was heated at 180 ꢁC for 50 min. Column chromatography
EtOAc/acetone/EtOH/water (15:3:4:3) afforded 300 mg (83%) of
yellowish product, mp 252 ꢁC (lit.29 mp 263 ꢁC); Rf (5% MeOH/
CHCl3) 0.28; 1H NMR (DMSO-d6): 12.16 (1H, br s, NH), 7.66 (1H, s, H-
8), 5.68 (2H, s, NH2), 3.36 (6H, s, CH3). 13C NMR (DMSO-d6): 159.6,
154.8, 153.6, 134.6, 113.6, 37.8. HRMS (ESI) m/z C7H11N6 [MþH]þ
calcd: 179.1040. Found: 179.1039.
4.4.1. 9-Benzyl-6-(dimethylamino)purine (10)26,31. The reaction
mixture was heated at 210 ꢁC for 1 min. Yield 1.045 g (92%) of white
solid, mp 129 ꢁC (lit.26 mp 126e128 ꢁC, lit.31 mp 131e132 ꢁC); Rf (5%
MeOH/CHCl3) 0.83; 1H NMR (CDCl3): 8.39 (1H, s, H-8), 7.69 (1H, s, H-
2), 7.33e7.26 (5H, m, H-30, H-40, H-20), 5.35 (2H, s, CH2), 3.53 (6H, s,
CH3). 13C NMR (CDCl3): 155.0 (C-4),152.6 (C-2),150.7 (C-6),138.0 (C-
8),135.9(C-10),128.9 (C-30),128.1 (C-40),127.6 (C-20),120.0 (C-5), 46.9
(CH2), 38.5 (CH3). GCeMS: 253.2. For C14H15N5 (253.3) calculated:
66.38% C, 5.97% H, 27.65% N; found 66.27% C, 5.89% H, 27.42% N.
4.5. 6-(Dimethylamino)-9-(b-D
-ribofuranosyl)purine (17)5,11
A solution of 8 (0.574 g, 2 mmol) in DMF (24 mL) was heated
under microwave irradiation at 190 ꢁC for 4 min and the solvent
was evaporated in vacuo. The residue was purified by silica gel
column chromatography in hexane/chloroform/methanol (6:4:1)
to give 205 mg (63%) of 14 (1H and 13C NMR data identical with
compound 14 in 4.4.5) and 91 mg (15%) of 17 as white solid. Mp
184 ꢁC (lit.5 mp 183e184 ꢁC, lit.11 mp 182e183 ꢁC); Rf (5% MeOH/
CHCl3) 0.25; 1H NMR (DMSO-d6): 8.37 (1H, s, H-8), 8.21 (1H, 0s, H-2),
4.4.2. 7-Benzyl-6-(dimethylamino)purine (11)31. The reaction mix-
ture was heated at 190 ꢁC for 3 min. Column chromatography
chloroform/MeOH (19:1) afforded 177 mg (70%) of white solid, mp
135e136 ꢁC (lit.31 mp 134e135 ꢁC); Rf (5% MeOH/CHCl3) 0.51; 1H
NMR (CDCl3): 8.65 (1H, s, H-8), 7.99 (1H, s, H-2), 7.34e7.32 (3H, m,
H-30, H-20), 7.12 (2H, m, H-20), 5.53 (2H, s, CH2), 3.04 (6H, s, CH3). 13C
NMR (CDCl3): 161.5 (C-4), 156.1 (C-6), 152.2 (C-2), 146.7 (C-8), 135.5
(C-10), 129.1 (C-30), 128.5 (C-40), 126.9 (C-20), 115.3 (C-5), 50.8 (CH2),
41.6 (CH3). GCeMS: 253.2. For C14H15N5 (253.3) calculated: 66.38%
C, 5.97% H, 27.65% N; found 65.57% C, 6.05% H, 27.04% N.
0
0
0
0
5.91 (1H, d, J1 e2 ¼6.0, H-1 ), 5.45 (1H, d, JOH-2 ¼6.2, OH-2 ), 5.38
0
0
0
0
(1H, dd, JOH-5 ¼4.6 and 6.9, OH-5 ), 5.190 (1H, d, JOH-3 ¼4.7, OH-3 ),
0
0
0
0
0
0
4.58 (1H, dd, 0J2 e1 ¼11.2, J2 e3 ¼5.9, H-2 ), 4.15 (1H,0 dd, J3 e2 ¼4.7,
0
0
0
0
J3 e4 ¼8.1, H-3 ), 3.96 (1H, dd, J4 e5 ¼3.4 and 3.6, H-4 ), 3.68 (1H, m,
H-50a), 3.55 (1H, m, H-50b), 3.45 (6H, vbr s, CH3). 13C NMR (DMSO-
d6): 154.5 (C-6),151.8 (C-2),150.1 (C-4),138.7 (C-8),120.0 (C-5), 88.0
(C-10), 85.9 (C-40), 73.7 (C-20), 70.7 (C-30), 61.7 (C-50), 38.1. ESIMS, m/
z (%): 296.2 (MHþ) (100). For C12H17N5O3 (279.3) calculated: 48.81%
C, 5.80% H, 23.72 N; found 49.05% C, 5.87% H, 22.95% N.
4.4.3. 2-Amino-9-benzyl-6-(dimethylamino)purine (12)27. The re-
action mixture was irradiated at 180 ꢁC for 3 min. Column chroma-
tography in EtOAc/acetone/EtOH/water (40:3:4:3) gave 434 mg
(67%) of white solid, mp 184 ꢁC; Rf (5% MeOH/CHCl3) 0.47; 1H NMR
(DMSO-d6): 7.80 (1H, s, H-8), 7.34e7.19 (5H, m, H-30, H-40, H-20), 5.85
(2H, s, NH2), 5.20 (2H, s, CH2), 3.34 (6H, s, CH3). 13C NMR (DMSO-d6):
159.5 (C-2),154.7 (C-4),152.7 (C-6),137.5 (C-8),136.3 (C-10),128.4 (C-
30), 127.3 (C-40), 126.9 (C-20), 113.5 (C-5), 45.3 (CH2), 37.5 (CH3).
ESIMS, m/z (%): 269.2 (MHþ) (100). For C14H16N6 (268.14) calculated:
62.67% C, 6.01% H, 31.32% N; found: 62.63% C, 6.13% H, 30.93% N.
4.6. 2-Amino-9-{2-[(diisopropoxyphosphoryl)methoxy]
ethyl}-6-(dimethylamino)-purine (18)
A solution of 9 (0.392 g, 1 mmol) in DMF (12 mL) was heated
under microwave irradiation at 190 ꢁC for 3 min and the solvent
was evaporated in vacuo. The residue was partitioned between
water (50 mL) and EtOAc (40 mL), extracted with EtOAc (2ꢂ30 mL),
dried over MgSO4, filtered, and evaporated to give 192 mg (48%) of
18 as colorless oil; Rf (5% MeOH/CHCl3) 0.38; 1H NMR (DMSO-d6):
7.66 (1H, s, H-8), 5.79 (2H, s, NH2), 4.52 (2H, m, CHeiPr), 4.14 (2H, t,
4.4.4. 2-Amino-7-benzyl-6-(dimethylamino)purine (13). The re-
action mixture was irradiated at 180 ꢁC for 9 min. Column chro-
matography in EtOAc/acetone/EtOH/water (15:3:4:3) afforded
305 mg (57%) of white solid, mp 180e182 ꢁC; Rf (5% MeOH/CHCl3)
0.31; nmax (liquid film) 3525 and 3419 (NH2), 2801 and 1414 (CH3),
1600, 1581, 1571, and 1486 (purine), 1497, 1455, 1030, and 697 cmꢀ1
(phenyl); 1H NMR (DMSO-d6): 8.22 (1H, s, H-8), 7.30e7.25 (3H, m,
H-30, H-40), 7.09e7.07 (2H, m, H-20), 5.85 (2H, s, NH2), 5.41 (2H, s,
CH2), 2.87 (6H, s, CH3). 13C NMR (DMSO-d6): 163.9 (C-4),159.2 (C-2),
156.1 (C-8), 146.9 (C-6), 137.4 (C-10), 128.5 (C-30), 127.5 (C-40), 126.7
(C-20), 108.1 (C-5), 50.0 (CH2), 40.8 (CH3). ESIMS, m/z (%): 269.3
(MHþ) (100). For C14H16N6 (268.32) calculated: 62.67% C, 6.01% H,
31.32% N; found: 58.77% C, 5.88% H, 29.33% N.
0
0
0
0
0
0
J1 e2 ¼5.2, H-1 ), 3.81 (2H, t, J2 e1 ¼5.2, H-2 ), 3.76 (2H, d, JHeP¼8.4,
CH2eP), 3.35 (6H, br s, CH3), 1.19 (3H, d, Jvic¼6.2, CH3), 1.16 (3H, d,
Jvic¼6.2, CH3). 13C NMR (DMSO-d6): 159.6 (C-2), 154.8 (C-4), 152.8
(C-6), 136.83 (C-8), 113.7 (C-5), 70.4 (d, JC,P¼11.6, C-20), 70.3 (d,
JC,P¼6.5, POC), 64.8 (d, JC,P¼164.0, CH2eP), 42.1 (C-10), 37.7 (CH3),
23.9 (d, JC,P¼3.8, CH3), 23.8 (d, JC,P¼4.5, CH3). ESIMS, m/z (%): 401.2
(MHþ) (100). For C16H29N6O4P (400.41) calculated: 47.99% C, 7.3% H,
20.99% N; found 45.88% C, 7.69% H, 19.44% N.
4.4.5. 6-(Dimethylamino)purine (14)28ꢀ30. The reaction mixture
was heated at 180 ꢁC for 10 min. Yield 271 mg (82%) of white solid,
mp 262 ꢁC (lit.30 mp 265e266 ꢁC, lit.31 mp 257 ꢁC, lit.32 mp
259e260 ꢁC); Rf (5% MeOH/CHCl3) 0.31; 1H NMR (DMSO-d6): 12.96
(1H, br s, NH), 8.18 and 8.08 (2ꢂ1H, s, H-2 and H-8), 3.43 (6H, br s,
CH3). 13C NMR (DMSO-d6): 154.3 (C-4), 151.9 (C-2), 151.3 (C-6), 137.9
(C-8), 119.0 (C-5), 38.0 (CH3). HRMS (ESI) m/z C7H10N5 [MþH]þ
calcd: 164.0931. Found: 164.0930.
4.7. Preparation of compounds 19aed
A solution of 3 (260 mg, 1 mmol) in a mixture of the corre-
sponding formamide (1 mL) and toluene (5 mL) was irradiated and
solvents were evaporated in vacuo. The residue was partitioned
between water (50 mL) and EtOAc (40 mL). The water layer was
extracted with EtOAc (2ꢂ30 mL), dried over anhydrous MgSO4,
filtered, and evaporated. Product was isolated by column chroma-
tography on silica gel in a EtOAc/acetone/EtOH/water (40:3:4:3)
mixture.
4.4.6. 2,6-Bis(dimethylamino)purine (15). The reaction mixture was
heated at 180 ꢁC for 25 min. Yield 72 mg (35%), mp 250e251 ꢁC; Rf

ꢀ
ꢁ
L. Cechova et al. / Tetrahedron 67 (2011) 866e871
871
4.7.1. 2-Amino-9-benzyl-6-(methylamino)purine (19a). A mixture
of 3 (260 mg, 1 mmol) and N-methylformamide (1 mL) in toluene
(5 mL) was irradiated at 190 ꢁC for 30 min to afford 168 mg (66%)
of white solid, mp 186 ꢁC; Rf (10%, MeOH/CHCl3) 0.67; nmax (liquid
film) 3529 and 3422 (NH2), 3451, 2969, and 1408 (NHMe), 1599,
1536, 1496, 1439, 1396, and 1349 (purine), 3092, 3068, and 3035
(CH2ephenyl), 1496, 1454, 1167, 1077, and 1030 cmꢀ1 (phenyl); 1H
NMR (DMSO-d6): 7.76 (1H, s, H-8), 7.32 (2H, m, H30), 7.26 (1H, m,
H-40), 7.2e7.23 (3H, m, H20, NH), 5.90 (2H, br s, NH2), 5.20 (2H, s,
CH2), 2.89 (3H, br s, CH3). 13C NMR (DMSO-d6): 160.55 (C-2),
155.61 (C-6), 151.0 (C-4), 137.88 (C-10), 137.27 (C-8), 128.77 (C-30),
127.62 (C-40), 127.24 (C-20), 113.59 (C-5), 45.62 (CH2), 27.23 (CH3).
HRMS (ESI) m/z C13H15N6, [MþH]þ calcd: 255.1353 Found:
255.1353.
29.28 (CH3). HRMS (ESI) m/z C16H21N6, [MþH]þ calcd: 297.1822.
Found: 297.1823.
Acknowledgements
This study was performed as
a part of research project
OZ40550506 of the Institute of Organic Chemistry and Bio-
chemistry. It was supported by Centre for new antivirals and anti-
neoplastics 1M0508 by the Ministry of Education, Youth and Sports
of the Czech Republic, by Grant Agency of the Academy of Sciences
of the Czech Republic through Project KJB400550903, and by Gilead
Sciences and IOCB Research Centre.
Supplementary data
4.7.2. 2-Amino-9-benzyl-6-(ethylamino)purine (19b). A mixture of
3 (260 mg,1 mmol) and N-ethylformamide (1 mL) in toluene (5 mL)
was irradiated at 180 ꢁC for 62 min to afford 158 mg (59%) of white
solid, mp 180e183 ꢁC; Rf (10%, MeOH/CHCl3) 0.73; nmax (liquid film)
3528 and 3424 (NH2), 2976, 2878, 1479, and 1383 (NHEt), 1600,
1530, 1493, 1438, 1400, and 1344 (purine), 3092, 3068, and 3035
(CH2ephenyl), 1493, 1455, 1318, 1166, 1077, and 1030 cmꢀ1 (phe-
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.12.040.
References and notes
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nyl); H NMR (DMSO-d6): 7.77 (1H, s, H-8), 7.32 (2H, m, H30), 7.26
(1H, m, H40), 7.20e7.23 (3H, m, H-20, NH), 5.85 (2H, br s, NH2), 5.19
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of 3 (260 mg, 1 mmol) and N,N-diethylformamide (1 mL) in toluene
(5 mL) was irradiated at 180 ꢁC for 56 min to afford 178 mg (60%) of
white solid, mp 97e99 ꢁC; Rf (10%, MeOH/CHCl3) 0.81; nmax (liquid
film) 3527 and 3419 (NH2), 2979, 2935, 2873, 1465, 1379, and 1368
(NEt2), 1591, 1572, 1528, 1493, 1443, 1404, and 1321 (purine), 3092,
3068, and 3025 (CH2ephenyl), 1493, 1455, 1080, and 1030 cmꢀ1
(phenyl); 1H NMR (DMSO-d6): 7.79 (1H, s, H-8), 7.32 (2H, m, H-30),
7.26 (1H, m, H-40), 7.23 (2H, m, H-20), 5.78 (2H, br s, NH2), 5.20 (2H,
s, 10-CH2), 3.86 (4H, br s, CH2), 1.15 (6H, t, JCH3eCH2¼7, CH3). 13C NMR
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136.82 (C-8), 128.76 (C-30), 127.61 (C-40), 127.28 (C-20), 113.21 (C-5),
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3425 (NH2), 2977, 2875, 1479, and 1396 (NH-t-Bu), 1610, 1523, 1504,
1491, 1447, 1439, and 1348 (purine), 3091 and 3068 (CH2ephenyl),
1504, 1491, 1455, 1316, 1167, 1076, and 1030 cmꢀ1 (phenyl); 1H NMR
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