Sp3C-H bond alkylation of ketones with alkenes via ruthenium(ii) catalysed dehydrogenation of alcohols

Article abstract of DOI:10.1039/c4cc00931b

The sp³C-H bond functionalisation of 2-pyridyl ethanols upon reaction with alkenes, in the presence of a [RuCl₂(arene)] ₂ catalyst and Cu(OAc)₂·H₂O, is performed under mild conditions without additional base. This reaction proceeds via a tandem alcohol dehydrogenation/alkylation with alkenes of the resulting ketone at its α sp³C-H bond. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00931b

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sp3C–H bond alkylation of ketones with alkenes
via ruthenium(II) catalysed dehydrogenation of
alcohols†
Cite this: Chem. Commun., 2014,
50, 5970
Received 4th February 2014,
Accepted 17th March 2014
Bin Li,‡ Christophe Darcel* and Pierre H. Dixneuf*
DOI: 10.1039/c4cc00931b
www.rsc.org/chemcomm
The sp3C–H bond functionalisation of 2-pyridyl ethanols upon reaction
with alkenes, in the presence of a [RuCl2(arene)]2 catalyst and Cu(OAc)2Á
H2O, is performed under mild conditions without additional base. This
reaction proceeds via a tandem alcohol dehydrogenation/alkylation
with alkenes of the resulting ketone at its a sp3C–H bond.
Scheme 1 Ru(II) catalysed dehydrogenation of 2-pyridyl alcohol and
tandem alkylation/condensation of 2-pyridyl ketone.
The functionalisation of sp3C–H bonds attracts interest in the
development of new synthetic methods and the fast building of often requires a coordinating directing group,8 we first considered
polyfunctional molecules,1 the easy modification of ligands or the the activation of coordinating 2-pyridyl alcohols, as some of
preparation of molecular luminescent and photochromic materials.2 their derivatives are bioactive,9,10 or constitute a class of useful
The direct catalytic functionalisation of sp3C–H bond via arylation at N,O-bidentate ligands in 5-membered cyclic metal complexes.11
the a position of the carbonyl of a ketone has been shown to be
Here we report the Ru(II) catalysed dehydrogenation of 2-pyridyl
promoted by palladium catalysts with strong base to generate the alcohols in the presence of Cu(OAc)2ÁH2O and the subsequent
enolate intermediate:1,3 the Pd(0)/diphosphine catalysed a-arylation alkylation at the a position of the resulting ketones with alkenes,
of ketones with aryl bromides has been initially performed by and with acrolein, the double alkylation and intramolecular aldol
Buchwald4 in the presence of NaOt-Bu, and by Hartwig5 using condensation, formally via sp3C–H bond functionalisation. We also
KN(SiMe3)2 as a base. However, recently, Lam reported a show that the 2-pyridyl ketone can be alkylated with alkene at the
ruthenium-catalysed oxidative annulation of 2-aryl-1,3-dicarbonyl a-position of the carbonyl using only Ru(OAc)2(p-cymene) catalyst
compounds with alkynes into spiroindenes via an easily generated but in the presence of isopropanol (Scheme 1).
enolate species.6
In an attempt to perform the competitive Ru(II) catalysed alcohol
To the best of our knowledge, the ruthenium(II) functionalisation dehydrogenation versus oxidative dehydrogenative alkenylation of
of sp3C–H bond at the b position of alcohols, by alkylation with the phenyl group12 of the N-coordinating benzyl 2-pyridyl alcohol 1a
alkenes, has not been reported yet, in spite of the well-established with methyl acrylate 2a, we first studied the action of [RuCl2-
hydrogen borrowing reactions especially using Ru(II) catalysts that (p-cymene)]2 as a pre-catalyst in the presence of carboxylates, and
are able to dehydrogenate alcohols via hydrido-ruthenium species Cu(OAc)2ÁH2O (1 equiv.) at 120 1C for 20 h, which surprisingly led to
formation.7 In the latter reactions generating aldehyde, alkylation the formation of a-alkylated ketone 3a (entries 1–2). Interestingly, in
can take place but via aldol condensation/hydrogenation.7g–j We thus the absence of an additive, 3a was produced in 53% yield (entry 3
became interested in investigating the consecutive catalytic alcohol and Table S1, ESI†). The reaction thus required the presence of both
dehydrogenation and neighbouring sp3C–H or sp2C–H bond func- [RuCl2(p-cymene)]2 and Cu(OAc)2ÁH2O (entries 4 and 5). Good results
tionalisation. As the C–H bond activation step by Ru(II) catalysts were obtained using only 0.8 equiv. of Cu(OAc)2ÁH2O without air
(entries 6 and 7 and Table S2, ESI†). Further experiments show that
an excess of 2a (4 equiv.) (entries 7 and 9) and a slight increase of the
ruthenium loading (7.5 mol%) (entry 10) improve the reaction
conversion up to 75%. It was found preferable to use only 5 mol%
of ruthenium catalyst for 36 h at 120 1C in 1,2-dichloroethane (DCE)
to reach 80% conversion and obtain 3a in a 68% isolated yield
(entries 11 and 12). Using Ru(OAc)2(p-cymene) as the catalyst is also
moderately operative with Cu(OAc)2ÁH2O (entry 13) (Table S3, ESI†).
´
UMR 6226 CNRS-Universite de Rennes 1 ‘‘Institut des Sciences Chimiques de
Rennes’’, Team ‘‘Organometallics: Materials and Catalysis’’, Centre for Catalysis
and Green Chemistry, Campus de Beaulieu, 35042 Rennes Cedex, France.
E-mail: christophe.darcel@univ-rennes1.fr, pierre.dixneuf@univ-rennes1.fr
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc00931b
‡ Present address: School of Chemical & Environmental Engineering, Wuyi
University, Jiangmen 529020, Guangdong Province, P.R. China.
5970 | Chem. Commun., 2014, 50, 5970--5972
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Scheme 3 Ru(II)-catalysed sp3 C–H alkylation of 2-pyridyl ethanol derivatives
with acrolein.
52–70% yields. The reaction was then extended to pyridyl
alcohols, having a benzyl group 1e (R2 = Bn, R3 = H) or alkyl
groups 1f (R2 = t-Bu, R3 = H) and 1g (R2 = R3 = Me) linked at the a
position of the hydroxyl group, and they afforded the derivatives
3l, 3m and 3n, respectively in 25–66% yields.
Scheme 2 Ruthenium(II) catalysed sp3C–H alkylation of 2-pyridyl methanol
derivatives with alkenes.
The reaction of 1a with 4 equiv. of acrolein under similar
conditions selectively led to the dicarbonyl cyclic derivative 4a in a
68% isolated yield (Scheme 3). This compound 4a results formally
from a double Michael addition to acrolein of the enolate of
ketone 5, arising from oxidation of 1a, followed by cyclisation via
intramolecular aldol condensation. The ketone 5 under the same
conditions does not lead to the formation of compound 4.
Analogously, the aryl substituted derivatives 4b–d were
obtained in 57–66% yields from the alcohols 1b–d. The alcohol
1e (R = Bn) similarly led to the derivative 4e in 37% yield,
resulting from C–C bond formations at the a carbon of the
ketone, rather than at the benzylic carbon. This reaction gives a
straightforward access to functional 2-pyridyl ketones containing
a conjugated formyl cyclohexene moiety.
The above reaction constitutes a straightforward way to
perform an alkylation at the a position of a coordinating ketone
starting from its alcohol. The conditions and results suggest
that the formation of 3 initially involves the dehydrogenation of
the alcohol 1 which generates a new active ruthenium species,
followed by a formal Michael addition of the enolate to the
alkene. First, we showed that only in the presence of both
[RuCl2(p-cymene)]2 and Cu(OAc)2ÁH2O, the alcohol 1a was
transformed into the (2-pyridyl)benzyl ketone 5 (eqn (1)) (see
also ESI,† Scheme S2).
Table
1
Ruthenium(II)-catalysed sp3 C–H bond alkylation of benzyl
2-pyridyl methanol 1a with methyl acrylate 2aa
Cu(OAc)2ÁH2O Conv.b
Entry 2a (equiv.) Additive
(equiv.)
(%)
1
2
3
4
5
6
2
2
2
2
2
2
4
4
6
4
4
4
4
C6H5CO2H (20 mol%)
C6H5CO2K (20 mol%)
1
1
1
0
52
57
53
—
—
i
—
— (no Ru catalyst)c
1
—
i
—
—
—
—
—
—
—
—
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
56
69(46)
9
72
75
80(68)
74(54)
60
7
8d
9
10e
11f
12g
13h
a
1a (0.25 mmol), 2a (2–6 equiv.), [RuCl2(p-cymene)]2 (5 mol%), additive
(20 mol%), Cu(OAc)2ÁH2O (0.8–1 equiv.), DCE (2 mL), 120 1C, 20 h. b Detected
by GC, in parentheses, isolated yields of 3a. c Without Ru catalyst. d Under
air. e 7.5 mol% of [RuCl2(p-cymene)]2. f Run in 0.5 mmol scale, 36 h. g In
toluene, 150 1C. h 10 mol% of [Ru(OAc)2(p-cymene)] was used. i Less than
5% of ketone 2-PyCOCH2Ph was formed.
We first explore the scope of the reaction with 1a (Scheme 2)
without addition of another base than the Cu(OAc)2 released
acetate.
(1)
Using the optimised conditions (Table 1, entry 11), the influence
of various activated alkenes was explored. In reaction of 1a with
The alkylation of the ketone 5 with methyl acrylate 2a was
various acrylates 2a–2d, the alkylated ketones 3a–3d were obtained then attempted: by action of both [RuCl2( p-cymene)]2 (5 mol%)
in 51–68% isolated yields. The same reaction took place easily with and Cu(OAc)2 (0.8 equiv.), but in the presence of i-PrOH
acrylonitrile 2e and N-isopropyl-acrylamide 2f to give 3e (57%) and (2 equiv.), the alkylated ketone 3a was obtained in only 10%
3f (50%). The reaction with p-bromostyrene, led to a small amount GC-yield (eqn (2)). However, when this reaction was performed
of 3g (12%) showing that electrophilic alkenes are more efficient. It in the presence of 10 mol% of Ru(OAc)2( p-cymene) in i-PrOH
is noteworthy that the reaction of 1a with the unsaturated ketone at 100 1C without addition of Cu(OAc)2, 3a was obtained in 56%
containing a disubstituted CQC bond CH3CHQCHCOt-Bu 2h, GC-yield. However, in DCE instead of isopropanol the alcohol
regioselectively affords the alkylated ketone 3h in 70% yield.
1f (R2 = p-F-C6H4; R3 = H) with Ru(OAc)2( p-cymene) but without
The reaction of aryl substituted derivatives 1b–d was then Cu(OAc)2ÁH2O leads only to 30% yield of 3j (see ESI,† Scheme S3).
performed under similar conditions. It led to ketones 3i–k in These results indicate that the key catalytic species arises from
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Notes and references
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Scheme 4 Proposed mechanism.
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and a Ru–H(OAc)Ln species.7,13 This latter species with the
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10 V. A. Barbosa, A. S. N. Formagio, F. C. Savariz, M. A. Foglio,
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from Ru(OAc)2( p-cymene) and isopropanol, likely the
Ru(H)(OAc)(arene) intermediate,13 which can deprotonate the
ketone more easily than Ru(OAc)2( p-cymene)16 and thus would
favour the Michael type reaction leading to product 3. These
processes involve the formal generation of hydrogen that can
be trapped by the excess of alkene.
13 The Ru–H intermediate was observed by the reaction of Ru(OAc)2-
( p-cymene) (0.1 mmol) with 2 mL of isopropanol at 80 1C for 20 h:
a mixture of ruthenium-hydride species was formed as indicated in
1H NMR by a major singlet at d = À13.87 ppm and two weaker
signals at d = À7.52 and À8.34 ppm.
In summary, we have described a mild procedure to perform b
sp3C–H bond functionalisation of (2-pyridyl)ethanol derivatives by
reaction with activated alkenes in the presence of a [RuCl2(arene)]2
catalyst and of Cu(OAc)2ÁH2O, without additional base. This reaction
proceeds by a tandem dehydrogenation of coordinating alcohol and
the alkylation with electrophilic alkenes of the resulting ketone.
Interestingly, when acrolein was used as the activated alkene, double
alkylation took place and led to original 3-formylcyclohex-3-en-1-yl
14 [RuCl2( p-cymene)]2 in the presence of KOAc or Cu(OAc)2 leads to the
formation of Ru(OAc)2( p-cymene)15
.
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ketone derivatives. This tandem reaction which can be profitably 16 E. Ferrer-Flegeau, C. Bruneau, P. H. Dixneuf and A. Jutand, J. Am.
Chem. Soc., 2011, 133, 10161.
17 Cu(II) species were shown to act as Lewis acid to activate unsatu-
promoted by Ru(OAc)2(arene) in iPrOH offers potential for further
mechanistic investigations, creation of new catalysts and applica-
rated ketones M. Zhang, H.-F. Jiang, H. Neumann, M. Beller and
tions that are currently underway.
P. H. Dixneuf, Angew. Chem., Int. Ed, 2009, 48, 1681.
5972 | Chem. Commun., 2014, 50, 5970--5972
This journal is ©The Royal Society of Chemistry 2014