Two-step three-component process for one-pot synthesis of 8-alkylmercaptocaffeine derivatives

Article abstract of DOI:10.1039/c6ra17814f

A highly efficient, odourless and two-step three-component process for one-pot synthesis of some 8-alkylmercaptocaffeine derivatives has been described. The catalyst-free three-component reaction of alkyl bromides, thiourea, and 8-bromocaffeine gave 8-alkylmercaptocaffeine products in excellent to quantitative yields. In addition, the impact of parameters on sample reaction is discussed.

Full text of DOI:10.1039/c6ra17814f

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Two-Step Three-Component Process for One-Pot Synthesis of 8-
Alkylmercaptocaffeine Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
M. N. Soltani Rad* and S. Maghsoudi
A highly efficient, odourless and two-step three-component process for one-pot synthesis of some 8-
alkylmercaptocaffeine derivatives has been described. The catalyst-free three-component reaction of alkyl bromides,
thiourea, and 8-bromocaffeine gave 8-alkylmercaptocaffeine products in excellent to quantitative yields. In addition, the
impact of parameters on sample reaction is discussed.
DOI: 10.1039/x0xx00000x
www.rsc.org/
O
H
N 7
6
HN
5
1
2
Introduction
8
4
3
N
H
N
O
9
Undoubtedly methylxanthines are one of the most interesting
classes of compounds that people around the world are exposed in
their everyday life.1 Methylxanthine alkaloids involving caffeine,
theophylline, theobromine and their related metabolite i.e.
paraxanthine are naturally found in berries, seeds and leaves of
many plants like coffee, cocoa and tea (Fig. 1).2 Methylxanthines are
unique molecules since the immense of their pharmaceutical
activities.3 This is due to the fact that xanthine-based scaffolds are
well-recognized by plenty of enzymes or receptors in human and
animal cells.4 Methylxanthines and their derivatives have received
much attention over the years for their magnificent
chemotherapeutic properties as bronchodilator (antiasthmatic,
expectorant), antiemetic, cardiotonic, coronary vasodilator,
diuretic, analgesic, anti-migraine, anti-rhinitis, analeptic,
antispasmodic, psychotonic, CNS stimulant and so on.5 Moreover,
methylxanthines are known as antagonizing agents for
phosphodiesterase enzymes6 and adenosine receptors.7 Among
methylxanthines, most chemical modifications were achieved on
theophylline and theobromine.8 Since the presence of nucleophilic
nitrogens (i.e.: N7 and N1 in theophylline and theobromine,
respectively) they readily prone to react with diverse carbon
electrophiles; whereas, the caffeine has neither the intense
nucleophilic nor electrophilic sites to react with active chemical
species (Fig. 1). In particular, the caffeine can be affected merely
from C(8) site through the reaction with certain electrophilies like
positive halogens and so on. 9
Xanthine
O
O
O
Me
O
Me
Me
Me
H
N
Me
O
N
Me
O
N
N
N
N
HN
N
N
N
N
N
N
O
O
N
H
N
N
Me
Me
Me
Theophylline
Theobromine
Paraxanthine
Caffeine
Fig. 1 The structures of xanthine and natural methylxanthines.
The structural activity relationship (SAR) studies of natural
methylxanthines and their synthetic derivatives have revealed that
the site of alkylation almost determines the pharmaceutical and the
biological behavior trend of the corresponding methylxanthine.10 As
an instance, the C(8) alkylation/substitution of caffeine has often
led to the new analogues with potential anti-rhinitis or antagonistic
property for adenosine receptors as well as phosphodiesterase
enzymes; whereas, the N(1)–alkylation of theobromine shifts the
property to vasodilatory activity (Fig. 2).11
Since the discovery of 6-mercaptopurine (6-MP) as an
immunosuppressive medication for treating acute lymphocytic
leukemia12 and also 8-methylmercaptoxanthine as
a main
metabolite of oncogene (i.e.: 3-hydroxyxanthine),13 efforts have
been made to incorporate the mercapto moiety into scaffolds of
diverse methylxanthines to access new bioactive derivatives. In this
connection, 8-thiosubstituted methylxanthines especially 8-
mercaptocaffeine derivatives have found particular attention since
their noticeable pharmaceutical profiles. Up to now, few numbers
of these derivatives have been developed. Petzer and coworkers
reported the synthesis of 8-[(alkyl) sulfanyl] caffeine derivatives 1 as
potent MAO-B inhibitors through C-8 substitution of caffeine with
thioether moieties.14,15 Krutovskikh et al. reported the synthesis of
8-β-dialkylaminoethylmercaptocaffeine analogous
2 with radio-
protective property.16 Caffeine-8-thioglycolic acid derivatives 3
were synthesized by Zlatkov and coworkers with brain antihypoxic
activity.17 In addition, several 8-mercapto-caffeine derivatives
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and/or related scaffolds 4-8 with certain biological activities have
To access 8-alkylmercaptocaffeine derivatives, diverse
been established.18-22 The structures of compounds 1-8 and their approaches have been reported so for comprising (i) reaction of 8-
corresponding therapeutic activities are shown in Fig. 3.
mercaptocaffeine [CAS No: 56223-58-6] with alkyl halides in the
presence of an efficient base,16,23 (ii) direct thiolation reaction of
mercaptans with 8-chlorocaffeine (8-CC) or 8-bromocaffeine (8-BC)
in basic media 14,15,24 and more recently, (iii) copper-catalyzed direct
thiolation of isocaffeine via disulfides utilized AgOAc as an additive
under O2 atmosphere.25 Despite the usefulness of the above
approaches for synthesis of some 8-alkylmercaptocaffeine
derivatives, the drawbacks still have remained. As instances, the
reaction of 8-mercaptocaffeine with alkyl halides16,23 requires
strong bases such as EtONa which often leads to the low yields of
products. The low yield of products is attributed to narrow
nucleophilic power of 8-mercaptocaffeine. The weak nucleophilic
potency of 8-mercaptocaffeine is owing to the fact that charge
density on –SH moiety is distributed between sulfur and adjacent
N7 and N9 atoms through the possible tautomerization effect.23
Therefore, the application scope of S-alkylation reaction for 8-
O
O
Me
N
Me
N
Modification here
enhances the
anti-rhinitis, MAO,
PDE and
Modification
here enhances
the vasodilation
properties
Me
O
HN
N
N
N
O
N
N
adenosine
inhibitory
Me
Me
Theobromine
Caffeine
Modification here
enhances the
psychotonic,
cardiotonic, diuretic
and antiasthmatic
properties
O
H
Me
O
N
N
N
N
Me
Theophylline
Fig.
2 The modifications (alkylation or substitution) to scaffolds of mercaptocaffeine via alkyl halides is very limited. The direct
methylxanthines lead to diverse pharmaceutical properties.
thiolation reaction of mercaptans with 8-chlorocaffeine (8-CC) or 8-
bromocaffeine (8-BC) in basic media also associates with two main
drawbacks involving the extreme of unpleasant and disgusting
odours of used mercaptans, and sensitivity of mercaptans toward
oxidizing agents like atmospheric oxygen which readily converts the
thiols into disulfides at basic pH (pH>7). Moreover, an approach
developed by Zhu and coworkers25 for straightforward thiolation of
isocaffeine requires less available and presynthesized disulfieds, the
use of an expensive additive and performing the reaction under an
O2 atmosphere which is not simple and easy to handle.
O
Me
O
Me
O
Me
N
X
N
N
NR2
Me
O
S
N
N
S
N
( )n
N
N
Me
2
Me
1
R= H, Me, Et
(Radioprotective Agent)
n=1, 2; X=H, Br
(Monoamine Oxidase-B Inhibitor)
O
O
O
Me
Me
Me
Me
O
N
N
Thiourea is a safe, cheap and widely available organosulfur
compound which has been extensively used for generation of thiols
from alkyl halides.26,27 The major advantages associated with the
use of thiourea is the in situ generation of thiols. The in situ
generated thiols subsequently can be used to react with set of
diverse carbon electrophiles in one-pot reaction condition to access
N
N
O
NHR
S
S
O
N
N
O
N
N
O
OH
Me
Me
3
4
(Antihyperlipidimic Agent)
R= ArCH2CH2-
(Brain Antihypoxic)
OR
O
O
Me
N
R1
R2
R3
N
Me
O
Me
O
H
N
N
a
plenty of thio-compounds. This advantage prevents the
N
S
S
N
N
N
N
requirement of extra procedure for separation and purification of
thiols and thus diminishes the intense of the odd smell of thiols and
N
O
Me
Me
6
5
largely reduces the oxidative homocoupling of thiols to disulfides.28-
-
R1, R2, R3 = H, OMe, Cl, OH
R=H,PO3
(P2X Receptor Agonists)
30
(Potential Chemotheraputic Agent)
O
O
N
R1
X
Regarding to remarkable therapeutic activity of 8-
alkylmercaptocaffeine derivatives and also in continuation of our
long-standing interest on synthesis of new methylxanthine
derivatives;8,31 hereby, we would like to report highly efficient,
catalyst-free, odourless and three-component process for one-pot
synthesis of some 8-alkylmercaptocaffeine (Scheme 1).
S
Me
N
N
N
N
N
N
H
S
O
O
O
N
8
R2
Me
7
X= C, N
R1, R2= H, OMe, ...
(Anti-Hepatitis)
(DNA Intercalating and Anticancer Agent)
Fig. 3 The structures and therapeutic activities of 8-alkylmercaptocaffeine
In this synthesis, the reaction of thiourea with alkyl bromides in
refluxing EtOH followed by addition of aqueous NaOH at room
temperature provided the corresponding 8-alkylmercaptocaffeine
derivatives 12a-q in excellent yields.
and their related derivatives.
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O
O
Me
N
Me
S
Me
Me
N
N
N
9+ 10/ EtOH, reflux
R1R2CHBr
R1
Br
S
+
+
NH2
H2N
NaOH (aq.), then 11, rt
excellent yield of 12k; however, since its toxicity, the use of ethanol
was preferred. Utilizing polar aprotic solvents (Table 1, entries 1-7)
acquired low to moderate yields of 12k in different times. Whereas,
toluene and a room temperature ionic liquid (i.e.: bmim[Br]) were
failed to improve the reaction (Table 1, entries 8 and 14).
N
N
12a-q
O
N
O
N
R2
11
10
Me
9a-n
Me
80-96%
17 examples
(8-BC)
j: R1= Ph, R2= H
k: R1= PhCH2, R2= H
l: R1= PhCH2CH2, R2= H
m: R1= β-naphtyl, R2= H
n: R1= Ph, R2= Ph
o: R1= CH2CH2(benzimidazol-1-yl), R2= H
p:(CH2)3CH2(2-methyl-4-nitroimidazol-1-yl), R2= H
q: CH2(phthalimid-N-yl), R2= H
a: R1= C2H5, R2= H
b: R1= n-C3H7, R2= H
c: R1= n-C4H9, R2= H,
d: R1= n-C5H11, R2= H
e: R1= n-C6H13, R2= H
f: R1= n-C7H15, R2= H
g: R1= n-C9H19, R2= H
Table 1 Effect of various solvents and bases on reaction of phenethyl
h: R1= CH2CH(Me)CH3, R2= H
i: R1= 4-Me-C6H4 R2= H
bromide, thiourea and 8-BCa
O
O
Me
N
Me
N
S
Scheme 1 Synthesis of 8-alkylmercaptocaffeine through one-pot, three-
Br
Me
Me
N
N
9k + 10/ solvent, reflux
base, H2O then 11, rt
S
Br
+
+
H2N
NH2
component reaction using thiourea, alkyl bromide and 8-BC.
N
N
O
N
O
N
11
12k
9k
10
Me
Me
Results and discussion
Entry
1
Solvent
DMFd
THF
Baseb
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
-
Time (h)
34
40
37
42
44
48
48
72
72
14
22
17
36
72
72
48
72
28
72
18
24
30
26
36
Yieldc (%)
42
To start synthesizing the title compounds, we first considered the
synthesis of 12k as a sample compound as this potent inhibitor of
MAO-B was previously synthesized by Petzer et al.14,15 We initially
attempted to synthesize 12k through the reaction of 8-
mercaptocaffeine with phenethyl bromide in refluxing absolute
ethanol. However, no reaction was carried out after refluxing for 48
h. Additionally, utilizing organic and inorganic bases to improve the
reaction yield were only acquired the moderate yield of 12k. As an
instance, the use of fresh EtONa in absolute ethanol only afforded
12k in 45% yield after prolonging the reaction time up to 72 h. As
mentioned earlier, the low yield of product obtained by direct
reaction of 8-mercaptocaffeine with alkyl halides is caused by weak
nucleophilic nature of 8-mercaptocaffeine.
2
38
3
DMSOd
MeCN
NMPd
HMPAd
Me2CO
PhMe
H2O
40
4
32
5
38
6
32
7
29
8
NRe
25
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
EtOH
90
i-PrOH
MeOH
PEG 200d
bmim[Br]d
EtOH
75
86
65
NR
NR
36
EtOH
TEA
8-Bromo- (8-BC) or 8-chlorocaffeine (8-CC) are known as
interesting compounds for introduction of 8-caffeinyl moiety to
diverse nucleophiles.14,15,17,24,32 As matter of fact, the linkage of C(8)
with three electron withdrawing elements in 8-BC or 8-CC
extensively enhances the positive charge density on C(8) which
dispose to be attacked by varied nucleophiles through SNAr-type
reaction. Thus, to obtain the higher yield of 12k, an alternative
approach was applied in which 2-phenylethanethiol (CAS NO: 4410-
99-5) was directly reacts with 8-BC in the presence of an efficient
base (NaOH) in EtOH at reflux condition due to procedure reported
by Petzer et al.14,15 and Long.24 Although a good yield of 12k (>78%)
EtOH
K2CO3
DBU
NR
38
EtOH
EtOH
MgO
NR
40
EtOH
EtONa
t-BuOK
DBN
EtOH
35
EtOH
39
EtOH
DMAP
DABCO
31
EtOH
29
a Reaction conditions: phenethyl bromide (10 mmol), thiourea (12 mmol), 8-
BC (10 mmol), solvent (25 mL) , base (20 mmol) and H2O (2 mL)
Except that of H2O as a solvent (entry 9), NaOH was primarily dissolved in
H2O (2 mL) and then was added to reaction mixture.
b
were obtained using current approach, this procedure suffer from c Isolated yield.
d The reaction was conducted at 100° C.
e No reaction.
the extreme of unpleasant odours of the used mercaptan.
Regarding to numerous benefits of one-pot multicomponent
reactions (MCR),33 we applied this strategy to overcome the
addressed issues. To this end, the one-pot two-step three
component reaction of thiourea as a sulfur source agent with alkyl
halides followed by addition of 8-BC seems to be an attractive and
effectual strategy to access 8-alkylmercaptocaffeine derivatives.
Afterward of determining a proper solvent, we then examined
the influence of diverse organic and inorganic bases. The use of an
efficient base has undeniable role in progress of reaction. In
absence of a base, the reaction was not conducted at all even if the
reaction time has been extended to three days and more (Table 1,
entry 15). As can be seen in Table 1, none of tested bases were
proper for progress of reaction. The only base that found suitable
for this synthesis was aqueous NaOH which employed for all
reactions.
To find out the optimized reaction conditions, we screened the
influence of parameters like solvent and base. In this connection,
the optimization was begun with studying the influence of various
aprotic, protic and other solvents on the sample reaction in the
presence of aqueous NaOH as a base (Table 1). As shown in Table 1,
through the examined solvents, ethanol (Table 1, entry 10) afforded
the best result and hence it was solvent of choice for all next
reactions. In general, the use of protic solvents (Table 1, entries 10-
13) gained the better results compared to aprotic solvents while in
contrary, water (Table 1, entry 9) was insufficient to process the
reaction. In addition to ethanol, methanol also afforded an
With the optimal reaction conditions in hand, we screened the
versatility and the scope of this current approach. In this regard, a
variety of alkyl bromides were proved to be effective to generate
products 12 in excellent to almost quantitative yields (Table 2).
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Table 2 Synthesis of 8-alkylmercaptocaffeine through one-pot two-Step
The alkyl bromides with different normal carbon chains readily
underwent the reactions with thiourea and 8-BC in excellent yields
(Table 2, entries 1-7). Interestingly, as expected, among tested alkyl
bromides, the maximum yields were obtained for alkyl bromides
with shorter normal carbon chains; whereas, the yields were
gradually diminished by increasing the number of carbons in a
chain. Also the utilizing alkyl bromide with a branched aliphatic
chain acquired a good yield of product (Table 2, entry 8). Moreover,
alkyl bromides with ω-substituted phenyl moieties (Table 2, entries
11 and 12) were afforded the corresponding products 12k and 12l
in excellent yields. This current approach also works well with
benzyl bromide derivatives in which 9i, 9j, 9m and benzhydryl
bromide were efficiently converted to the corresponding products
also in quantitative yields. In addition, alkyl bromides with N-
heterocyclic compounds at ω-position involving benzimidazolyl
(9o), 2-methyl-4-nitroimidazolyl (9p) and phthalimidyl (9q) were
almost quantitatively converted to corresponding 8-alkylmercapto-
caffeine (12o-12q). It is worth mentioning that the other alkyl
halides involving alkyl chlorides and iodides along with alkyl
sulfonates could be applied; however, to our experience the best
results were obtained when alkyl bromides were employed.
three-component reaction using thiourea, alkyl bromide and 8-BC
Entry
Product a
Me
Time (h)
18
Yield b (%)
O
Me
O
N
N
N
N
N
1
95
S
N
N
12a
Me
O
Me
N
Me
O
2
3
4
20
22
19
93
90
90
S
N
N
12b
Me
O
Me
N
Me
O
S
N
N
12c
Me
O
Me
N
Me
O
S
N
N
12d
Me
O
Me
Me
O
N
N
N
5
6
20
19
88
85
(
)
4
S
N
N
12e
Me
O
Me
Me
O
N
(
)
5
S
N
N
12f
Me
O
Me
Me
O
N
N
On the basis of the experimental results, a plausible mechanism
for the formation of products is proposed (Scheme 2). As shown in
Scheme 2, the thiourea first performs the nucleophilic attack to
alkyl bromide to generate alkylthiouronium hydrobromide salt (I).
The generation of this salt was obviously observed during the
reaction course. Afterward, salt (I) is hydrolyzed to urea and
corresponding thiol (II) by addition of hydroxide ion. The in situ
generated thiol (II) is then activated by extra hydroxide ion and
attacks to 8-BC through SNAr-type reaction to afford 8-
alkylmercaptocaffeine.
(
)
7
7
22
26
83
84
S
N
N
12g
Me
O
Me
N
Me
O
N
8
S
N
N
12h
Me
O
Me
Me
O
CH3
N
N
9
12
16
96
94
S
N
N
12i
Me
O
Me
Me
O
10
N
N
N
S
N
N
12j
R1
Me
O
R2 CH
R2
H2N
H2N
NH2
NH2
Me
Br
(I)
S
R1
C
H
Br
Me
O
S
N
S
14
17
20
90
83
93
O
11
12
13
N
N
12k
Me
HO
H2N
NH2
O
O
Me
Me
Me
O
Me
N
R2
N
N
N
N
S
Br
N
S
H
C
H
R1
(II)
N
N
12l
O
N
Me
O
O
Me
Me
Me
Me
O
N
Me
O
HO
N
N
S
R1
S
N
N
N
N
R2
12m
Me
Me
O
R1=alkyl, phenyl,...
R2=phenyl, H
Me
N
Me
O
N
N
S
48
17
80
92
14
15
N
N
12n
Scheme
2
A
plausible mechanism for synthesis of 8-
Me
O
Me
N
alkylmercaptocaffeine using thiourea, alkyl bromide and 8-BC
Me
O
S
N
N
N
N
N
12o
Me
O
N
Me
Me
N
N
16
18
90
92
16
17
S
NO2
Conclusions
N
O
12p
N
Me
O
Me
O
In conclusion, we have developed an efficient, odourless and
practical route for one-pot two-step three-component
synthesis of some 8-alkylmercaptocaffeine derivatives. The
three-component reaction of alkyl bromides, thiourea and 8-
BC in the presence of aqueous NaOH in ethanol acquired 8-
alkylmercaptocaffeine derivatives in excellent to quantitative
yields. The influence of parameters effective on reaction
O
Me
Me
N
N
N
S
N
O
N
12q
Me
a All products were characterized by 1H and 13C NMR, IR, CHN, and MS
analysis.
b Isolated yield.
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progress involving solvent and base effects has been studied. SCH2), 1.86–1.71 (m, 2 H, SCH2CH2), 1.05 (t, J = 7.3 Hz, 3 H,
This catalyst-free approach proceeds smoothly under mild CH3).
conditions from readily available starting materials and 13C NMR (CDCl3, 62.5 MHz): δ = 155.1, 152.2, 151.3, 150.4,
provides diverse 8-alkylmercaptocaffeine as potential 105.1, 38.7, 33.5, 30.0, 24.8, 21.3, 13.8.
chemotherapeutic agents.
MS (EI): m/z (%) = 268 (15.7) [M+].
Anal. Calcd for C11H16N4O2S: C, 49.24; H, 6.01; N, 20.88. Found:
C, 49.32; H, 6.15; N, 20.96.
Experimental
All chemical reagents except that of 8-Bromocaffeine (8-BC)34 8-(Butylthio)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione
were purchased from Fluka, Sigma-Aldrich or Merck (12b)24
companies. Solvents were purified by standard procedures, Recrystallization (EtOH) afforded a white solid; yield: 2.62 g
and stored over 3Å molecular sieves.35 Reactions were (93%); mp 81–83 °C; Rf = 0.36 (EtOAc-n-hexane, 1:6).
followed by TLC using SILG/UV 254 silica-gel plates. Column IR (KBr): 2964, 2873, 1701, 1671, 1560, 1426, 1372 cm–1.
chromatography was performed on silica gel 60 (0.063-0.200 1H NMR (CDCl3, 250 MHz): δ = 3.69 (s, 3 H, N(7)-CH3), 3.46 (s, 3
mm, 70-230 mesh; ASTM). IR spectra were obtained using a H, N(1)-CH3), 3.32 (s, 3 H, N(3)-CH3), 3.17 (t, J = 7.1 Hz, 2 H,
Shimadzu FT-IR-8300 spectrophotometer. 1H- and 13C-NMR SCH2), 1.52–1.20 (complex, 4 H, 2 CH2), 0.88 (t, J = 7.1 Hz, 3 H,
spectrum was recorded on Brüker Avance-DPX-250 CH3).
spectrometer operating at 250/62.5 MHz, respectively. 13C NMR (CDCl3, 62.5 MHz): δ = 155.8, 152.8, 151.8, 150.6,
Chemical shifts are given in δ relative to tetramethylsilane 107.3, 37.2, 33.2, 32.6, 29.6, 22.0, 21.7, 13.8.
(TMS) as an internal standard, coupling constants J are given in MS (EI): m/z (%) = 282 (13.4) [M+].
1
Hz. Abbreviations used for H NMR signals are: s = singlet, d = Anal. Calcd for C12H18N4O2S: C, 51.04; H, 6.43; N, 19.84. Found:
doublet, t = triplet, q = quartet, m = multiplet, br = broad and C, 51.17; H, 6.51; N, 19.76.
etc. GC/MS was performed on a Shimadzu GC/MS-QP 1000-EX
apparatus (m/z; rel.%). Elemental analyses were performed on 1,3,7-Trimethyl-8-(pentylthio)-1H-purine-2,6(3H,7H)-dione
a Perkin–Elmer 240-B micro-analyser.
(12c)
Column chromatography (silica gel, EtOAc-n-hexane, 1:15)
General Procedure for synthesis of 8-alkylmercaptocaffeine afforded a white solid; yield: 2.66 g (90%); mp 75–77 °C; Rf =
12a-12q 0.36 (EtOAc-n-hexane, 1:6).
(
)
In a triple-necked round bottom flask (100 mL) equipped with IR (KBr): 2946, 2847, 1702, 1663, 1538, 1444, 1349 cm–1.
a condenser and additional funnel, it was added a mixture, 1H NMR (CDCl3, 250 MHz): δ = 3.82 (s, 3 H, N(7)-CH3), 3.53 (s, 3
consisting of alkyl bromide (10 mmol) and thiourea (12 mmol, H, N(1)-CH3), 3.36 (s, 3 H, N(3)-CH3), 3.26 (t, J = 7.3 Hz, 2 H,
0.91g) in 96% EtOH (25 mL). The mixture was heated at reflux SCH2), 1.82–1.70 (m, 2 H, SCH2CH2), 1.49–1.30 (m, 4 H, 2 CH2),
and heating was continued until TLC indicated the completion 0.92 (t, J = 7.0 Hz, 3 H, CH3).
of reaction. Afterward, the solution of NaOH (0.02 mol, 0.8 g) 13C NMR (CDCl3, 62.5 MHz): δ = 154.9, 151.9, 150.6, 149.1,
in distillated water (2 mL) was added to reaction mixture 108.8, 36.9, 32.3, 31.0, 30.1, 29.5, 22.7, 21.8, 14.4.
through the connected addition funnel at reflux for an extra MS (EI): m/z (%) = 296 (18.9) [M+].
hour. The reaction media was chilled to room temperature and Anal. Calcd for C13H20N4O2S: C, 52.68; H, 6.80; N, 18.90. Found:
then 8-BC (10 mmol, 2.73 g) was added and the mixture was C, 52.83; H, 6.87; N, 19.02.
stirred at room temperature. In most cases, the suspension of
8-BC crystals immediately vanished which is a good evidence 8-(Hexylthio)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione
for rapid progression of reaction (Note: 8-BC is not dissolved in (12d)
EtOH at room temperature). After completion of the reaction Column chromatography (silica gel, EtOAc-n-hexane, 1:15)
(TLC check), the solvent was evaporated in vacuo and the afforded a white solid; yield: 2.79 g (90%); mp 67–69 °C; Rf =
remaining residue was diluted in CHCl3 (100 mL) and 0.35 (EtOAc-n-hexane, 1:6).
subsequently washed with water (2×100 mL). The organic layer IR (KBr): 2942, 2910, 1710, 1652, 1551, 1478, 1362 cm–1.
was dried (Na2SO4) and evaporated. The crude product was 1H NMR (CDCl3, 250 MHz): δ = 3.73 (s, 3 H, N(7)-CH3), 3.44 (s, 3
purified by recrystallization and/or column chromatography on H, N(1)-CH3), 3.26 (s, 3 H, N(3)-CH3), 3.17 (t, J = 7.3 Hz, 2 H,
silica gel eluting with proper solvents described below.36
SCH2), 1.72–1.60 (m, 2 H, SCH2CH2), 1.38–1.22 (complex, 6 H, 3
CH2), 0.78 (t, J = 7.3 Hz, 3 H, CH3).
1,3,7-Trimethyl-8-(propylthio)-1H-purine-2,6(3H,7H)-dione
(12a)24
Recrystallization (EtOH) afforded a white solid; yield: 2.55 g MS (EI): m/z (%) = 310 (17.5) [M+].
13C NMR (CDCl3, 62.5 MHz): δ = 155.6, 152.0, 151.1, 149.7,
106.5, 37.1, 33.3, 31.8, 30.6, 29.1, 28.5, 22.9, 21.7, 15.8.
(95%); mp 82–84 °C; Rf = 0.36 (EtOAc-n-hexane, 1:6).
IR (KBr): 2952, 2832, 1701, 1658, 1583, 1447, 1341 cm–1.
1H NMR (CDCl3, 250 MHz): δ = 3.84 (s, 3 H, N(7)-CH3), 3.55 (s, 3
Anal. Calcd for C14H22N4O2S: C, 54.17; H, 7.14; N, 18.05. Found:
C, 54.09; H, 7.21; N, 18.13.
H, N(1)-CH3), 3.38 (s, 3 H, N(3)-CH3), 3.25 (t, J = 7.2 Hz, 2 H, 8-(Heptylthio)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione
(12e)
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Recrystallization (EtOH) afforded a white solid; yield: 2.85 g Anal. Calcd for C13H20N4O2S: C, 52.68; H, 6.80; N, 18.90. Found:
(88%); mp 75–77 °C; Rf = 0.34 (EtOAc-n-hexane, 1:6).
IR (KBr): 2943, 2863, 1703, 1682, 1579, 1431, 1388 cm–1.
C, 52.82; H, 6.87; N, 18.95.
1H NMR (CDCl3, 250 MHz): δ = 3.84 (s, 3 H, N(7)-CH3), 3.55 (s, 3 1,3,7-Trimethyl-8-(4-methylbenzylthio)-1H-purine-
H, N(1)-CH3), 3.38 (s, 3 H, N(3)-CH3), 3.26 (t, J = 7.3 Hz, 2 H, 2,6(3H,7H)-dione (12i)
SCH2), 1.80–1.72 (m, 2 H, SCH2CH2), 1.46–1.29 (complex, 8 H, 4 Column chromatography (silica gel, EtOAc-n-hexane, 1:15)
CH2), 0.88 (t, J = 6.8 Hz, 3 H, CH3).
afforded a white solid; yield: 3.17g (96%); mp 75–77 °C; Rf =
13C NMR (CDCl3, 62.5 MHz): δ = 156.2, 152.9, 151.4, 150.2, 0.28 (EtOAc-n-hexane, 1:6).
108.9, 37.0, 32.4, 31.8, 30.6, 29.7, 28.8, 27.9, 22.5, 21.8, 14.3.
MS (EI): m/z (%) = 324 (19.3) [M+].
IR (KBr): 3028, 2987, 2931, 1698, 1674, 1596, 1469, 1368 cm–1.
1H NMR (CDCl3, 250 MHz): δ = 7.28 (d, J = 8.0 Hz, 2 H, aryl),
Anal. Calcd for C15H24N4O2S: C, 55.53; H, 7.46; N, 17.27. Found: 7.16 (d, J = 7.9 Hz, 2 H, aryl), 4.45 (s, 2 H, SCH2), 3.76 (s, 3 H,
C, 55.61; H, 7.40; N, 17.35.
N(7)-CH3), 3.63 (s, 3 H, N(1)-CH3), 3.42 (s, 3 H, N(3)-CH3), 2.36
(s, 3 H, PhCH3).
1,3,7-Trimethyl-8-(octylthio)-1H-purine-2,6(3H,7H)-dione
13C NMR (CDCl3, 62.5 MHz): δ = 154.4, 151.8, 150.9, 150.3,
137.0, 136.6, 129.8, 127.2, 107.3, 39.1, 32.6, 30.0, 25.2, 22.2.
(12f)
Column chromatography (silica gel, EtOAc-n-hexane, 1:15) MS (EI): m/z (%) = 330 (14.6) [M+].
afforded a white solid; yield: 2.87 g (85%); mp 66–68°C; Rf = Anal. Calcd for C16H18N4O2S: C, 58.16; H, 5.49; N, 16.96. Found:
0.34 (EtOAc-n-hexane, 1:6).
IR (KBr): 2945, 2852, 1702, 1672, 1586, 1463, 1357 cm–1.
C, 58.29; H, 5.40; N, 16.85.
1H NMR (CDCl3, 250 MHz): δ = 3.76 (s, 3 H, N(7)-CH3), 3.47 (s, 3 8-(Benzylthio)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione
H, N(1)-CH3), 3.30 (s, 3 H, N(3)-CH3), 3.18 (t, J = 7.3 Hz, 2 H, (12j)15,24
SCH2), 1.72–1.61 (m, 2 H, SCH2CH2), 1.36–1.20 (complex, 10 H, Column chromatography (silica gel, EtOAc-n-hexane, 1:15)
5 CH2), 0.77 (t, J = 6.8 Hz, 3 H, CH3).
afforded a white solid; yield: 2.97 g (94%); mp 74–76 °C; Rf =
13C NMR (CDCl3, 62.5 MHz): δ = 154.8, 152.1, 151.8, 149.4, 0.26 (EtOAc-n-hexane, 1:6).
105.1, 37.0, 32.6, 31.6, 30.8, 30.5, 29.9, 29.6, 28.7, 22.5, 20.4, IR (KBr): 3030, 2946, 2895, 1711, 1671, 1544, 1436, 1310 cm–1.
15.3.
MS (EI): m/z (%) = 338 (20.6) [M+].
1H NMR (DMSO-d6, 250 MHz): δ = 7.45–7.31 (m, 5 H, aryl), 4.49
(s, 2 H, SCH2), 3.63 (s, 3 H, N(7)-CH3), 3.41 (s, 3 H, N(1)-CH3),
Anal. Calcd for C16H26N4O2S: C, 56.78; H, 7.74; N, 16.55. Found: 3.17 (s, 3 H, N(3)-CH3).
C, 56.88; H, 7.81; N, 16.47.
13C NMR (DMSO-d6, 62.5 MHz): δ = 155.1, 152.4, 151.8, 149.4,
138.6, 128.7, 128.4, 127.3, 104.8, 37.4, 31.4, 30.5, 22.1.
MS (EI): m/z (%) = 316 (20.1) [M+].
8-(Decylthio)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione
(12g)
Anal. Calcd for C15H16N4O2S: C, 56.94; H, 5.10; N, 17.71. Found:
Recrystallization (EtOH) afforded a white solid; yield: 3.04 g C, 57.03; H, 5.21; N, 17.79.
(83%); mp 83–85 °C; Rf = 0.32 (EtOAc-n-hexane, 1:6).
IR (KBr): 2986, 2880, 1706, 1674, 1536, 1472, 1313 cm–1.
1,3,7-Trimethyl-8-(phenethylthio)-1H-purine-2,6(3H,7H)-
1H NMR (CDCl3, 250 MHz): δ = 3.90 (s, 3 H, N(7)-CH3), 3.62 (s, 3 dione (12k)14,15
H, N(1)-CH3), 3.46 (s, 3 H, N(3)-CH3), 3.29 (t, J = 7.3 Hz, 2 H, Column chromatography (silica gel, EtOAc-n-hexane, 1:8)
SCH2), 1.74–1.21 (complex, 19 H, 8 CH2, CH3).
afforded a white solid; yield: 2.97 g (90%); mp 71–73 °C; Rf =
13C NMR (CDCl3, 62.5 MHz): δ = 155.4, 151.1, 150.5, 149.1, 0.23 (EtOAc-n-hexane, 1:6).
105.0, 36.9, 33.1, 32.0, 30.6, 30.0, 29.1, 28.8, 28.6, 28.0, 27.4, IR (KBr): 3032, 2941, 1719, 1668, 1542, 1456, 1372 cm–1.
21.7, 20.2, 12.5.
MS (EI): m/z (%) = 366 (23.8) [M+].
1H NMR (DMSO-d6, 250 MHz): δ = 7.29–7.14 (m, 5 H, aryl), 3.62
(s, 3 H, N(7)-CH3), 3.44 (t, J = 7.2 Hz, 2 H, SCH2), 3.34 (s, 3 H,
Anal. Calcd for C18H30N4O2S: C, 58.98; H, 8.25; N, 15.29. Found: N(1)-CH3), 3.13 (s, 3 H, N(3)-CH3), 2.97 (t, J = 7.1 Hz, 2 H,
C, 59.05; H, 8.36; N, 15.38.
PhCH2).
13C NMR (DMSO-d6, 62.5 MHz): δ = 157.6, 152.7, 151.8, 150.3,
139.6, 128.7, 127.5, 125.9, 105.3, 38.3, 36.5, 33.1, 30.7, 22.5.
MS (EI): m/z (%) = 330 (22.6) [M+].
8-(Isopentylthio)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione
(12h)15
Recrystallization (EtOH) afforded a white solid; yield: 2.48 g Anal. Calcd for C16H18N4O2S: C, 58.16; H, 5.49; N, 16.96. Found:
(84%); mp 82–84 °C; Rf = 0.39 (EtOAc-n-hexane, 1:6).
IR (KBr): 2956, 2864, 1710, 1678, 1557, 1468, 1369 cm–1.
C, 58.27; H, 5.55; N, 16.90.
1H NMR (CDCl3, 250 MHz): δ = 3.76 (s, 3 H, N(7)-CH3), 3.47 (s, 3 1,3,7-Trimethyl-8-(3-phenylpropylthio)-1H-purine-2,6(3H,7H)-
H, N(1)-CH3), 3.31 (s, 3 H, N(3)-CH3), 3.19 (t, J = 7.4 Hz, 2 H, dione (12l)14
SCH2), 1.71–1.51 (m, 3 H, CH2CH), 0.89 (d, J = 6.3 Hz, 6 H, 2 Column chromatography (silica gel, EtOAc-n-hexane, 1:10)
CH3).
afforded a white solid; yield: 2.86 g (83%); mp 86–88 °C; Rf =
13C NMR (CDCl3, 62.5 MHz): δ = 155.4, 152.4, 151.5, 150.5, 0.23 (EtOAc-n-hexane, 1:6).
106.1, 37.3, 34.2, 31.5, 29.3, 26.9, 22.0, 20.5.
MS (EI): m/z (%) = 296 (17.6) [M+].
IR (KBr): 3050, 2934, 2843, 1701, 1661, 1544, 1431, 1376 cm–1.
6 | RSC Adv., 2012, 00, 1-3
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1H NMR (CDCl3, 250 MHz): δ = 7.32–7.17 (m, 5 H, aryl), 3.82 (s, MS (EI): m/z (%) = 384 (21.6) [M+].
ARTICLE
3 H, N(7)-CH3), 3.51 (s, 3 H, N(1)-CH3), 3.37 (s, 3 H, N(3)-CH3), Anal. Calcd for C18H20N6O2S: C, 56.23; H, 5.24; N, 21.86. Found:
3.26 (t, J = 7.0 Hz, 2 H, SCH2), 2.77 (t, J = 7.3 Hz, 2 H, PhCH2), C, 56.35; H, 5.32; N, 21.78.
2.16–2.03 (m, 2 H, SCH2CH2).
13C NMR (CDCl3, 62.5 MHz): δ = 156.3, 153.3, 152.1, 151.6, 1,3,7-Trimethyl-8-(5-(2-methyl-4-nitro-1H-imidazol-1-
139.7, 129.3, 128.0, 126.3, 107.9, 36.1, 35.8, 35.2, 33.7, 30.1, yl)pentylthio)-1H-purine-2,6(3H,7H)-dione (12p)
21.8.
MS (EI): m/z (%) = 344 (21.8) [M+].
Column chromatography (silica gel, EtOAc-n-hexane, 2:1)
afforded a yellow oil; yield: 3.79 g (90%); Rf = 0.36 (EtOAc-n-
Anal. Calcd for C17H20N4O2S: C, 59.28; H, 5.85; N, 16.27. Found: hexane, 4:1).
C, 59.41; H, 5.94; N, 16.14.
IR (film): 3047, 2965, 2861, 1718, 1680, 1552, 1534, 1473,
1348 cm–1.
1H NMR (CDCl3, 250 MHz): δ = 7.65 (s, 1H, C(5)-H, imidazole),
3.86 (t, J = 7.0 Hz, 2H, NCH2), 3.64 (s, 3 H, N(7)-CH3), 3.44 (s, 3
1,3,7-Trimethyl-8-(naphthalen-2-ylmethylthio)-1H-purine
2,6(3H,7H)-dione (12m)
Column chromatography (silica gel, EtOAc-n-hexane, 1:10) H, N(1)-CH3), 3.29 (s, 3 H, N(3)-CH3), 3.13 (t, J = 7.0 Hz, 2H,
afforded a white solid; yield: 3.40 g (93%); mp 126–128°C; Rf = SCH2), 1.79–1.73 (m, 2H, CH2), 1.49–1.43 (m, 2H, CH2), 1.34–
0.23 (EtOAc-n-hexane, 1:6).
1.28 (m, 2H, CH2).
IR (KBr): 3037, 2934, 2843, 1701, 1661, 1542, 1431, 1376 cm–1. 13C NMR (CDCl3, 62.5 MHz): δ = 155.9, 152.9, 152.6, 151.7,
1H NMR (CDCl3, 250 MHz): δ = 8.03 (d, J = 7.9 Hz, 1 H, aryl), 151.1, 139.0, 132.5, 106.5, 46.0, 36.8, 33.3, 31.2, 30.9, 29.4,
7.83–7.68 (m, 2 H, aryl), 7.52–7.27 (m, 4 H, aryl), 4.86 (s, 2 H, 27.7, 22.4, 12.6.
SCH2), 3.57 (s, 3 H, N(7)-CH3), 3.54 (s, 3 H, N(1)-CH3), 3.31 (s, 3 MS (EI): m/z (%) = 421 (20.3) [M+].
H, N(3)-CH3).
Anal. Calcd for C17H23N7O4S: C, 48.44; H, 5.50; N, 23.26. Found:
13C NMR (CDCl3, 62.5 MHz): δ = 156.9, 152.4, 151.2, 150.9, C, 48.35; H, 5.41; N, 23.34.
134.2, 133.0, 132.1, 129.3, 128.8, 128.2, 127.9, 127.3, 126.1,
125.2, 106.4, 39.5, 33.5, 30.8, 23.1.
MS (EI): m/z (%) = 366 (18.3) [M+].
8
-(2-(1,3-Dioxoisoindolin-2-yl)ethylthio)-1,3,7-trimethyl-1H-
purine-2,6(3H,7H)-dione (12q)
Anal. Calcd for C19H18N4O2S: C, 62.28; H, 4.95; N, 15.29. Found: Column chromatography (silica gel, EtOAc-n-hexane, 1:1)
C, 62.19; H, 5.01; N, 15.22.
afforded a creamy foam; yield: 3.67 g (92%); Rf = 0.49 (EtOAc-
n-hexane, 4:1).
IR (KBr): 3068, 2971, 2879, 1716, 1697, 1662, 1541, 1460 cm–1.
1H NMR (CDCl3, 250 MHz): δ = 7.18–7.13 (m, 2H, aryl), 6.99–
8-(Benzhydrylthio)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-
dione (12n)
Column chromatography (silica gel, EtOAc-n-hexane, 1:15) 6.92 (m, 2H, aryl), 3.77 (s, 3 H, N(7)-CH3), 3.43–3.30 (complex,
afforded a white solid; yield: 3.1 g (80%); mp 74–76 °C; Rf = 10 H, NCH2, SCH2, N(1)-CH3, N(3)-CH3).
0.22 (EtOAc-n-hexane, 1:6).
IR (KBr): 3025, 2964, 1701, 1671, 1660, 1426, 1372 cm–1.
13C NMR (CDCl3, 62.5 MHz): δ = 168.4, 155.3, 152.1, 151.9,
151.0, 133.5, 132.4, 127.7, 107.1, 35.6, 33.0, 30.4, 29.8, 22.3.
1H NMR (CDCl3, 250 MHz): δ = 7.43–7.40 (m, 4 H, aryl), 7.34– MS (EI): m/z (%) = 399 (21.2) [M+].
7.24 (m, 6 H, aryl), 6.17 (s, 1 H, SCH), 3.71 (s, 3 H, N(7)-CH3), Anal. Calcd for C18H17N5O4S: C, 54.13; H, 4.29; N, 17.53. Found:
3.53 (s, 3 H, N(1)-CH3), 3.34 (s, 3 H, N(3)-CH3).
13C NMR (CDCl3, 62.5 MHz): δ = 156.7, 152.4, 151.6, 150.6,
142.8, 129.5, 128.6, 127.2, 105.5, 51.3, 33.9, 30.2, 22.6.
MS (EI): m/z (%) = 392 (25.4) [M+].
C, 54.21; H, 4.40; N, 17.65.
Acknowledgements
Anal. Calcd for C21H20N4O2S: C, 64.27; H, 5.14; N, 14.28. Found:
C, 64.39; H, 5.23; N, 14.35.
The authors wish to thank Shiraz University of Technology
research council for partial support of this work.
8-(3-(1H-Benzo[d]imidazol-1-yl)propylthio)-1,3,7-trimethyl-
1H-purine-2,6(3H,7H)-dione (12o)
Column chromatography (silica gel, EtOAc-n-hexane, 2:1)
afforded a pale-yellow foam; yield: 3.53 g (92%); Rf = 0.38
(EtOAc-n-hexane, 4:1).
Notes and references
1
R. Franco, A. Oñatibia-Astibia and E. Martínez-Pinilla,
Nutrients, 2013, , 4159.
5
IR (KBr): 3050, 2991, 2876, 1715, 1678, 1537, 1464 cm–1.
2
B. B. Fredholm, Methylxanthines, Handbook of Experimental
Pharmacology, Vol.200, Springer-Verlag Berlin Heidelberg,
2011.
1H NMR (CDCl3, 250 MHz):
δ = 8.25 (s, 1H, C(2)-H,
benzimidazole), 7.77–7.74 (m, 2 H, aryl), 7.66–7.62 (m, 2 H,
aryl), 3.71 (t, J = 6.8 Hz, 2H, NCH2), 3.62 (s, 3 H, N(7)-CH3), 3.41
(s, 3 H, N(1)-CH3), 3.27 (s, 3 H, N(3)-CH3), 3.06 (t, J = 6.8 Hz, 2H,
SCH2), 2.34–2.25 (m, 2H, NCH2CH2).
13C NMR (CDCl3, 62.5 MHz): δ = 155.5, 152.5, 152.1, 151.0,
144.9, 139.1, 134.6, 123.6, 123.0, 115.7, 115.4, 107.0, 54.8,
35.1, 32.9, 31.7, 29.6, 21.7.
3
4
Ullmann's Encyclopedia of Industrial Chemistry, 7th edn.,
Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2005.
B. G. Katzung, S. B. Masters and A. T. Trevor, Basic and
Clinical Pharmacology, 12th edn, Lange Basic Science, Mc
Graw Hill, New York, 2012.
5
A. Kleeman, J. Engel, B. Kutscher and D. Reichert, In
Pharmaceutical Substances, 3rd edn., Thieme, Stuttgart,
1999.
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
6
7
8
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V. Boswell-Smith , D. Spina and C. P. Page, Br. J. Pharmacol.,
2006, 147, 252.
M. Williams and M. F. Jarvis, Pharmacol. Biochem. Behav.,
1988, 29, 433.
M. N. Soltani Rad, S. Behrouz and H. Najafi, Synthesis, 2014,
46, 1380.
L. Zhang and Y. J. Zhang, Tetrahedron Lett., 2006, 47, 775.
from the reaction mixture via simple filtration before solvent
evaporation.
10 C. O. Wilson, O. Gisvold and J. H. Block, In Wilson and
Gisvold’s Textbook of Organic Medicinal and Pharmaceutical
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8 | RSC Adv., 2012, 00, 1-3
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DOI: 10.1039/C6RA17814F
Journal Name
ARTICLE
Two-Step Three-Component Process for One-Pot Synthesis of 8-Alkylmercaptocaffeine Derivatives
Mohammad Navid Soltani Rad and Saeid Maghsoudi
A two-step three-component process for one-pot synthesis of some 8-alkylmercaptocaffeine derivatives has
been described using alkyl bromides, thiourea, and 8-bromocaffeine.
S
2
H2N
NH2
1
3
O
Me
N
O
Me
N
Me
O
R1R2CHBr
Me
O
N
N
S
R1
Br
N
N
N
R2
N
Me
Me
80-96%
17 examples
2
/ EtOH, reflux
1
+
R1 =Alkyl, Aryl,...
2 =Aryl, H
R
NaOH (aq.), then
3
, rt
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