C-H bond oxidation initiated pummerer- And knoevenagel-Type reactions of benzyl sulfide and 1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/ol702934k

A novel Pummerer-type reaction was developed via o-chloranil-mediated C-H bond oxidation. The reaction provides a simple and efficient method to construct sulfide derivatives. A Knoevenagel-type reaction was also achieved via multiple C-H bonds activation under neutral reaction conditions.

Full text of DOI:10.1021/ol702934k

ORGANIC
LETTERS
2008
Vol. 10, No. 5
803-805
C−H Bond Oxidation Initiated
Pummerer- and Knoevenagel-Type
Reactions of Benzyl Sulfide and
1,3-Dicarbonyl Compounds
Zhiping Li,* Haijun Li, Xingwei Guo, Lin Cao, Rong Yu, Huanrong Li, and
Shiguang Pan
Department of Chemistry, Renmin UniVersity of China, Beijing 100872, China
zhipingli@ruc.edu.cn
Received December 6, 2007
ABSTRACT
A novel Pummerer-type reaction was developed via o-chloranil-mediated C−H bond oxidation. The reaction provides a simple and efficient
method to construct sulfide derivatives. A Knoevenagel-type reaction was also achieved via multiple C−H bonds activation under neutral
reaction conditions.
Selective and efficient activation of C-H bonds to generate
functional molecules with minimal energy, cost, and envi-
ronment impacts is one of the challenging research areas in
synthetic chemistry.1,2 Among the C-H functionalizations,
activation of the C-H bond adjacent to a heteroatom (such
as N or O) has been widely investigated because the success
of such a method could lead to future efficient synthesis of
natural products and pharmaceuticals with heteroatoms
imbedded.3 However, all reported methods in this line have
their limitations. For example, usually one or two transition
metal catalysts have to be used in these transformations. In
addition, the heteroatoms in the substrates are restricted to
oxygen and nitrogen atoms. Therefore, developing metal-
free activation of a C-H bond adjacent to a heteroatom
ranging from oxygen4 and nitrogen to sulfur and other atoms
would advance the state of the art of today’s C-H bond
functionalization.
The Pummerer reaction is one elegant synthetic method
to functionalize a C-H bond adjacent to a sulfur atom and
has been widely applied in the synthesis of natural products
and biologically active compounds.5 However, in the classical
Pummerer reactions, sulfoxide starting materials and harsh
acidic initiators have to be used (Scheme 1). Therefore, to
expand the scope of the Pummerer reaction, efforts focused
on novel ways to generate thionium intermediates from
sulfides have been undertaken.6,7 The most challenging part
in this regard resides in developing a novel way that can
generate thionium intermediates or their equivalents from
(1) (a) Bergman, R. G. Nature 2007, 446, 391. (b) Godula, K.; Sames,
D. Science 2006, 312, 67. (c) Handbook of C-H Transformations; Dyker,
D., Ed.; Wiley-VCH: Weinheim, 2005.
(2) For representative reviews, see: (a) Crabtree, R. H. J. Organomet.
Chem. 2004, 689, 4083. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV.
2002, 102, 1731. (c) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res.
2001, 34, 633. (d) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698. (e)
Shilov, A. E.; Shul’pin, G. B. Chem. ReV. 1997, 97, 2879.
(3) (a) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006,
103, 8928. (b) Zhang, Y.; Li, C.-J. Angew. Chem., Int. Ed. 2006, 45, 1949.
(c) Wan, X.; Xing, D.; Fang, Z.; Li, B.; Zhao, F.; Zhang, K.; Yang, L.;
Shi, Z. J. Am. Chem. Soc. 2006, 128, 12046. (d) Maruyama, T.; Suga, S.;
Yoshida, J.-I. J. Am. Chem. Soc. 2005, 127, 7324. (e) DeBoef, B.; Pastine,
S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126, 6556. (f) Murahashi, S.-I.;
Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc. 2003, 125, 15312. (g)
Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai, S.
J. Am. Chem. Soc. 2001, 123, 10935. (h) Yoshida, J.-I.; Suga, S.; Suzuki,
S.; Kinomura, N.; Yamamoto, A.; Fujiwara, K. J. Am. Chem. Soc. 1999,
121, 9546.
(4) DDQ-mediated C-H bond activation was reported: Zhang, Y.; Li,
C.-J. J. Am. Chem. Soc. 2006, 128, 4242.
(5) (a) Feldman, K. S. Tetrahedron 2006, 62, 5003. (b) Bur, S. K.; Padwa,
A. Chem. ReV. 2004, 104, 2401.
(6) Feldman, K. S.; Violulova, D. B. Tetrahedron Lett. 2004, 45, 5035.
10.1021/ol702934k CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/01/2008

Table 1. o-Chloranil-Mediated Pummerer-Type Reactionsa
Scheme 1. Classic Pummerer Reaction
sulfides under mild and neutral reaction conditions, which
are also compatible with nucleophilic addition reaction at
the same time. Herein, we wish to report our endeavor to
develop a metal-free activation of a C-H bond adjacent to
sulfur that can efficiently generate Pummerer-type products
when o-chloranil (tetrachloro-o-benzoquinone) was used as
the oxidant (Scheme 2).
Scheme 2. o-Chloranil-Mediated Pummerer- or
Knoevenagel-Type Reactions
To begin our study, ethyl 3-oxo-3-phenylpropanoate 1a
and benzyl methyl sulfide 2a were chosen as the standard
substrates to search for suitable reaction conditions. After
many failures, we found that the desired product 3a was
obtained in 87% isolated yield in 30 min by using 1.5 equiv
of o-chloranil as an oxidant at 80 °C (Table 1, entry 1).8
Subsequently, various substrates were tested under the
optimized conditions, and some representative results are
shown in Table 1. When benzyl phenyl sulfide 2b and
dibenzyl sulfide 2c were used, 3b and 3c were obtained in
87% and 70%, respectively (Table 1, entries 2 and 3). It
should be noted that monoalkylation product 3c was the only
isolated product. The desired products were also obtained
with good isolated yields when 1, 3-diketones 1b and 1c
reacted with sulfides (Table 1, entries 4-8). Interestingly,
4a, a Knoevenagel-type condensation product, was formed
in 12% yield together with the oxidative product 3g obtained
in 77% yield (Table 1, entry 7).
Subsequently, we optimized the reaction conditions aiming
to obtain the Knoevenagel-type condensation products
selectively. Studies showed that the yield of 4a was increased
up to 81% together with 19% yield of 3g in the presence of
3.0 equiv of o-chloranil, at 100 °C (Table 2, entry 1). When
2b and 2c were used, 4a was exclusively obtained in 97%
and 93% yields and no Pummerer-type oxidative coupling
products 3 were observed (Table 2, entries 2 and 3). When
1a was used, 4b was obtained in excellent yields (Table 2,
entries 4-6). The desired products 4 were also obtained with
good to excellent yields when cyclic substrate 1d and
â-ketoimide 1e were used (Table 2, entries 7-10). 2,4-
a 1 (0.25 mmol), 2 (1.5 mmol), and o-chloranil (0.38 mmol) were used.
b Isolated yields are reported, and the ratios of two diastereomers are reported
in the parentheses. c 4a was obtained in 12%.
Pentadione 1g reacted with 2b and 2c to give Knoevenagel-
type product 4f in 62% and 80% yields, respectively (Table
2, entries 12 and 13). However, the corresponding Pummerer
product 3i was also obtained in 28% when 2b was used
(Table 2, entry 12). In all entries in Table 2, products 4 were
obtained as single regioisomer when unsymmetrical dicar-
bonyl compounds were used.
A tentative mechanism of the o-chloranil-mediated Pum-
merer-type and Knoevenagel-type reactions is shown in
Scheme 3. C-H oxidation of 2 by o-chloranil gives a
thionium intermediate, 5a,9 which could also exist as a
neutral species, 5b, in which a possible weak C-O bond is
formed between the two charged moieties in 5a. Nucleophilic
addition of 5a to 1 then generates the coupling product 3.10
If excess o-chloranil is used, compound 3 is transformed to
product 4 via the C-S bond cleavage.11
(7) An alternative method for generation of the thionium precursor,
hemithioacetal, is based on the addition of thiols to glyoxamide; see:
McAllister, L. A.; McCormick, R. A.; Brand, S.; Procter, D. J. Angew.
Chem., Int. Ed. 2005, 44, 452.
(8) No desired product was obtained when p-fluoranil, p-chloranil, and
p-bromanil were used as oxidants under the same reaction conditions.
(9) One of possibilities of C-H bond oxidation is initiated by single
electron transfer from sulfur to quinone; see: Gorner, H. Photochem.
Photobiol. 2006, 82, 71.
804
Org. Lett., Vol. 10, No. 5, 2008

Table 2. o-Chloranil-Mediated Knoevenagel-Type Reactionsa
Scheme 3. Tentative Mechanism for the o-Chloranil-Mediated
C-H Bond Oxidation Initiated C-C Bond and CdC Formation
The metal-free, neutral, and mild reaction conditions make
these attractive reactions for potential applications. The
scope, mechanism, and synthetic application of these reac-
tions are under investigation.
Acknowledgment. We are grateful to the Scientific
Research Starting Foundation of Renmin University of China
(to Z.L.) and the National Natural Science Foundation of
China (no. 20602038). We also thank Prof. Zhenfeng Xi and
Prof. Zhi-Xiang Yu, Peking University, for helpful discus-
sions.
Supporting Information Available: Representative ex-
perimental procedure, characterization of all new compounds
and 1H NMR and 13C NMR data. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Compounds 1 (0.25 mmol) and 2 (1.5 mmol) and o-chloranil (0.75
mmol) were used unless otherwise noted. b Isolated yields are reported.c 2
equiv of o-chloranil was used; 3 g was obtained in 19%. d 2 equiv of
o-chloranil was used; 120 °C. e 2 equiv of o-chloranil was used. f Compound
3i was obtained in 28%.
OL702934K
(10) This step is reversible. Compound 3e was obtained as a major
product by the reaction of 3d and 2b. Oxidative cleavage benzylic C-C
bonds assisted by heteroatoms: Wang, L.; Seiders, J. R., II; Floreancig, P.
E. J. Am. Chem. Soc. 2004, 126, 12596.
(11) Compound 3a was transformed into 4b in 93% isolated yield at
100 °C for 8 h in the presence of 2 equiv of o-chloranil. For related examples
of C-S bond cleavage, see: (a) Baciocchi, E.; Del, Giacco, T.; Giombolini,
P.; Lanzalunga, O. Tetrahedron 2006, 62, 6566. (b) Mukaiyama, T.;
Narasaka, K.; Hokonok, H. J. Am. Chem. Soc. 1969, 91, 4315.
In summary, a novel Pummerer-type reaction and a
Knoevenagel-type reaction have been developed via a metal-
free C-H bond oxidation strategy. The high selectivity of
the reactions is achieved by controlled reaction conditions.
Org. Lett., Vol. 10, No. 5, 2008
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