Copper-catalyzed direct thiolation of xanthines and related heterocycles with disulfides

Article abstract of DOI:10.1016/j.tetlet.2013.08.097

A novel copper-catalyzed, base-free direct thiolation of xanthines and related heterocycles is described, featuring the use of inexpensive Cu(OAc) ₂·H₂O as the catalyst, O₂ as a clean and cheap oxidant, and easy-to-handle

Full text of DOI:10.1016/j.tetlet.2013.08.097

Tetrahedron Letters xxx (2013) xxx–xxx
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Tetrahedron Letters
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Copper-catalyzed direct thiolation of xanthines and related
heterocycles with disulfides
⇑
⇑
Zuying He, Fang Luo , Yinglong Li, Gangguo Zhu
Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel copper-catalyzed, base-free direct thiolation of xanthines and related heterocycles is described,
featuring the use of inexpensive Cu(OAc)2ÁH2O as the catalyst, O2 as a clean and cheap oxidant, and easy-
to-handle disulfides as the thiolation reagents. It works well for both aryl and alkyl disulfides. Moreover,
the resultant products can be converted into 8-(hetero)aryl- or alkenyl-substituted xanthines in good
yields via the Liebeskind–Srogl coupling reaction.
Received 4 June 2013
Revised 20 August 2013
Accepted 25 August 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Xanthines
Thiolation
Copper
Disulfides
Xanthines, including caffeine, theophylline, and theobromine,
are important heterocycles commonly found in a wide range of
agrochemically useful and pharmaceutically active compounds.
Among these, the C-8 substituted xanthines as high affinity and
selective adenosine receptor antagonists1 have gained much atten-
tion. Undoubtedly, the direct C–H bond activation is the most
straightforward and efficient approach to these motifs. Thus, over
the past few years, a number of Pd or Cu-promoted direct C-8 ary-
lation of xanthines have been achieved with aryl (pseudo)halides,2
arylboronic acids,3 arylsilanes,4 arylsulfonyl derivatives,5 or (het-
ero)arenes.6 In contrast, there are only limited examples on the
synthesis of heteroatom-substituted xanthines so far.7
Petzer reported that C-8 substitution of xanthines with a thioe-
ther group might exhibit an enhanced MAO-B inhibition activity.8
However, as far as the thiolation of xanthines is concerned, it usu-
ally involves the transformation of prefunctionalized xanthines
with thiols or thiolates, which suffers from low step and atom
economy.9 Moreover, thiols often possess an odd smell and are
susceptible to undergo the oxidative homocoupling reaction.
Recently, the direct thiolation of C–H bonds,7b,10 including the non-
chelation-assisted ones,7b,10b,i,j has become an intriguing and effec-
tive alternative to access sulfides. In this regard, Bolm7b reported
an elegant metal-free direct thiolation of xanthines and related
heterocycles very recently; however, the use of excess strong base,
moderate yield (55% for caffeine), and incompatibility with alkyl
disulfides limit the synthetic utility of this method. To overcome
these drawbacks, we report here a copper-catalyzed, base-free C-
8 direct thiolation of xanthines and related heteroarenes featuring
the use of inexpensive Cu(OAc)2ÁH2O as the catalyst and O2 as a
clean and cheap oxidant. Notably, both aryl and alkyl disulfides
can be employed as effective thiolation reagents.
Initially, the reaction of caffeine (1a) with diphenyldisulfide
(2a) was chosen as the model system to evaluate the reaction
parameters. As shown in Table 1, the copper sources had a signif-
icant influence on the reaction, and Cu(OAc)2ÁH2O appeared to be
the best choice, delivering 3aa in 70% yield (Table 1, entries 1–5).
A brief survey of the solvents, including polar and nonpolar sol-
vents, revealed that a better yield (78%) could be obtained in xy-
lene (Table 1, entries 6–10). Furthermore, the yield increased to
85% when the reaction was performed under an O2 atmosphere,
while under N2, only 30% of 3aa was isolated (Table 1, entry 10).
To reduce the catalyst loading, a variety of additives were inves-
tigated, and we were pleased to find that 3aa was obtained in 95%
yield when 2 mol % of AgOAc was added (Table 1, entry 16). On the
other hand, Lewis acids,11 such as FeCl3 and AlCl3Á6H2O, were to-
tally ineffective (Table 1, entries 17 and 18). It should be noted that
the reaction did not occur in the absence of Cu(OAc)2ÁH2O. Finally,
the optimized reaction conditions consisted of 20 mol % of
Cu(OAc)2ÁH2O, 2 mol % of AgOAc, and xylene under O2 at 145 °C
for 15 h.12
With the optimum reaction conditions in hand, the scope of this
reaction with respect to xanthines was investigated (Table 2). In
general, various N-substituted xanthines underwent the thiolation
reaction smoothly and generated the thiolated xanthines in good
to excellent yields. As an example, thiolation of benzylic theophyl-
line led to 3ba in 95% yield (Table 2, 3ba).
⇑
Corresponding authors. Tel.: +86 579 82283702; fax: +86 0579 82282610.
E-mail addresses: luofang19@zjnu.cn (F. Luo), gangguo@zjnu.cn (G. Zhu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.097
Please cite this article in press as: He, Z.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.08.097

2
Z. He et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Table 1
Table 3
Screening of the reaction conditionsa
The scope of disulfides 2a
O
O
N
O
O
N
.
Cu(OAc)2 H2O (20 mol %)
N
N
N
N
N
N
N
N
CuXn, additive
solvent
N
N
AgOAc (2 mol %)
xylene, O2
N
S
PhSSPh
SPh
SR
+ RSSR
N
N
O
O
O
N
O
1a
2a
3aa
1a
2
3
O
O
Entry
CuXn (mol %)
Additive (mol %)
Solvent
Yieldb (%)
N
N
N
N
N
1
2
3
4
5
6
7
8
CuI (100)
/
/
/
/
/
/
/
/
NMP
NMP
NMP
NMP
<5
18
25
37
70
72
60
75
S
CuBr2 (100)
CuCl2 (100)
CuSO4 (100)
N
N
O
O
N
O
O
N
O
3ab, 95%
3ac, 70%
Cu(OAc)ÁH2O (100)
Cu(OAc)2ÁH2O (100)
Cu(OAc)2ÁH2O (100)
Cu(OAc)2ÁH2O (100)
Cu(OAc)2ÁH2O (100)
Cu(OAc)2ÁH2O (100)
Cu(OAc)2ÁH2O (20)
Cu(OAc)2ÁH2O (20)
Cu(OAc)2ÁH2O (20)
Cu(OAc)2ÁH2O (20)
Cu(OAc)2ÁH2O (20)
Cu(OAc)2ÁH2O (20)
Cu(OAc)2ÁH2O (20)
Cu(OAc)2ÁH2O (20)
NMP
DMSO
DMF
N
S
N
N
S
N
N
N
Cl
Br
DMAc
Toluene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
N
O
N
N
9
/
/
/
74
O
10
11
12
13
14
15
16
17
18
78 (85)c (30)d
3ad, 85%
3ae, 92%
40c
<5c
23c
42c
72c
95c
<5c
<5c
O
N
DDQ (100)
K2S2O8 (100)
Ag2CO3 (100)
AgOAc (100)
AgOAc (2)
AlCl3.6H2O (2)
FeCl3 (2)
N
S
N
N
S
CH2Ph
N
O
N
O
O
S
NO2
3af, 75%
3ag, 65%
O
N
O
a
N
N
N
N
N
Reaction conditions: 1a (0.5 mmol), 2a (0.3 mmol), CuXn (20–100 mol %) and
additive (0–100 mol %) in 2 mL of solvent at 145 °C for 15 h.
N
N
N
SEt
N
SCy
b
n-Pr
O
N
N
O
O
Isolated yield.
Under O2.
Under N2.
c
3ah, 78%
3ai, 70%
3aj, 75%
d
a
Reaction conditions: 1a (0.5 mmol), 2 (0.3 mmol), Cu(OAc)2ÁH2O (20 mol %) and
AgOAc (2 mol %) in 2 mL of xylene at 145 °C for 15 h.
Table 2
Cu-catalyzed thiolation of xanthines and related heterocycles with 2aa
.
conditions
xylene, 145 oC
Cu(OAc)2 H2O (20 mol %)
1a
N
N
X
3aa
yield
NR
AgOAc (2 mol %)
H + PhSSPh
SPh
SPh
xylene, O2
X
1
conditions
2a
3
PhSCu (100 mol %), N2
PhSCu (100 mol %), O2
O
O
N
O
N
(eq 1)
52% (eq 2)
86% (eq 3)
10% (eq 4)
N
N
N
N
N
N
N
N
N
N
N
N
PhSCu (100 mol %), AgOAc (2 mol %), O2
PhSCu (1 mol %), AgOAc (2 mol %), O2
SPh
SPh
O
O
N
O
O
O
Bn
n-Bu
i-Bu
3da, 70%
3ba, 95%
3ca, 87%
Scheme 1. Preliminary mechanism study.
O
O
O
N
and 70% (Table 2, 3ca and 3da). Interestingly, the coupling of N-
methyl indole (1k) with 2a gave rise to the C-3 thiolated product
3ka13 in 70% yield (Table 2, 3ka). Under the standard conditions,
the reaction of benzothiazole (1l) and 4,5-dimethylthiazole (1m)
furnished the desired products in excellent yields (Table 2, 3la
and 3ma).
Then, the disulfide component was varied and the results were
summarized in Table 3. To our delight, all aromatic disulfides were
found to undergo the thiolation reaction with 1a smoothly. Both 4-
chlorophenyl disulfide (2d) and 4-bromophenyl disulfide (2e) gave
high yields of thiolated products without affecting the C–Hal bonds
(Table 3, 3ad and 3ae), which could be used for installing other
functional groups via the transformations of the C–Hal bonds. An
electron-withdrawing group such as NO2 was also well-tolerated,
giving rise to 3af in 75% yield (Table 3, 3af). Moreover, the aliphatic
disulfides were effective coupling partners for this transformation,
and even for the steric demanding substrate 2j, a good yield was
still observed (Table 3, 3aj). Notably, the two RS groups in disul-
fides 2 could be utilized for the thiolation reaction, thus providing
an atom-economical entry to the synthesis of sulfides.
Bn
O
N
SPh
N
N
N
N
N
SPh
SPh
SPh
SPh
N
N
N
N
N
N
3ea, 83%
O
3fa, 75%
3ga, 81%
O
O
n-Bu
i-Bu
N
N
N
N
SPh
N
N
N
N
N
N
O
O
O
3ha, 73%
3ia, 65%
3ja, 68%
SPh
S
S
N
SPh
SPh
N
N
3ka, 70%
3la, 95%
3ma, 91%
a
Reaction conditions: 1 (0.5 mmol), 2a (0.3 mmol), Cu(OAc)2ÁH2O (20 mol %) and
AgOAc (2 mol %) in 2 mL of xylene at 145 °C for 15 h.
The steric hindrance had some effect on the reaction. For
example, N-n-Bu-substituted xanthine 1c and N-i-Bu-substituted
xanthine 1d produced 3ca and 3da in respective yields of 87%
To gain insights into the mechanism of this reaction, we con-
ducted the following experiments. Treating 1a with 100 mol % of
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Z. He et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
Table 4
N
X
Transformations of sulfanylxanthinesa
H
Cu(I)
O
O
N
[O]
1
Pd(dba)2 (5 mol %)
CuTC (1.5 equiv)
N
N
N
N
N
N
SPh + RB(OH)2
R
THF, 60 o
C
O
N
O
O
4
ArCu
Cu(0)
3aa
5
A
3
RSSR (2)
O
O
N
N
N
N
O
N
N
N
N
N
X
Ph
SR
N
Ph
O
N
O
N
O
N
N
[O]
RSCu
CuSR
5aa, 90%
5ab, 75%
5ac, 70%
3
X
C
B
a
Reaction conditions: 3 (0.2 mmol), 4 (0.3 mmol), Pd(dba)2 (0.01 mmol), CuTC
(1.5 equiv), THF, 60 °C, 24 h.
1
[O] = AgOAc, O2
Scheme 2. A possible mechanism.
90% and 75% yields, respectively (Table 4, 5aa and 5ab).15 More-
over, 8-styrylxanthines, a type of A2A AR antagonists,1a,16 could also
be synthesized via this protocol. For instance, (E)-styrylboronic
acid reacted with 3aa successfully to give (E)-8-styryl-l,3,7-trim-
ethylxanthine (5ac) in 70% yield (Table 4, 5ac).
In conclusion, we have developed a copper-catalyzed, base-free
direct thiolation of xanthines and related heterocycles featuring
the use of inexpensive Cu(OAc)2ÁH2O as the catalyst, O2 as a clean
and cheap oxidant, and air stable as well as easy-to-handle disul-
fides as the thiolation reagents. Both aryl and alkyl disulfides are
suitable substrates for this thiolation reaction. Furthermore, this
protocol provides a facile and effective alternative to construct
8-(hetero)aryl- or alkenyl-substituted xanthines using the Liebes-
kind–Srogl coupling reaction. Further investigations on the
reaction mechanism are currently undergoing in our group.
OAc
HOAc
N
N
2
H
3 + RS
X
X
E
1
D
Cu(II)
D
E
+
[O]
ArCuSR
Cu
C
3
Scheme 3. An alternative mechanism.
Acknowledgments
PhSCu10b,i under O2 atmosphere provided 52% of 3aa, while the
reaction did not occur by replacing O2 with N2 (Scheme 1, Eqs. 1
and 2). The yield further increased to 86% when 2 mol % of AgOAc
was added (Scheme 1, Eq. 3). Moreover, the reaction performed
with 1 mol % of PhSCu and 2 mol % of AgOAc under O2 resulted in
3aa in 10% yield (Scheme 1, Eq. 4).
We thank for the financial support from the Natural Science
Foundation of the Zhejiang Province (Nos. LY12B02002 and
LR12B02001), and National Natural Science Foundation of China
(Nos. 20902084 and 21172199).
Based on the above results and previous reports,10b,i a plausible
mechanism for this Cu-catalyzed thiolation reaction is illustrated
in Scheme 2. Initially, the cupration of 1 forms an intermediate
A, which reacts with disulfides 2 to generate the thiolation prod-
ucts 3 and concurrent formation of RSCu (B). Subsequently, the
oxidation of B followed by cupration of 1 produces the species C.
Finally, the reductive elimination of C affords 3 and Cu(0) which
can be oxidized to Cu(I) by O2 with the help of AgOAc (Scheme 2).
Meanwhile, in view of a recent work from Bolm,7b an alterna-
tive mechanism initiated by the deprotonation of xanthines can
be proposed in Scheme 3, which consists of the following steps:
(1) deprotonation of xanthines 1 forming an anion intermediate
D; (2) nucleophilic substitution of 2 with D generating 3 as well
as RSÀ (E); (3) reaction of Cu(II) with D and E providing the species
C; (4) reductive elimination of C leading to the thiolation products
3 and Cu(0); and (4) regeneration of the Cu(II) catalyst via oxida-
tion of Cu(0) with AgOAc and O2 (Scheme 3). So far, the detailed
mechanism is still not clear.
Supplementary data
Supplementary data (experimental details, NMR spectra, and
analytical data of products 3 and 5) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.08.097.
References and notes
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4
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2 mol %) was added 2 mL of xylene. After stirring at 145 °C for 15 h under an O2
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29.7, 27.9.
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Please cite this article in press as: He, Z.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.08.097