N 7-Tosyltheophylline (TsTh): A highly efficient reagent for the one-pot synthesis of n 7-alkyltheophyllines from alcohols

Article abstract of DOI:10.1055/s-0033-1341026

A convenient and highly efficient one-pot N-alkylation of theophylline from alcohols via N ⁷-tosyltheophylline (TsTh) is described. In this protocol, the treatment of primary and/or secondary alcohols with a mixture of TsTh and 1,8-diazabicyclo[5.4.0]undec-7-ene in refluxing acetonitrile affords the corresponding N ⁷-alkyltheophylline in good to excellent yields; the reaction was optimized for solvent and base. This methodology is highly efficient for various structurally diverse primary and secondary alcohols. A plausible mechanism for the one-pot N-alkylation of theophylline with alcohols via TsTh has been suggested. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341026

1380▌
PAPER
7
pNape-r Tosyltheophylline (TsTh): A Highly Efficient Reagent for the One-Pot
Synthesis of N7-Alkyltheophyllines from Alcohols
One-Pot Synthesis of N7-Alkyltheophyllines
Mohammad Navid Soltani Rad,* Somayeh Behrouz,* Hosnieh Najafi
Department of Chemistry, Shiraz University of Technology, Shiraz 71555-313, Iran
Fax +98(711)7354520; E-mail: soltani@sutech.ac.ir; E-mail: behrouz@sutech.ac.ir
Received: 21.12.2013; Accepted after revision: 25.02.2014
and their corresponding therapeutic properties are given
in Figure 1.
To access N7-alkyltheophyllines, theophylline is normally
treated with different carbon electrophiles, particularly al-
kyl halides, in basic media.7
Abstract: A convenient and highly efficient one-pot N-alkylation
of theophylline from alcohols via N7-tosyltheophylline (TsTh) is
described. In this protocol, the treatment of primary and/or second-
ary alcohols with a mixture of TsTh and 1,8-diazabicyclo[5.4.0]un-
dec-7-ene in refluxing acetonitrile affords the corresponding N7-
alkyltheophylline in good to excellent yields; the reaction was opti-
mized for solvent and base. This methodology is highly efficient for
various structurally diverse primary and secondary alcohols. A
plausible mechanism for the one-pot N-alkylation of theophylline
with alcohols via TsTh has been suggested.
The direct N-alkylation of theophyllines via alcohols
would be a highly advantageous and attractive strategy,
since alcohols are versatile reagents that are readily avail-
able in comparison with their corresponding alkyl ha-
lides.8
Key words: N-alkylation, alcohol, theophylline, TsTh, DBU
Furthermore, alcohols are less toxic than alkyl halides and
they can be easily handled. However, there are few meth-
ods that have been established for the one-pot N-alkyl-
ation of purine nucleobases, which are close related
scaffolds to theophylline. The most distinguished protocol
for the N-alkylation of purine nucleobases uses the
Mitsunobu conditions.9 However, this method is accom-
panied by several drawbacks including utilizing toxic, ex-
pensive, and explosive reagents such as diethyl
azodicarboxylate and diisopropyl azodicarboxylate. Fur-
thermore, the presence of unreacted triphenylphosphine
and also the formation of triphenylphosphine oxide causes
the workup and separation process to become tedious.
Therefore, the development of a method for the N-alkyla-
tion of theophylline using alcohols is still required. Re-
cently, we developed protocols for the direct N-alkylation
of nucleobases and theophylline using alcohols.8 In con-
tinuation of our ongoing research on the direct N-alkyla-
tion of nucleobases and theophylline via alcohols, herein,
we report the one-pot N-alkylation of theophylline with
alcohols via N7-tosyltheophylline (TsTh) as an efficient
reagent in the presence of 1,8-diazabicyclo[5.4.0]undec-
7-ene in refluxing acetonitrile (Scheme 1). To the best of
Xanthine alkaloids are critically important compounds in
human healthcare.1 Methylxanthines including theophyl-
line, caffeine, and theobromine are well known, since they
are significant ingredients in food stuffs that are major di-
etary sources, such as coffee, tea, cola beverages, energy
drinks, and chocolates.2 It is well known that methylxan-
thines show remarkable pharmacological activity.3
Among methylxanthines, theophylline has a greater bind-
ing efficacy with DNA compared to theobromine and caf-
feine and it has been used in the design of new therapeutic
agents.4 Although the combination of theophylline with
various drugs has been widely used for the treatment for
both chronic obstructive pulmonary disease (COPD) and
asthma, the limitations and side effects of theophylline re-
lated to its narrow therapeutic index has restricted the
applications of the parent compound.5 N7-Alkyltheophyl-
lines, however, show more specific chemotherapeutic ac-
tivity with lower toxicity and side effects;6 their
chemotherapeutic activity includes bronchodilator activi-
ty (with consequent efficacy in the treatment of asthma),
analeptic, diuretic, cardiotonic, CNS stimulant, etc.6 The
structures of some N7-alkyl derivatives of theophylline
R1
O
O
O
R2
O
R2
S
Me
N
Me
O
DBU, MeCN
N
N
N
+
R1
OH
reflux, 3–15 h
N
O
N
N
N
Me
1a–s
R1 = alkyl, aryl
R2 = H, alkyl
Me
TsTh
Scheme 1 One-pot N-alkylation of theophylline with alcohols via TsTh (DBU, MeCN, reflux)
SYNTHESIS 2014, 46, 1380–1388
Advanced online publication: 25.03.2014
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0
3
9
-
7
8
8
1
1
4
3
7
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2
1
0
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DOI: 10.1055/s-0033-1341026; Art ID: SS-2013-Z0828-OP
© Georg Thieme Verlag Stuttgart · New York

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One-Pot Synthesis of N7-Alkyltheophyllines
1381
OH
N
O
O
O
O
O
CO2H
O
OH
Me
O
Me
O
N
N
Me
O
N
N
Me
O
N
N
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
acefylline
diprophylline
(expectorant, bronchodilator)
doxofylline
(antiasthmatic, bronchodilator)
etamiphylline
(cardiotonic, diuretic)
(cardiotonic, diuretic,
antispasmodic
bronchodilator)
O
HN
HN
O
O
O
O
( )3
OH
Me
Me
N
N
Me
Me
O
N
N
N
N
N
N
N
N
N
O
N
N
N
N
N
O
N
O
Me
Me
lomifylline
(vasodilator)
Me
Me
etofylline
(cardiotonic, bronchodilator)
fenethylline
(CNS stimulant)
pimefylline
(vasodilator)
Cl
OH
HO
OH
O
HN
O
N
O
O
O
O
O
Me
OH
Me
OH
N
N
Me
O
Me
O
Me
N
OH
N
N
N
N
N
N
N
N
O
N
N
N
N
O
N
Me
Me
Me
Me
proxyphylline
(cardiotonic, bronchodilator)
theofibrate
(antihyperlipoproteinemic)
theodrenaline
(circulary analeptic, diuretic,
cardiotonic)
xanthinol
(vasodilator)
Figure 1 The structures of some N7-alkyltheophylline derivatives and their corresponding therapeutic activity
our knowledge, this current research is the first reported depicted in Table 1. Of the solvents examined, acetonitrile
application of TsTh in organic transformations.
(entry 4) afforded the best result and, hence, it was solvent
of choice for all further reactions. The use of N,N-dimeth-
ylformamide, dimethyl sulfoxide, N-methylpyrrolidin-2-
one, and anhydrous acetone (entries 1, 3, 5, and 8) led to
N7-butyltheophylline (1i) in reasonable yields. However,
the yield of 1i using hexamethylphosphoramide was poor
(entry 6), and the use of THF, toluene, and water failed to
generate 1i even after a reaction time of 24 hours (entries
2, 7, and 9).
TsTh was prepared by the reaction of anhydrous theoph-
ylline with tosyl chloride and triethylamine in acetonitrile
at reflux for three hours (Scheme 2). TsTh was obtained
in almost quantitative yield (ca. 96%) and it was recrystal-
lized from hot dichloromethane–hexane (1:1) solution as
white cotton-like needles. TsTh is quite stable and can be
stored in a refrigerator for many months.10
The first step of this synthetic approach was initiated by
optimizing the reaction conditions. As a model reaction,
we examined the reaction of butan-1-ol with TsTh to give
N7-butyltheophylline (1i). The optimization began by
studying the influence of various aprotic and other sol-
vents on the model reaction in the presence of freshly pre-
pared ThTs with DBU as the base. The results are
With acetonitrile as the solvent, next the model reaction
was examined for the most suitable base (Table 2); in ab-
sence of a base, the reaction failed, even after 24 hours
(entry 1). DBU proved to be the most appropriate base in
the model reaction and it was utilized in all further reac-
tions (entry 4). Additionally, the use of triethylamine,
DBN, and 4-(dimethylamino)pyridine gave satisfactory
O
O
O
O
H
S
O
S
Me
O
N
Et3N, MeCN
reflux, 3 h
Me
O
N
N
+
N
Cl
N
O
N
N
N
Me
Me
TsTh
Scheme 2 Preparation of TsTh from theophylline and TsCl
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1380–1388

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M. N. Soltani Rad et al.
PAPER
Table 1 Effect of Various Solvents on the Reaction of TsTh with Butan-1-ol To Give N7-Butyltheophylline
O
O
O
N
O
S
Me
O
N
N
Me
O
N
DBU, solvent
reflux, 3–15 h
N
N
+
OH
N
N
Me
Me
1i
Entry
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
DMF
5
24
5
69
b
THF
–
DMSO
MeCN
NMP
62
90
53
41
3
6
HMPA
toluene
7
b
24
8
–
acetonec
H2O
60
b
24
–
a Isolated yield.
b No reaction.
c Anhydrous solvent.
Table 2 Effect of Various Bases on the Reaction of TsTh with Butan-1-ol To Give N7-Butyltheophylline
O
O
O
O
S
Me
O
N
N
Me
O
N
base, MeCN
reflux, 3–15 h
N
N
+
OH
N
N
N
Me
1i
Me
Entry
Base
Time (h)
Yielda (%)
b
1
2
–
24
5
–
Et3N
80
47
90
10
35
52
84
68
56
3
K2CO3
DBU
KOH
MgO
Cs2CO3
DBN
DMAP
DABCO
8
4
3
5
12
10
8
6
7
8
4
9
5
10
7
a Isolated yield.
b No reaction.
Synthesis 2014, 46, 1380–1388
© Georg Thieme Verlag Stuttgart · New York

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One-Pot Synthesis of N7-Alkyltheophyllines
1383
yields of 1i (entries 2, 8, and 9), whereas potassium car- The optimized stoichiometric ratio of reactants was found
bonate, cesium carbonate, and DABCO afforded moder- to be 1.2:1:2 for alcohol, TsTh, and DBU, respectively.
ate yields of 1i (entries 3, 7, and 10). Other bases Various alcohols were next examined under the optimized
examined gave 1i in low yield.
one-pot reaction conditions with TsTh to give the corre-
sponding N7-alkyltheophyllines (Table 3); structurally di-
Table 3 One-Pot N-Alkylation of Theophylline with Alcohols via TsTh (DBU, MeCN)a
R1
O
O
O
R2
O
R2
S
Me
O
N
N
Me
O
DBU, MeCN
N
N
N
+
R1
OH
reflux, 3–15 h
N
N
N
Me
1a–s
R1 = alkyl, aryl
R2 = H, alkyl
Me
TsTh
Entry
R1R2CHOH
Time (h)
Yieldb (%)
1
2
3
4
BnOH
5
3
94
92
90
84
Ph(CH2)2OH
Ph(CH2)3OH
5
Cy(CH2)2OH
10
O
OH
5
9
86
6
7
8
9
Me2C=CHCH2OH
NC(CH2)2OH
5
5
8
3
92
81
87
90
Me(CH2)9OH
BuOH
O
OH
10
11
12
6
9
4
80
87
92
Cl
N
N
OH
OH
N
O2N
N
13
14
15
16
17
i-PrOH
11
10
14
15
7
76
79
69
79
87
Ph(Me)CHOH
Me(CH2)5(Me)CHOH
Et(Me)CHOH
H2C=CHCH2OH
Cl
Cl
18
4
82
84
OH
O
O
OH
O
19
20
7
c
t-BuOH
48
–
a All products were characterized by 1H and 13C NMR, IR, CHN, and MS analysis.
b Isolated yield.
c No reaction.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1380–1388

1384
M. N. Soltani Rad et al.
PAPER
OH
OH
OH
+
+
OH
MeCN, reflux
15 h
MeCN, reflux
10 h
O
O
O
O
Me
N
Me
O
N
N
N
N
+
N
Me
O
Me
O
N
N
N
N
N
N
+
O
N
N
N
N
Me
Me
Me
Me
1i 82%
1p 12%
1n 22%
1b 75%
Scheme 3 Competitive one-pot N-alkylation of TsTh with primary and secondary alcohols
verse alcohols including primary and secondary alcohols droxy group was replaced with theophylline and
were used. In general, good to excellent yields were ob- proxyphylline was obtained as the sole product in 56%
tained when both primary and secondary alcohols were yield (Scheme 4).
applied. This protocol works well with benzylic (entries 1
A plausible mechanism for the one-pot N-alkylation of
and 14), allylic (entries 6 and 17), secondary alcohols (en-
theophylline with alcohols via TsTh with DBU as the base
tries 13, 15, and 16), and primary alcohols with various
is suggested (Scheme 5). In this mechanism, DBU first
functionalities (entries 5, 7, 10–12, 18, and 19). However,
scavenges a proton from the alcohol, and then the activat-
the use of tertiary alcohols, such as tert-butyl alcohol, did
ed alcohol (alkoxide ion) attacks TsTh at the tosyl site to
give an alkyl tosylate and the anion of theophylline. Next,
not lead to the desire product (entry 20).
The selectivity of this method was examined by perform- the theophylline anion attacks the electrophilic carbon in
ing a competitive reaction between a mixture of primary the in situ produced alkyl tosylate to afford the corre-
and secondary alcohols with TsTh under the optimized sponding N7-alkyltheophylline. The experimental obser-
conditions. For this purpose, a mixture consisting of an vations confirmed that the reaction, indeed, progresses by
equimolar ratio of two isomeric alcohols, butan-1-ol and the proposed mechanism. For example, the generation of
butan-2-ol, was treated with an equimolar amount of TsTh the corresponding alkyl tosylate and theophylline was
in the presence of DBU (2 equiv). As shown in Scheme 3, readily observed during the early stages of the reaction
entry 1, TsTh reacts with apparent selectivity with the pri- process. The in situ generated theophylline and the corre-
mary alcohol and 1i was predominantly obtained; com- sponding alkyl tosylate were confirmed by comparing
pound 1p was generated in trace amounts. A competitive them with authentic samples.
reaction between a mixture of two isomeric alcohols 1-
In conclusion, a convenient protocol for the one-pot N-al-
phenylethanol (1 equiv) and 2-phenylethanol (1 equiv)
kylation of theophylline using primary and secondary al-
with TsTh (1 equiv) in the presence of DBU (2 equiv),
cohols starting from TsTh and using DBU in refluxing
gave 1b as the major product (entry 2).
acetonitrile has been developed. In this method various
To further assess the selectivity in the reaction of TsTh primary and secondary alcohols reacted with TsTh to af-
with primary and secondary hydroxy groups, we reacted ford N7-alkyltheophylline derivatives in good to excellent
TsTh with propane-1,2-diol to obtain proxyphylline, a yields. However, this method was not effective for the N-
well-known and in-use drug with cardiotonic and bron- alkylation of theophylline by tertiary alcohols. A plausible
chodilator activity (Figure 1), under the optimized condi- mechanism has also been suggested in which the reaction
tions with the ratio of propane-1,2-diol, TsTh, and DBU proceeds through the simultaneous tosylation and nucleo-
(1.2:1:2) (Scheme 4). Of the primary and secondary hy- philic attack on alcohol via TsTh.
droxy groups in propane-1,2-diol, only the primary hy-
O
O
O
O
S
OH
Me
O
N
N
Me
O
N
N
DBU, MeCN
reflux, 12 h
N
OH
+
OH
N
N
N
Me
Me
proxyphylline
Scheme 4 Selectivity of TsTh with propane-1,2-diol; synthesis of proxyphylline
Synthesis 2014, 46, 1380–1388
© Georg Thieme Verlag Stuttgart · New York

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One-Pot Synthesis of N7-Alkyltheophyllines
1385
O
O
O
R2
••
– DBUH+
N
S
Me
O
+
+
N
H
N
R1
O
N
N
N
R1 = alkyl, aryl
R2 = H, alkyl
TsTh
R2
DBU
Me
R1
O
O
R2
–
O O
Me
N
N
Me
O
S
+
N
N
– TsO–
N
R1
O
N
O
N
N
Me
Me
Scheme 5 A plausible mechanism for one-pot N-alkylation of theophylline with alcohols via TsTh using DBU
All chemicals reagents were purchased from either Fluka or Merck.
Solvents were purified by standard procedures, and stored over 3-Å
molecular sieves.11 Reactions were followed by TLC using
SILG/UV 254 silica gel plates. Column chromatography was per-
formed on silica gel 60 (0.063–0.200 mm, 70–230 mesh; ASTM).
Melting points were measured using Electrothermal IA 9000 melt-
ing point apparatus in open capillary tubes and are uncorrected. IR
spectra were obtained using a Shimadzu FT-IR-8300 spectropho-
tometer. 1H and 13C NMR spectra were recorded on Brüker Avance-
DPX-250/400 spectrometer operating at 250/62.5 and/or 400/100
MHz, respectively, relative to TMS as an internal standard. GC/MS
was performed on a Shimadzu GC/MS-QP 1000-EX apparatus. El-
emental analyses were performed on a Perkin–Elmer 240-B micro-
analyzer.
7-Benzyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1a)8a
Column chromatography (silica gel, EtOAc–n-hexane, 1:1) afford-
ed a white solid; yield: 2.53 g (94%); mp 159–160 °C; Rf = 0.48
(EtOAc).
IR (KBr): 3100, 2980, 2895, 1720, 1705, 1451 cm–1.
1H NMR (250 MHz, CDCl3): δ = 3.31 (s, 3 H, N3-CH3), 3.49 (s, 3
H, N1-CH3), 5.32 (s, 2 H, NCH2), 7.12–7.31 (m, 5 H, HAr), 7.54 (s,
1 H, H8theo).
13C NMR (62.5 MHz, CDCl3): δ = 27.9, 29.6, 50.1, 106.8, 127.3,
127.8, 128.6, 135.3, 140.8, 148.7, 151.5, 155.1.
MS (EI): m/z (%) = 270 (31.4) [M+].
Anal. Calcd for C14H14N4O2: C, 62.21; H, 5.22; N, 20.73. Found: C,
62.32; H, 5.35; N, 20.81.
N7-Tosyltheophylline (TsTh)10
To a two-necked round-bottom flask (100 mL) equipped with a con-
denser was added a mixture of theophylline (1.8 g, 0.01 mol), TsCl
(2.47 g, 0.013 mol), and Et3N (2.0 g, 0.02 mol) in MeCN (40 mL).
The mixture was refluxed for 3–4 h. The solvent was evaporated un-
der vacuum and the remaining solid was diluted with CHCl3 (100
mL) and subsequently washed with distilled H2O (2 × 100 mL). The
organic layer was dried (Na2SO4), filtered, and evaporated. The re-
maining solid was recrystallized (CH2Cl2–n-hexane, 50:50, 50 mL).
After flash filtration, white cotton-like needle crystals were ob-
tained; yield: 3.2 g (96%); mp 198–201 °C; Rf = 0.47 (EtOAc–
n-hexane, 2:1).
1,3-Dimethyl-7-phenethyl-3,7-dihydro-1H-purine-2,6-dione
(1b)
Column chromatography (silica gel, EtOAc–n-hexane, 1:2) afford-
ed a white foam; yield: 2.61 g (92%); Rf = 0.36 (EtOAc–n-hexane,
2:1).
IR (liquid film): 3070, 2965, 2871, 1715, 1702, 1475 cm–1.
1H NMR (250 MHz, CDCl3): δ = 2.94 (t, J = 7.0 Hz, 2 H, CH2Ph),
3.21 (s, 3 H, N3-CH3), 3.31 (s, 3 H, N1-CH3), 4.28 (t, J = 7.0 Hz, 2
H, NCH2), 6.90–7.07 (m, 5 H, HAr), 7.14 (s, 1 H, H8theo).
13C NMR (62.5 MHz, CDCl3): δ = 27.5, 29.3, 36.8, 48.2, 106.1,
126.5, 128.3, 128.4, 136.9, 141.0, 148.5, 151.1, 154.5.
MS (EI): m/z (%) = 284 (15.9) [M+].
IR (KBr): 3130, 2966, 2927, 1715, 1703, 1531, 1437, 1386 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.45 (s, 3 H, CH3C6H4), 3.35 (s, 3
H, N3-CH3), 3.56 (s, 3 H, N1-CH3), 7.37 (d, J = 8.4 Hz, 2 H, HAr),
8.12 (d, J = 8.4 Hz, 2 H, HAr), 8.31 (s, 1 H, H8theo).
Anal. Calcd for C15H16N4O2: C, 63.37; H, 5.67; N, 19.71. Found: C,
63.28; H, 5.75; N, 19.79.
13C NMR (100 MHz, CDCl3): δ = 21.8, 28.5, 30.1, 106.8, 129.4,
130.0, 133.2, 142.0, 147.0, 150.4, 151.1, 152.8.
MS (EI): m/z (%) = 334 (17.5) [M+].
1,3-Dimethyl-7-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-
dione (1c)
Column chromatography (silica gel, EtOAc–n-hexane, 1:3) afford-
ed a white foam; yield: 2.68 g (90%); Rf = 0.30 (EtOAc–n-hexane,
1:1).
IR (liquid film): 3050, 2987, 2870, 1718, 1704, 1462 cm–1.
Anal. Calcd for C14H14N4O4S: C, 50.29; H, 4.22; N, 16.76; S, 9.59.
Found: C, 50.38; H, 4.27; N, 16.68; S, 9.50.
7-Alkyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-diones 1;
General Procedure
1H NMR (250 MHz, CDCl3): δ = 2.09 (quint, J = 7.2 Hz, 2 H,
CH2CH2CH2), 2.53 (t, J = 7.2 Hz, 2 H, CH2Ph), 3.31 (s, 3 H, N3-
CH3), 3.48 (s, 3 H, N1-CH3), 4.16 (t, J = 7.2 Hz, 2 H, NCH2), 7.05–
7.21 (m, 5 H, HAr), 7.40 (s, 1 H, H8theo).
13C NMR (62.5 MHz, CDCl3): δ = 28.9, 30.9, 32.2, 33.2, 50.5,
105.6, 127.9, 128.2, 129.0, 135.8, 147.7, 151.6, 152.1, 155.9.
To a two-necked round-bottom flask (100 mL) equipped with a con-
denser was added a mixture, consisting of an alcohol (0.012 mol),
TsTh (3.3 g, 0.01 mol), and DBU (3.0 g, 0.02 mol) in MeCN (50
mL). The mixture was heated at reflux and heating was continued
until TLC indicated no further improvement in the conversion (Ta-
ble 3). The solvent was evaporated under vacuum and the remaining
foam was dissolved in CHCl3 (100 mL) and subsequently washed
with H2O (2 × 100 mL). The organic layer was dried (Na2SO4) and
evaporated. The crude product was purified by recrystallization
and/or column chromatography (silica gel).
MS (EI): m/z (%) = 298 (24.6) [M+].
Anal. Calcd for C16H18N4O2: C, 64.41; H, 6.08; N, 18.78. Found: C,
64.52; H, 6.16; N, 18.71.
© Georg Thieme Verlag Stuttgart · New York
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M. N. Soltani Rad et al.
PAPER
7-Decyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1h)
Column chromatography (silica gel, EtOAc–n-hexane, 1:3) afford-
ed a white foam; yield: 2.78 g (87%); Rf = 0.50 (EtOAc–n-hexane,
1:1).
7-(2-Cyclohexylethyl)-1,3-dimethyl-3,7-dihydro-1H-purine-
2,6-dione (1d)
Column chromatography (silica gel, EtOAc–n-hexane, 1:2) afford-
ed a white solid; yield: 2.43 g (84%); mp 86–88 °C; Rf = 0.36
(EtOAc–n-hexane, 1:1).
IR (liquid film): 3100, 2982, 1718, 1705, 1557, 1450 cm–1.
IR (KBr): 3111, 2941, 2852, 1718, 1702, 1444 cm–1.
1H NMR (250 MHz, CDCl3): δ = 0.49 (t, J = 6.7 Hz, 3 H, CH3),
0.89–0.96 (m, 14 H, 7CH2), 1.50–1.55 (m, 2 H, NCH2CH2), 3.05 (s,
3 H, N3-CH3), 3.23 (s, 3 H, N1-CH3), 3.91 (t, J = 7.2 Hz, 2 H, NCH2),
7.24 (s, 1 H, H8theo).
13C NMR (62.5 MHz, CDCl3): δ = 13.0, 20.3, 25.0, 26.3, 26.4, 26.7,
27.5, 29.5, 30.1, 32.5, 34.2, 49.4, 105.1, 140.1, 147.3, 151.6, 156.2.
1H NMR (250 MHz, CDCl3): δ = 0.97–1.01 (m, 2 H, CH2), 1.17–
1.26 (m, 4 H, 2 CH2), 1.68–1.82 (m, 7 H, 3 CH2, CH), 3.41 (s, 3 H,
N3-CH3), 3.59 (s, 3 H, N1-CH3), 4.29 (t, J = 7.5 Hz, 2 H, NCH2),
7.58 (s, 1 H, H8theo).
13C NMR (62.5 MHz, CDCl3): δ = 25.7, 27.9, 29.9, 31.3, 32.6, 33.8,
34.2, 48.4, 106.9, 142.5, 149.7, 152.2, 154.6.
MS (EI): m/z (%) = 320 (18.7) [M+].
MS (EI): m/z (%) = 290 (18.2) [M+].
Anal. Calcd for C17H28N4O2: C, 63.72; H, 8.81; N, 17.48. Found: C,
63.79; H, 8.73; N, 17.54.
Anal. Calcd for C15H22N4O2: C, 62.05; H, 7.64; N, 19.30. Found: C,
62.17; H, 7.57; N, 19.39.
7-Butyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1i)
Recrystallization (CH2Cl2–MeOH) afforded a cream solid; yield:
2.12 g (90%); mp 88–90 °C; Rf = 0.30 (EtOAc–n-hexane, 2:1).
IR (KBr): 3105, 2956, 2875, 1718, 1702, 1549, 1476 cm–1.
1H NMR (400 MHZ, CDCl3): δ = 0.86 (t, J = 7.2 Hz, 3 H, CH3),
1.23–1.32 (m, 2 H, CH2CH3), 1.75 (quint, J = 7.6 Hz, 2 H,
NCH2CH2CH2), 3.34 (s, 3 H, N3-CH3), 3.51 (s, 3 H, N1-CH3), 4.20
(t, J = 7.2 Hz, 2 H, NCH2), 7.47 (s, 1 H, H8theo).
13C NMR (100 MHz, CDCl3): δ = 14.3, 21.1, 29.6, 31.5, 32.8, 51.5,
105.3, 143.7, 149.2, 151.2, 156.4.
MS (EI): m/z (%) = 236 (24.9) [M+].
7-(Furan-2-ylmethyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-
dione (1e)
Column chromatography (silica gel, EtOAc–n-hexane, 1:3) afford-
ed a bright brown solid; yield: 2.23 g (86%); mp 137–140 °C; Rf =
0.27 (EtOAc–n-hexane, 1:1).
IR (KBr): 3086, 2957, 1717, 1701, 1546, 1473 cm–1.
1H NMR (250 MHz, CDCl3): δ = 3.31 (s, 3 H, N3-CH3), 3.47 (s, 3
H, N1-CH3), 5.42 (s, 2 H, NCH2), 6.26 (br s, 1 H, H3furyl), 6.43 (br
s, 1 H, H4furyl), 7.31 (br s, 1 H, H5furyl), 7.56 (s, 1 H, H8theo).
13C NMR (62.5 MHz, CDCl3): δ = 29.2, 32.2, 44.7, 105.1, 107.5,
112.0, 141.9, 143.8, 148.6, 150.6, 156.2, 158.0.
Anal. Calcd for C11H16N4O2: C, 55.92; H, 6.83; N, 23.71. Found: C,
56.03; H, 6.91; N, 23.85.
MS (EI): m/z (%) = 260 (17.4) [M+].
Anal. Calcd for C12H12N4O3: C, 55.38; H, 4.65; N, 21.53. Found: C,
55.47; H, 4.76; N, 21.62.
7-[2-(4-Chlorophenoxy)ethyl]-1,3-dimethyl-3,7-dihydro-1H-
purine-2,6-dione (1j)
Recrystallization (EtOAc–MeOH) afforded a white solid; yield:
2.67 g (80%); mp 80–83 °C; Rf = 0.29 (EtOAc–n-hexane, 7:1).
1,3-Dimethyl-7-(3-methylbut-2-enyl)-3,7-dihydro-1H-purine-
2,6-dione (1f)
Column chromatography (silica gel, EtOAc–n-hexane, 1:3) afford-
ed a white solid; yield: 2.28 g (92%); mp 130–133 °C; Rf = 0.27
(EtOAc–n-hexane, 1:1).
IR (KBr): 3120, 2956, 2884, 1720, 1705, 1479, 1248, 743 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.33 (s, 3 H, N3-CH3), 3.51 (s, 3
H, N1-CH3), 4.20 (t, J = 4.8 Hz, 2 H, NCH2), 4.60 (t, J = 4.8 Hz, 2
H, OCH2), 6.68 (d, J = 8.8 Hz, 2 H, HAr), 7.12 (d, J = 8.8 Hz, 2 H,
HAr), 7.62 (s, 1 H, H8theo).
13C NMR (100 MHz, CDCl3): δ = 28.7, 32.0, 50.3, 71.1, 104.8,
116.7, 128.3, 131.1, 142.5, 150.9, 153.3, 156.4, 156.8.
IR (KBr): 3121, 2967, 2921, 1725, 1708, 1545, 1490 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.72 (s, 6 H, 2 CH3), 3.32 (s, 3 H,
N3-CH3), 3.49 (s, 3 H, N1-CH3), 4.82 (d, J = 7.5 Hz, 2 H, NCH2),
5.36–5.37 (m, 1 H, =CH), 7.49 (s, 1 H, H8theo).
13C NMR (62.5 MHz, CDCl3): δ = 18.8, 24.1, 28.6, 32.0, 37.5,
105.5, 116.1, 132.2, 144.1, 149.9, 152.3, 156.2.
MS (EI): m/z (%) = 334 (28.1) [M+].
Anal. Calcd for C15H15ClN4O3: C, 53.82; H, 4.52; Cl, 10.59; N,
16.74. Found: C, 53.89; H, 4.42; Cl, 10.51; N, 16.82.
MS (EI): m/z (%) = 248 (25.8) [M+].
Anal. Calcd for C12H16N4O2: C, 58.05; H, 6.50; N, 22.57. Found: C,
57.94; H, 6.58; N, 22.47.
7-[2-(1H-Benzimidazol-1-yl)ethyl]-1,3-dimethyl-3,7-dihydro-
1H-purine-2,6-dione (1k)
Column chromatography (silica gel, EtOAc–MeOH, 14:1) afforded
a pale-yellow solid; yield: 2.81 g (87%); mp 244–246 °C; Rf = 0.24
(EtOAc–MeOH, 5:1).
3-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-
yl)propanenitrile (1g)
Column chromatography (silica gel, EtOAc–n-hexane, 1:2) afford-
ed a white solid; yield: 1.88 g (81%); mp 153–155 °C; Rf = 0.30
(EtOAc–n-hexane, 3:1).
IR (KBr): 3094, 2952, 1718, 1702, 1479 cm–1.
1H NMR (250 MHZ, CDCl3): δ = 3.44 (s, 3 H, N3-CH3), 3.54 (s, 3
H, N1-CH3), 4.67–4.71 (m, 4 H, NCH2CH2N), 6.98 (s, 1 H,
H2benzimid), 7.28–7.42 (m, 4 H, Hbenzimid), 7.59 (s, 1 H, H8theo).
13C NMR (62.5 MHz, CDCl3): δ = 29.4, 31.4, 50.3, 56.2, 105.9,
115.1, 117.1, 124.3, 126.2, 133.0, 136.1, 142.6, 146.1, 149.6, 152.0,
155.7.
IR (KBr): 3138, 2971, 2253, 1715, 1702, 1549, 1472 cm–1.
1H NMR (250 MHz, CDCl3): δ = 3.03 (t, J = 5.5 Hz, 2 H, CH2CN),
3.34 (s, 3 H, N3-CH3), 3.54 (s, 3 H, N1-CH3), 4.45 (t, J = 5.5 Hz, 2
H, NCH2), 7.64 (s, 1 H, H8theo).
13C NMR (62.5 MHz, CDCl3): δ = 18.1, 27.8, 32.0, 33.8, 107.5,
120.2, 145.5, 150.0, 152.1, 155.4.
MS (EI): m/z (%) = 324 (20.4) [M+].
MS (EI): m/z (%) = 233 (19.5) [M+].
Anal. Calcd for C16H16N6O2: C, 59.25; H, 4.97; N, 25.91. Found: C,
59.37; H, 5.06; N, 25.98.
Anal. Calcd for C10H11N5O2: C, 51.50; H, 4.75; N, 30.03. Found: C,
51.62; H, 4.87; N, 30.12.
Synthesis 2014, 46, 1380–1388
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of N7-Alkyltheophyllines
1387
1,3-Dimethyl-7-[2-(2-methyl-4-nitro-1H-imidazol-1-yl)ethyl]-
3,7-dihydro-1H-purine-2,6-dione (1l)
Recrystallization (EtOAc–MeOH) afforded a white solid; yield:
3.02 g (92%); mp 254–257 °C; Rf = 0.37 (EtOAc–MeOH, 6:1).
7-sec-Butyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1p)
Column chromatography (silica gel, EtOAc–n-hexane, 1:3) afford-
ed a bright brown solid; yield: 1.86 g (79%); mp 81–82 °C; Rf = 0.27
(EtOAc–n-hexane, 3:1).
IR (KBr): 3109, 2954, 1720, 1706, 1542, 1473, 1336 cm–1.
IR (KBr): 3062, 2931, 2859, 1721, 1707, 1438 cm–1.
1H NMR (250 MHZ, DMSO-d6): δ = 2.19 (s, 3 H, imid-CH3), 3.19
(s, 3 H, N3-CH3), 3.38 (s, 3 H, N1-CH3), 4.54–4.59 (m, 4 H,
NCH2CH2N), 7.81 (s, 1 H, H5imid), 8.04 (s, 1 H, H8theo).
13C NMR (62.5 MHz, DMSO-d6): δ = 15.1, 27.6, 31.6, 49.6, 52.0,
105.3, 121.1, 140.1, 146.7, 149.1, 151.0, 153.2, 156.2.
1H NMR (400 MHZ, CDCl3): δ = 0.78 (t, J = 7.2 Hz, 3 H, CH2CH3),
1.12–1.24 (m, 3 H, NCHCH2CH3), 1.50 (d, J = 6.8 Hz, 3 H,
NCHCH3), 3.36 (s, 3 H, N3-CH3), 3.54 (s, 3 H, N1-CH3), 7.60 (s, 1
H, H8theo).
13C NMR (100 MHz, CDCl3): δ = 11.1, 23.5, 28.3, 29.7, 33.5, 47.2,
MS (EI): m/z (%) = 333 (26.7) [M+].
107.7, 143.8, 149.9, 152.1, 158.1.
MS (EI): m/z (%) = 236 (25.9) [M+].
Anal. Calcd for C13H15N7O4: C, 46.85; H, 4.54; N, 29.42. Found: C,
46.93; H, 4.59; N, 29.51.
Anal. Calcd for C11H16N4O2: C, 55.92; H, 6.83; N, 23.71. Found: C,
55.87; H, 6.91; N, 23.82.
7-Isopropyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
(1m)
Recrystallization (EtOAc–MeOH) afforded a bright brown solid;
yield: 1.68 g (76%); mp 180–184 °C; Rf = 0.33 (EtOAc–n-hexane,
3:1).
7-Allyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1q)8b
Column chromatography (silica gel, EtOAc–n-hexane, 1:1) afford-
ed a white solid; yield: 1.91 g (87%); mp 102–104 °C; Rf = 0.38
(EtOAc).
IR (KBr): 3109, 2979, 2940, 1719, 1704, 1545, 1456 cm–1.
IR (KBr): 3050, 2987, 2890, 1722, 1708, 1448 cm–1.
1H NMR (250 MHZ, CDCl3): δ = 1.13 (d, J = 6.8 Hz, 6 H, 2 CH3),
2.95 (s, 3 H, N3-CH3), 3.13 (s, 3 H, N1-CH3), 4.57–4.62 (m, 1 H,
NCH), 7.22 (s, 1 H, H8theo).
13C NMR (62.5 MHz, CDCl3): δ = 25.7, 30.4, 33.1, 47.3, 106.5,
143.5, 149.4, 152.3, 156.8.
1H NMR (250 MHz, CDCl3): δ = 3.17 (s, 3 H, N3-CH3), 3.36 (s, 3
H, N1-CH3), 4.73 (d, J = 5.2 Hz, 2 H, NCH2), 5.00–5.13 (m, 2 H,
=CH2), 5.77–5.93 (m, 1 H, =CH), 7.40 (s, 1 H, H8theo).
13C NMR (62.5 MHz, CDCl3): δ = 27.8, 29.6, 48.8, 106.7, 119.1,
132.0, 140.7, 148.6, 151.5, 154.9.
MS (EI): m/z (%) = 222 (21.3) [M+].
MS (EI): m/z (%) = 220 (25.4) [M+].
Anal. Calcd for C10H14N4O2: C, 54.04; H, 6.35; N, 25.21. Found: C,
54.12; H, 6.42; N, 25.32.
Anal. Calcd for C10H12N4O2: C, 54.54; H, 5.49; N, 25.44. Found: C,
54.62; H, 5.40; N, 25.51.
1,3-Dimethyl-7-(1-phenylethyl)-3,7-dihydro-1H-purine-2,6-di-
7-[2-(2,4-Dichlorophenyl)-2-oxoethyl]-1,3-dimethyl-3,7-di-
hydro-1H-purine-2,6-dione (1r)
Column chromatography (silica gel, EtOAc–n-hexane, 3:1) afford-
ed a creamy solid; yield: 3.01 g (82%); mp 193–194 °C; Rf = 0.61
(EtOAc–n-hexane, 6:1).
one (1n)
Column chromatography (silica gel, EtOAc–n-hexane, 1:3) afford-
ed a yellow foam; yield: 2.24 g (79%); Rf = 0.29 (EtOAc–n-hexane,
2:1).
IR (liquid film): 3070, 2964, 2921, 1718, 1702, 1553, 1471 cm–1.
1H NMR (250 MHZ, CDCl3): δ = 1.54 (d, J = 7.1 Hz, 3 H,
NCHCH3), 3.18 (s, 3 H, N3-CH3), 3.32 (s, 3 H, N1-CH3), 4.36 (q, J =
7.1 Hz, 1 H, NCH), 6.93–7.14 (m, 5 H, HAr), 7.82 (s, 1 H, H8theo).
13C NMR (62.5 MHz, CDCl3): δ = 22.9, 29.9, 33.1, 55.1, 106.3,
123.0, 125.1, 127.0, 142.1, 145.7, 148.8, 150.5, 154.1.
MS (EI): m/z (%) = 284 (29.8) [M+].
IR (KBr): 3065, 2983, 2958, 1723, 1715, 1709, 1569, 1481, 750
cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 3.23 (s, 3 H, N3-CH3), 3.36 (s,
3 H, N1-CH3), 5.55 (s, 2 H, NCH2), 7.22 (d, J = 6.4 Hz, 1 H, HAr),
7.24 (d, J = 6.4 Hz, 1 H, HAr), 7.52 (s, 1 H, HAr), 7.83 (s, 1 H, H8theo).
13C NMR (62.5 MHz, DMSO-d6): δ = 27.3, 29.2, 41.3, 106.2, 126.1,
126.2, 128.2, 128.8, 133.6, 142.4, 147.5, 150.6, 151.9, 154.7, 180.1.
MS (EI): m/z (%) = 366 (19.3) [M+].
Anal. Calcd for C15H16N4O2: C, 63.37; H, 5.67; N, 19.71. Found: C,
63.45; H, 5.74; N, 19.83.
Anal. Calcd for C15H12Cl2N4O3: C, 49.07; H, 3.29; Cl, 19.31; N,
15.26. Found: C, 49.19; H, 3.36; Cl, 19.18; N, 15.39.
1,3-Dimethyl-7-(octan-2-yl)-3,7-dihydro-1H-purine-2,6-dione
(1o)
Column chromatography (silica gel, EtOAc–n-hexane, 1:2) afford-
ed a pale yellow liquid; yield: 2.01 g (69%); Rf = 0.34 (EtOAc–
n-hexane, 2:1).
Benzyl 2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-
7-yl)acetate (1s)
Column chromatography (silica gel, EtOAc–n-hexane, 2:1) afford-
ed a creamy solid; yield: 2.75 g (84%); mp 124–125 °C; Rf = 0.56
(EtOAc–n-hexane, 4:1).
IR (liquid film): 3100, 2985, 1715, 1701, 1561, 1443 cm–1.
IR (KBr): 3100, 2976, 2942, 1738, 1720, 1705, 1574, 1451 cm–1.
1H NMR (400 MHZ, CDCl3): δ = 1.49–1.56 (m, 5 H, CH2CH3),
1.61–1.69 (m, 6 H, 3 CH2), 2.38 (s, 3 H, N3-CH3), 2.44 (s, 3 H, N1-
CH3), 2.78 (q, J = 6.4 Hz, 2 H, NCHCH2), 3.22–3.24 (m, 1 H,
NCH), 3.36 (d, J = 7.4 Hz, 3 H, NCHCH3), 7.73 (s, 1 H, H8theo).
13C NMR (100 MHz, CDCl3): δ = 14.0, 22.5, 26.3, 27.2, 29.0, 29.1,
31.76, 33.4, 35.2, 48.8, 105.0, 140.7, 148.5, 151.0, 157.4.
1H NMR (250 MHz, DMSO-d6): δ = 3.15 (s, 3 H, N3-CH3), 3.29 (s,
3 H, N1-CH3), 5.34 (s, 2 H, NCH2), 5.72 (s, 2 H, OCH2), 7.29–7.33
(m, 5 H, HAr), 7.82 (s, 1 H, H8theo).
13C NMR (62.5 MHz, DMSO-d6): δ = 27.5, 29.3, 41.6, 65.1, 106.2,
126.8, 127.6, 129.6, 137.1, 142.5, 147.6, 150.6, 153.4, 165.7.
MS (EI): m/z (%) = 292 (18.1) [M+].
MS (EI): m/z (%) = 328 (15.8) [M+].
Anal. Calcd for C15H24N4O2: C, 61.62; H, 8.27; N, 19.16. Found: C,
61.72; H, 8.36; N, 19.23.
Anal. Calcd for C16H16N4O4: C, 58.53; H, 4.91; N, 17.06. Found: C,
58.69; H, 5.02; N, 17.14.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1380–1388

1388
M. N. Soltani Rad et al.
PAPER
(4) Nafisi, S.; Manouchehri, F.; Tajmir-Riahi, H.-A.;
Varavipour, M. J. Mol. Struct. 2008, 875, 392.
(5) Theophylline; Wikipedia, the Free Encyclopedia,
Acknowledgement
We wish to thank Shiraz University of Technology Research Coun-
cil for partial support of this work.
http://en.wikipedia.org/wiki/Theophylline. Accessed 26
September 2013.
(6) Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. In
Pharmaceutical Substances, 3rd ed; Thieme: Stuttgart,
1999.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(7) (a) Ananthalakshmi, K. V. V.; Bartl, T.; Aziza, M. H.;
Novotný, L.; Marek, R.; Beneš, L.; Kombian, S. B. Bioorg.
Med. Chem. 2008, 16, 8142. (b) Pascal, J.-C.; Beranger, S.;
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(8) (a) Soltani Rad, M. N.; Khalafi-Nezhad, A.; Behrouz, S.;
Asrari, Z.; Behrouz, M.; Amini, Z. Synthesis 2009, 3067.
(b) Soltani Rad, M. N.; Khalafi-Nezhad, A.; Behrouz, S.;
Faghihi, M. A.; Zare, A.; Parhami, A. Tetrahedron 2008, 64,
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(9) Mitsunobu, O. Synthesis 1981, 1.
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(11) Vogel, A. I. In Practical Organic Chemistry; Longmans,
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Synthesis 2014, 46, 1380–1388
© Georg Thieme Verlag Stuttgart · New York