DOI: 10.1002/cssc.201100744
Ruthenium-catalyzed [2+2+2] Cycloaddition of Diynes with Nitriles in Pure
Water
Fen Xu, Chunxiang Wang, Xincheng Li, and Boshun Wan*[a]
The transition metal-catalyzed [2+2+2] cycloaddition of two
alkyne molecules and a nitrile, particularly involving catalysis
by Co, Ru, Rh, Ni, Ti, and Fe species,[1–6] has been widely inves-
tigated as a valuable tool for the synthesis of substituted pyri-
dines.[7,8] However, highly diluted conditions and techniques of
slow addition are generally required to suppress the compet-
ing side reactions, such as dimerization and trimerization of
the diynes.[9a] Despite substantial advances, metal-catalyzed
[2+2+2] cycloaddition remains a formidable challenge. Thus,
new tactics should be applied to the reaction, aimed at attenu-
ating or controlling the side reactions. It has been shown that
the Diels–Alder reaction can be intensified in aqueous
media,[9b] and we expect that water can also expedite the
[2+2+2] cycloaddition.
with a yield of up to 99%. However, hydrophilic functional
groups on the alkynes were necessary.[12] In 2002, Butenschçn
reported another cobalt complex with pendant phosphane
substituents on the cyclopentadienyl ring. These substituents
made the cobalt complex stable in water, thus allowing the
preparation of pyridine derivatives at room temperature in
a mixture of water and ethanol.[13] In aqueous medium, acceler-
ation of the cycloaddition by water should outweigh the low-
ered efficiency and reaction rate due to the highly dilute reac-
tion conditions.[9] In addition, water can induce rate enhance-
ments,[14] chemoselectivity,[15] and stereoselectivity[16] in numer-
ous synthetic transformations. However, to the best of our
knowledge mixed solvents or photochemical activation were
necessary in previous works, and the cycloaddition of diynes
and a nitrile in neat water without irradiation has never been
reported. The development of a new catalytic system to cir-
cumvent these restrictions is still highly desirable.
Although the [2+2+2] cycloaddition reaction has been
widely explored in the last few decades, there are only limited
examples of the use of water as solvent (Scheme 1). Heller and
Generally, two crucial problems are encountered in the
[2+2+2] cycloaddition of alkynes and nitriles in water: 1) the
poor solubility of the metal precursor and substrates in pure
water, and 2) easy hydrolysis of the nitriles in water under the
reaction conditions.[17] To overcome these issues, we surmised
that a water-soluble ligand might connect the metal precursor
and substrates in the aqueous phase, and that hydrolysis of
the nitriles could be somewhat inhibited by choosing an ap-
propriate temperature. Very recently, we reported an iron-cata-
lyzed [2+2+2] cycloaddition of alkynes and nitriles involving
an in situ-generated iron catalyst.[6a] However, the moisture
sensitivity of this catalytic system hampered further investiga-
tions in aqueous medium. Inspired by recent advances in
ruthenium-catalyzed cycloadditions (ruthenium being in the
same group of the periodic table as iron),[2] we hoped that this
metal-based catalyst might effectively promote the transforma-
tion of alkynes and nitriles in water to afford the desired pyri-
dine products. Herein, we report the first example of efficient
and selective ruthenium-catalyzed pyridine formation by
[2+2+2] cycloaddition of diynes and nitriles with yields up to
87% in pure water, the most environmentally benign solvent.
The [2+2+2] cycloaddition in Table 1 was conducted in pure
water at 508C[18] using diyne 2a and chloroacetonitrile 3a as
representative reactants, without photochemical activation. Be-
cause of the poor solubility of Cp*Ru(COD)Cl 1 in water, hydro-
philic phosphine ligand was added to prepare a new rutheni-
um catalyst, soluble in the aqueous phase, in situ.[19] To im-
prove the catalytic efficiency, different hydrophilic phosphine
ligands were examined. As described in Table 1, the trisodium
salt of tris(m-sulfonatophenyl) phosphine (tppts) L1 afforded
the product in 72% yield (entry 1). Txpts L2, which is highly
soluble in water, afforded the desired product 4aa in only
27% yield because steric hindrance prevented formation of
Scheme 1. Methods for the synthesis of pyridines in aqueous medium.
co-workers reported that acetylene and nitriles in water effi-
ciently undergo co-cyclization under visible-light irradiation in
the presence of CpCo(COD) (COD: 1,5-cyclooctadiene) and its
derivatives, resulting in excellent product selectivities and
moderate yields.[10] Parsons and Jerome reported a reaction of
hexyne and acetonitrile in supercritical water at 3748C, afford-
ing the corresponding pyridine isomers in a yield of 15%.[11]
Eaton and co-workers showed that a water-soluble cobalt com-
plex catalyzes the [2+2+2] cycloaddition of two alkyne mole-
cules and a nitrile in a mixture of water and methanol at 858C,
[a] F. Xu, C. Wang, Dr. X. Li, Prof. Dr. B. Wan
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023 (PR China)
Fax: (+86) 0411-84379223
Supporting Information for this article is available on the WWW under
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ChemSusChem 2012, 5, 854 – 857