Angewandte
Chemie
Table 2: Scope of the catalytic alkene–alkyne coupling.[a]
and gave a complex mixture of products.[18] Nevertheless,
coupling between 4a and phenylacetylene was effectively
catalyzed by 2a to form 5v with E,E stereoselectivity in 65%
yield upon isolation.[14b]
Three types of reaction mechanisms have been proposed
for ruthenium-catalyzed alkene–alkyne couplings to form 1,3-
dienes:[14,19] 1) C C bond formation by alkene–alkyne oxida-
ꢀ
tive cyclization (Scheme 2), followed by b-hydride elimina-
ꢀ
tion and C H reductive elimination (Path 1); 2) alkyne
insertion into a ruthenium hydride, followed by alkene
insertion into the resulting ruthenium–alkenyl bond and
2
ꢀ
subsequent b-hydride elimination (Path 2); 3) sp C H bond
activation of an alkene, followed by alkyne insertion into the
ꢀ
ruthenium–alkenyl bond, and C H bond formation by either
ꢀ
reductive elimination or protonation of the Ru C bond
(Path 3). Although the latter two pathways cannot be
completely ruled out, the oxidative cyclization mechanism
(Path 1) is most consistent with the observed regio- and
stereochemistry in coupling products. In particular, high
regioselectivity with nonsymmetric alkyne substrates (5k–s)
[a] Reaction conditions: 3 (0.20 mmol, 1.0 equiv), 4 (2.0 equiv), 1a
(0.050 equiv), toluene (0.5 mL), 20–228C, 24 h. The reported yields are
an average of the yields of the isolated products from two runs. [b] Yield
of isolated product under scale-up conditions: 3 (20 mmol, 1.0 equiv), 4
(2.0 equiv), 1a (0.010 equiv), toluene (6.0 mL), 228C, 48 h. [c] Using 2a
as catalyst precursor. [d] Reactions at 608C. [e] Combined yield of two
regioisomers (ratios determined by NMR analysis). The structure of the
major isomer is shown. [f] Using 0.20 mmol methyl acrylate as limiting
reagent and 2.0 equiv of alkyne. [g] Yield of the isolated major stereo-
isomer, which was isolated from a 5:1 mixture; minor isomer was not
purified.
ꢀ
supports C C bond formation by either oxidative cyclization
(Path 1) or alkyne insertion into a ruthenium–alkenyl bond
[19]
ꢀ
(Path 3), and not by alkyne insertion to Ru H (Path 2).
The complete lack of 2Z stereoisomers as coupling products
also argues against the proposed alkene C H activation
stereochemistry in Path 3, which should favor 2Z isomers by
ꢀ
ꢀ
ester- or amide-directed C H activation/cyclometalation.
The proposed oxidative cyclization pathway has prompted
ꢀ
us to extend our study to other mechanistically related C C
coupling product 5e, the yield was improved from 58% to
87% by replacing 1a with 2a as the catalyst precursor. Such
reactivity enhancement is likely due to facile catalyst
activation by substrate replacement of the more labile
pyridine ligands compared to the chelating diene ligand.
When coupling between 3a and 4a was scaled up from
0.2 mmol to 20 mmol, the loading of 1a could be reduced to
1.0 mol% to acquire 5a in 90% yield upon isolation (4.8 gram
purified product) after a reaction time of 48 h. Coupling
between 3a and N,N-dimethyl acrylamide gave the product
5g in 72% yield, but heating at 608C was needed to improve
the yield of the N,N-diethyl product 5h to 85%. Compared to
less reactive N,N-dialkylacrylamides, N-isopropyl- and N-tert-
butylacrylamide reacted with 3a in good reactivity to form the
products 5i and 5j, respectively, although the latter required
2a as the catalyst precursor for satisfactory yield. The scope of
alkyne substrates was studied by coupling reactions with
methyl acrylate (4a) to give the products 5k–v. High
reactivity and regioselectivity was observed for phenylacety-
lene derivatives with alkyl substituents (5k–s), thus favoring
the formation of the 4-alkyl-5-aryl regioisomer in greater than
10:1 selectivity. The mild reaction conditions allow good
compatibility with functional groups such as acyl, formyl, and
Br substituents (5p, 5r and 5s), thus providing synthetic
handles for further functional-group transformations. Ali-
phatic internal alkynes such as 3-hexyne and 4-octyne
displayed lower reactivity than aromatic alkynes, and a 2:1
alkyne/acrylate stoichiometry was used to obtain the coupling
products 5t and 5u in moderate yields. Coupling between 4a
and terminal alkynes generally suffered from low reactivity
couplings using the current catalyst system. Thus, 1a was
found to catalyze the room-temperature dimerization of
methyl acrylate with high efficiency and exclusive tail-to-tail
regioselectivity [Eq. (1)].[17] In addition, a [2+2] norbornene/
alkyne cycloaddition was effectively catalyzed by 1a at 1208C
[Eq. (2)], which further supports the proposed RuII/RuIV
catalytic cycle involving oxidative cyclization.[19,20]
In summary, we have developed a new class of bis(cyclo-
metalated) ruthenium(II) catalyst precursors with readily
available h2-[C,X] ligands derived from aromatic NH keti-
mines and ketones. The catalytic activity of the bis(imine)
ꢀ
complex 1a was evaluated in several catalytic C C coupling
reactions which are proposed to proceed by RuII/Ru(IV)
catalytic cycles involving oxidative cyclization. A room-
temperature alkene–alkyne coupling was promoted to form
a,b,g,d-unsaturated esters and amides with high regio- and
stereoselectivities, good functional-group tolerance, and very
high catalyst efficiency in a representative gram-scale syn-
thesis. The major limitation of the current catalyst system is
the limited scope of alkene substrates,[21,22] and we aim to
improve this scope through a more systematic study on
structure–reactivity correlations of bis(cyclometalated) ruth-
enium(II) complexes with various h2-[C,X] ligands.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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