Double C-H activation: The palladium-catalyzed direct C-arylation of xanthines with arenes

Article abstract of DOI:10.1021/ol200065s

The novel Pd-catalyzed C(sp²)-H/C(sp²)-H cross-coupling of unactivated xanthines with unactivated arenes utilizing a combination of Ag(I) and O₂ as oxidants exclusively yields C-8 arylated xanthines in a single synthetic o

Full text of DOI:10.1021/ol200065s

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1378–1381
Double C-H Activation: The Palladium-
Catalyzed Direct C-Arylation of Xanthines
with Arenes
€
Chandi C. Malakar, Dietmar Schmidt, Jurgen Conrad, and Uwe Beifuss*
€
Institut fu€r Chemie, Universitat Hohenheim, Garbenstrasse 30, D-70599 Stuttgart,
Germany
ubeifuss@uni-hohenheim.de
Received January 10, 2011
ABSTRACT
The novel Pd-catalyzed C(sp2)-H/C(sp2)-H cross-coupling of unactivated xanthines with unactivated arenes utilizing a combination of Ag(I) and
O2 as oxidants exclusively yields C-8 arylated xanthines in a single synthetic operation.
Many natural products and other biologically active
compounds contain a bis(hetero)aryl moiety as a key struc-
tural motif. During the last decades a number of reliable
Scheme 1. Synthesis of Bis(hetero)aryls
transition metal-catalyzed cross-coupling reactions between
(hetero)aryl halides Ar-X and stoichiometric amounts of
organometallic reagents Ar-M have been developed to
synthesize this kind of structure element by C(sp2)-C(sp2)
bond formation (Scheme 1a).1 However, many of the re-
quired organometallic reagents Ar-M cannot always be
obtained commercially, and often their synthesis is difficult
to achieve. Another disadvantage of this type of cross-
challenging. Meanwhile, a number of intramolecular oxi-
dative C-H functionalizations of this type allowing for the
preparation of dibenzofurans4 and carbazoles5 have been
developed. In addition, ample evidence exists for the
intermolecular homocoupling of both arenes and
heteroarenes.6 Intermolecular cross-coupling reactions be-
tween unactivated reactants are much more difficult to
achieve because the problems that need to be addressed are
not limited to reactivity issues but also include regioselec-
tivity control. Important contributions have come from
coupling is their low step and atom economy.
This is why the concept of direct (hetero)arylation via
C-H bond cleavage is highly attractive and has received
considerable attention over the past few years.2 (Hetero)
arylation can either be performed by coupling of an
activated (hetero)arene with an unactivated (hetero)-
arene (Scheme 1b) or by reacting two unactivated
(hetero)arenes (Scheme 1c). It has been shown that a
number of oxidants can be employed for the dehydrogena-
tive(hetero)arylations.3 UsingO2 forthispurposeprovides
an appealing option. Naturally, the C(sp2)-C(sp2) bond-
ing between two unactivated (hetero)arenes is most
(4) Akermark, B.; Eberson, L.; Jonsson, E.; Pettersson, E. J. Org.
Chem. 1975, 40, 1365–1367.
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(5) (a) Gruner, K. K.; Knolker, H.-J. Org. Biomol. Chem. 2008, 6,
*To whom correspondence should be addressed. Fax: (þ) (49) 711-
459-22951.
(1) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, Germany, 2004.
(2) Reviews: (a) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew.
Chem., Int. Ed. 2009, 48, 9792–9826. (b) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174–238.
3902–3904. (b) Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou,
K. J. Org. Chem. 2008, 73, 5022–5028. (c) Watanabe, T.; Ueda, S.; Inuki,
S.; Oishi, S.; Fujii, N.; Ohno, H. Chem. Commun 2007, 4516–4518.
(6) Lessene, G.; Feldman, K. S. Modern Arene Chemistry; Astruc, D.,
Ed.; Wiley-VCH: Weinheim, Germany, 2002; p 479.
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Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129,
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r
10.1021/ol200065s
Published on Web 02/21/2011
2011 American Chemical Society

Table 1. Pd-Catalyzed C-H Activation of Caffeine (1a) with Benzene (2a)a
entry
Pd(OAc)2 (mol %)
oxidant
PivOH (equiv)
yield of 3a (%)
1
2
10
10
10
15
20
30
Ag2CO3 (3 equiv); Ar
Ag2CO3 (3 equiv); O2
Ag2CO3 (3 equiv); O2
Ag2CO3 (3 equiv); O2
Ag2CO3 (3 equiv); O2
Ag2CO3 (3 equiv); O2
Ag2CO3 (3 equiv); O2
10
21
41
46
56
75
3
3
3
3
3
3
3
4
5
6
7
8
10
trace
20b
17c
8d
9
2.5
10
Cu(OAc)2 H2O (1.5 equiv); Ar
3
10
11
Cu(OAc)2 (2 equiv); Ar
Ag2CO3 (1.5 equiv); Ar
1.5
2.5
a All reactions were performed with 0.5 mmol of 1a and 20 mmol of 2a in a sealed vial, unless otherwise indicated. b Reaction was carried out with 1 equiv of
pyridine as an additive at 120 °C for 20 h in 0.6 mL of 1,4-dioxane. c In a sealed vial, 0.2 mmol of 1a was reacted with 22.4 mmol of 2a, using 0.75 equiv of Na2CO3 at
110 °C for 24 h in 2 mL of DMA. d Reaction was carried out with 1 equiv of AcOH at 120 °C for 7 h in 2 mL of DMF and 100 μL (5%) of DMSO.
the groups of Fagnou7 and DeBoef,8 who demonstrated
that indoles and benzofurans can be coupled with arenes.
Although intermolecular cross-coupling has been ex-
tended to intermolecular (hetero)arylations of pyrrols,7b
pyridin-N-oxides,9 anilides,10 benzo[h]quinolines,11 N-
acetyl tetrahydroquinolines,12 and perfluoroarenes,13 the
range of substrates that can be cross-coupled remains
small.
Xanthines such as caffeine, theophilline, and theobro-
mine are important biologically active alkaloids. In the
field of medicinal chemistry, C-8 (hetero)aryl-substituted
xanthines are of considerable interest as they are known to
act as selective antagonists of the human A2B adenosine
receptor.14 By using the classic methods repertoire of
heterocyclic chemistry the synthesis of C-8 arylated
xanthines can only be achieved by multistep synthesis of
the xanthine skeleton itself. And therefore, a modular,
straightforward approach allowing for the synthesis of C-8
arylated xanthines in a single step is highly desirable, which
iswhy considerableefforthas been devoted tothe arylation
of xanthines over the past few years. Recently, Daugulis15
and You16 have developed the Pd- and the Cu-catalyzed
C-8 arylation of xanthines, respectively, by using aryl
halides as coupling partners, while Ackermann reported
on similar reactions using the corresponding aryl tosylates
as substrates.17 The use of arylboronic acids for the aryla-
tion of xanthines has also been described.18 Recently, the
direct heteroarylation of xanthines with thiophenes and
furans has been achieved.19 The direct arylation of
xanthines, however, has not been achieved so far.
Here we disclose that C-8 arylated xanthines can be
efficiently synthesized via Pd-catalyzed double C-H acti-
vation of unactivated xanthines with unactivated arenes.
The starting point of our study (Table 1) was the
observation that the reaction of caffeine (1a) and benzene
(2a) performed in the presence of 10 mol % of Pd(OAc)2 as
a catalyst, Ag2CO3 as an oxidant, and under an atmo-
sphere of Ar led to the exclusive isolation of the cross-
coupling product 8-phenylxanthine (3a) with 10% yield
(Table 1, entry 1). Remarkably, the yield of the product 3a
could be doubled to 21% by replacing Ar with O2 (Table 1,
entry 2). When pivalic acid was added (Table 1, entry 3)
8-phenylxanthine (3a) was formed in 41% yield. Other
(8) (a) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef,
B. Org. Lett. 2007, 9, 3137–3139. (b) Potavathri, S.; Dumas, A. S.;
Dwight, T. A.; Naumiec, G. R.; Hammann, J. M.; DeBoef, B. Tetra-
hedron Lett. 2008, 49, 4050–4053. (c) Potavathri, S.; Pereira, K. C.;
Gorelsky, S. I.; Pike, A.; LeBris, A. P.; DeBoef, B. J. Am. Chem. Soc.
2010, 132, 14676–14681.
(9) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130,
9254–9256.
(10) Brasche, G.; Garcia-Fortanet, J.; Buchwald, S. L. Org. Lett.
2008, 10, 2207–2210.
(11) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904–
11905.
(15) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449–1451.
(16) (a) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.;
You, J. Angew. Chem., Int. Ed. 2009, 48, 3296–3300. (b) Zhao, D.; Wang,
W.; Lian, S.; Yang, F.; Lan, J.; You, J. Chem.;Eur. J. 2009, 15, 1337–
1340.
(12) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem., Int. Ed.
2008, 47, 1115–1118.
(13) (a) Wei, Y.; Su, W. J. Am. Chem. Soc. 2010, 132, 16377–16379.
(b) He, C.-Y.; Fan, S.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 12850–
12852.
(17) Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem., Int.
Ed. 2009, 48, 201–204.
(18) Liu, B.; Qin, X.; Li, K.; Li, X.; Guo, Q.; Lan, J.; You, J. Chem.;
Eur. J. 2010, 16, 11836–11839.
(19) Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan, J.; Gao, G.; Hu, C.;
You, J. J. Am. Chem. Soc. 2010, 132, 1822–1824.
(14) (a) Hayallah, A. M.; Sandoval-Ramırez, J.; Reith, U.; Schobert,
´
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2002, 45, 1500–1510. (b) Yan, L.; Muller, C. E. J. Med. Chem. 2004, 47,
1031–1043. (c) Kalla, R. V.; Elzein, E.; Perry, T.; Li, X.; Palle, V.;
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Org. Lett., Vol. 13, No. 6, 2011
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but could also be catalyzed by other Pd complexes as well,
including Pd(TFA)2, PdCl2(PhCN)2, or PdCl2(PPh3)2
(Table 2, entries 1-5). The best results were achieved with
15 mol % of PdCl2(PPh3)2. Further experiments with
PdCl2(PPh3)2 revealed that Ag2CO3 could be replaced
with AgOAc and that the amount of Ag2CO3 could also
be decreased to 2.2 equiv (Table 2, entries 6 and 7).
However, avoidance of silver salts has so far not been
possible. Replacing O2 by air or Ar is possible but only at
the cost of decreasing the yield of 3a; the same holds true
when the excess of benzene is substantially reduced
(Table 2, entries 8-10). The best yield of 3a (73%) was
Table 2. Optimization of the Intermolecular Cross-Coupling of
1a and 2aa
entry Pd-source (mol %)
oxidant
yield of 3a (%)
1
2
Pd(TFA)2/20
Ag2CO3 (3 equiv); O2
41
25
PdCl2(PhCN)2/20 Ag2CO3 (3 equiv); O2
PdCl2(PPh3)2/20 Ag2CO3 (3 equiv); O2
PdCl2(PPh3)2/10 Ag2CO3 (3 equiv); O2
PdCl2(PPh3)2/15 Ag2CO3 (3 equiv); O2
PdCl2(PPh3)2/15 AgOAc (3 equiv); O2
PdCl2(PPh3)2/15 Ag2CO3 (2.2 equiv); O2
PdCl2(PPh3)2/15 Ag2CO3 (3 equiv); air
PdCl2(PPh3)2/15 Ag2CO3 (3 equiv); Ar
PdCl2(PPh3)2/15 Ag2CO3 (3 equiv); O2
3
70b
51
4
5
73
Table 3. Pd-Catalyzed C-H Arylation of 1a with Substituted
Arenes 2b-ja
6
55
7
69
8
58
9
50
56c
10
a All reactions were performed with 0.5 mmol of 1a and 20 mmol of
2a in a sealed vial. b In addition, an unpolar product was observed that
could not be identified. c 20 equiv of 2a.
additives, including acetic acid and isovaleric acid,
proved to be less effective in producing 3a. However,
the yields of the desired product 3a could be improved
by gradually increasing the amounts of Pd(OAc)2: with
30 mol % of Pd(OAc)2 the product 3a was finally
formed in 75% yield (Table 1, entries 4-6). The experi-
ments clearly demonstrate that the best way to proceed
with the selective cross-coupling of 1a and 2a is by using
Pd(OAc)2 as the catalyst, a combination of Ag2CO3 and
O2 as oxidants, and pivalic acid as an additive (Table 1,
entries 1, 2, 7, and 8). In addition, we have also tested
reaction conditions that have been reported for double
C-H activations between (a) electron-deficient poly-
fluoroarenes and simple arenes,13a (b) electron-deficient
polyfluoroarenes and heteroaromatic compounds,13b
and (c) xanthines and heteroaromatic compounds.19
The results obtained for the reaction of 1a with 2a
clearly demonstrate that the reagents/reaction condi-
tions employed are not suitable for the successful
arylation of xanthines as the yields of the arylated
xanthine 3a did not exceed 20% (Table 1, entries 9-11).
Then we found that the cross-coupling reaction of 1a
and 2a was not restricted to using Pd(OAc)2 as a catalyst,
Scheme 2. Pd-Catalyzed C-H Arylation of N-Substituted
Xanthines 1b-d with 2a
a All reactions were performed with 0.5 mmol of 1a and 20 mmol of
2a in a sealed vial. b m/p = 1.25:1. c o/p = 1:4. d m/p = 3:2. e m/p = 2.5:1.
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Org. Lett., Vol. 13, No. 6, 2011

obtained when the reaction was performed with 15 mol %
of PdCl2(PPh3)2 and 3 equiv of each Ag2CO3 and pivalic
acid under an atmosphere of O2 (Table 2, entry 5). In
summary, two efficient catalytic systems based on Pd
catalysts have been identified which can be used for further
cross-coupling reactions.
revealed that the use of the PdCl2(PPh3)2-based protocol
produced lower yields of 3e-m. The formation of the
arylated xanthenes is notable for its excellent regio-
selectivity. This holds true for the selectivity toward both
the caffeine and the arenes. The only exceptions observed
were the transformations with the monosubstituted arenes
toluene (2b), anisole (2e), chlorobenzene (2h), and fluor-
obenzene (2i).
To summarize, the Pd-catalyzed direct C-H arylation of
unactivated xanthines with unactivated arenes has been
reported for the first time. This method allows for a highly
regioselective preparation of C-8 arylated xanthines in a single
step without previously activating the substrates. The aryla-
tion of xanthines is not restricted to benzene itself but may
also be conducted with mono-, di-, and trisubstituted arenes.
The next goal was to explore the scope of the method.
We started off with the application of the PdCl2(PPh3)2-
based protocol to the cross-coupling of various N-substi-
tuted xanthines 1b-d with benzene (2a) (Scheme 2). The
arylated xanthines (3b-d) were isolated in yields ranging
from 68% to 71%. As with all other transformations
presented no homocoupling products could be detected.
Then we focused on the reactions of 1a with different
substituted arenes 2b-j and found that a number of mono-,
di-, and trisubstituted arenes carrying methyl-, methoxy-,
chloro-, and fluoro-groups can be used to arylate caffeine (1a).
The arylated xanthines 3e-m could be isolated with yields
ranging from 47% to 73% (Table 3). These results clearly
demonstrate that the methodeasilytolerates bothelectron-
donating and electron-withdrawing groups. It should be
noted that most of these couplings were carried out with
Pd(OAc)2 as a catalyst after preliminary experiments
Acknowledgment. We thank S. Mika for NMR spectra
and H.-G. Imrich and C. Asta for mass spectra.
Supporting Information Available. Experimental de-
tails and spectra of all compounds. This material is
available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 6, 2011
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