Ruthenium-catalyzed three-component coupling via hydrative conjugate addition of alkynes to alkenes: One-pot synthesis of 1,4-dicarbonyl compounds

Article abstract of DOI:10.1002/asia.201100266

A catalytic three-way rendezvous: Terminal alkynes undergo metal vinylidene formation, anti-Markovnikov hydration to give a metal acyl complex, and conjugate addition to produce synthetically useful 1,4-dicarbonyl compounds under ruthenium catalysis. This one-pot three-component coupling reaction is a useful platform for further exploration in alkyne functionalization.

Full text of DOI:10.1002/asia.201100266

COMMUNICATION
DOI: 10.1002/asia.201100266
Ruthenium-Catalyzed Three-Component Coupling via Hydrative Conjugate
Addition of Alkynes to Alkenes: One-Pot Synthesis of 1,4-Dicarbonyl
Compounds
Yiyun Chen,[b] Sung Hwan Park,[a] Chung Whan Lee,[a] and Chulbom Lee*[a]
Dedicated to Professor Eun Lee on the occasion of his retirement and 65th birthday
The addition reaction of alkynes catalyzed by transition
metals is a useful method for the formation of a wide variety
of carbon–carbon and carbon–heteroatom bonds.[1] A readi-
ly conceivable merit of this powerful process is the prospect
of carrying out multicomponent coupling reactions by cap-
turing the incipient metal alkenyl intermediate for further
bond formations. While an array of such strategies has
Scheme 1. Ruthenium-catalyzed three-component coupling reaction.
indeed been practiced utilizing the 1,2-addition of transition
metal alkyne p-complexes,[2] a less common approach in-
volves a 1,1-addition, wherein an alkyne engages in the mul-
ticomponent reaction (MCR) process through catalysis
mediated by a metal vinylidene complex. In our previous
studies, this type of geminal addition was demonstrated to
be feasible in intramolecular settings, thus leading to the de-
velopment of a range of novel addition–cyclization reac-
tions.[3] We questioned if the same mechanistic mode could
be operative in intermolecular processes, thus achieving
carbon–carbon bond formation between an alkyne and an
alkene with concomitant addition of water (Scheme 1).
Herein we report the results of our investigation of a ruthe-
nium-catalyzed hydrative conjugate addition of alkynes to
alkenes that affords 1,4-dicarbonyl compounds. This three-
component reaction represents a process of high atom econ-
omy, which furnishes a product of well established utility.[4]
Based on the findings from the hydrative cyclization in
which [Ru3Cl5ACTHNUTRGEN(UNG dppm)3]PF6 (dppm=bis(diphenylphosphino)-
methane) proved to be the most effective catalyst,[3a] our in-
vestigation started with testing the efficacy of this trinuclear
ruthenium complex in the reaction of 4-phenylbutyne (1a),
water, and methyl vinyl ketone (2a; Scheme 2). Subjecting
the mixture of 1a and 2a (5 equiv) in wet dioxane (1:2=v/
v) to the same reaction conditions employed for the cycliza-
tion process gave the desired 1,4-diketone 3aa in 29% yield.
However, monoketones 4aa (14%) and 5a (7%) were also
generated, which presumably arose from simple two-compo-
nent reactions, Michael addition and Markovnikov hydra-
tion,[5,6] respectively. In contrast, the reactions using rutheni-
[a] S. H. Park, C. W. Lee, Prof. C. Lee
Department of Chemistry
Seoul National University
599 Gwanak-ro, Gwanak-gu, Seoul 151-742 (Korea)
Fax : (+82)2-889-1568
um complexes such as [CpRu
(PRPh2)2A(CH3CN)]PF6
ACHTUNGTRENNUNG
E-mail: chulbom@snu.ac.kr
N
CHTUNGTRENNUNG
[b] Dr. Y. Chen+
butylpyridine)[8] known to mediate vinylidene catalysis did
not produce diketone 3aa but induced anti-Markovnikov hy-
dration to give aldehyde 6a in low yield, whilst recovering
unreacted alkyne 1a.
Department of Chemistry
Princeton University
Princeton, NJ 08544 (USA)
[+] Current address:
Howard Hughes Medical Institute
Department of Chemistry and Chemical Biology
Harvard University
With the initial results, we set out to optimize the trinu-
clear complexes [Ru3Cl5ACHTNUGTRENUNG(dppm)3]X (X=Cl, PF6) and exam-
ine whether they are active catalysts or simply precursors of
12 Oxford Street, Cambridge, MA 02138 (USA)
mononuclear complexes.[9] Thus, the trinuclear complex
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100266.
[Ru3Cl5ACHTNUTRGENNG(U dppm)3]Cl was heated at reflux in acetonitrile to
2000
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Chem. Asian J. 2011, 6, 2000 – 2004

With the mononuclear ruthe-
nium complex 7 in hand, the
scope of the three-component
reaction was evaluated with an
assortment of alkynes and a,b-
unsaturated carbonyl com-
pounds. As summarized in
Table 1, the new catalyst
proved to be effective in the hy-
drative Michael addition of a
Scheme 2. Ruthenium-catalyzed hydrative conjugate addition of alkyne to enone.
variety of terminal alkynes to
conjugated ketones and alde-
obtain the mononuclear complex [RuCl
(7) as a yellow solid in 65% yield (Scheme 3). Alternatively,
the same complex 7 could also be prepared in higher yield
from the reaction of [RuCl2ACHTNUTRGENNUG(p-cymene)]2 with dppm in ace-
tonitrile. An X-ray crystallographic analysis revealed com-
(dppm)
E
hydes to furnish 1,4-dicarbonyl compounds as products. In
general, alkyl-substituted alkynes gave rise to 1,4-diketones
3 as the major or exclusive products, whereas simple alkyne
Michael addition adducts 4 were preferentially formed from
the reactions of alkenyl and aryl alkynes (Table 1, entries 5–
7).[11] The reaction conditions were tolerant of a range of
functional groups such as ethers, nitriles, esters, carboxylic
acids, alcohols, enones, and imides. In the case of an alkyne
with propargylic branching (e.g. 1d, Table 1, entry 4), the re-
action was sluggish and afforded 1,4-diketone 3da in low
yield with no alkynyl ketone formation. While 1,5-enyne 1m
produced 1,4-diketone 3ma in 55% yield without cycliza-
tion, interestingly, the reaction of demethylated free alcohol
1n led to the formation of alkynone 4na as the sole product
in 63% yield; this suggests a possible influence of the allylic
alcohol on the partition between ruthenium alkynyl and vi-
nylidene reaction manifolds (Table 1, entry 13 vs. 14). Ethyl
vinyl ketone (2b) exhibited reactivity similar to that of
methyl vinyl ketone (2a; Table 1, entry 15). With the more
reactive phenyl vinyl ketone acceptor (2c),[12] the reaction
gave only the diketone 3ac product (Table 1, entry 16). By
contrast, alkynylation was a dominant pathway when the
same alkyne was treated with acrolein (2d; Table 1,
entry 17). Except for the reaction of 1l (Table 1, entry 12),
the formation of simple hydration products (e.g. 5 and 6)
was negligible (<5%) in all cases.
plex 7 to be a C2v-symmetric octahedral complex with a
Scheme 3. Synthesis of ruthenium catalyst [RuCl2ACHTNUTRGNENU(G dppm)ACHTUNGTERN(NUNG NCCH3)2] (7).
square-planar disposition of dppm and chlorine ligands
(Figure 1).[10] Gratifyingly, the new ruthenium complex was
found to be more effective in the three-component coupling
as shown in Scheme 1; the desired 1,4-diketone 3aa was
formed in 65% yield with formation of the alkynylation
product 4aa in only 6% yield. It was noteworthy that nei-
ther simple alkyne hydration product (e.g. 5a or 6a) was
generated in this reaction.
The ruthenium-catalyzed three-component coupling reac-
tion could also be expanded to include conjugate enoates as
acceptors (Table 2). The reaction of alkyne 1a with methyl,
ethyl, phenyl, and tert-butyl acrylates 8a–d proceeded well
to provide a mixture of g-keto esters 9 and acid 10 in 58–
68% combined yield. In contrast to the reactions of conju-
gate enones and enals (compare Table 1), the formation of
an alkynylation adduct (e.g. 4) was suppressed. A set of con-
trol experiments established that acid 10 arose from esters 9
under the reaction conditions, most likely through facilitated
hydrolysis, owing to the anchimeric assistance of the g-keto
group.[13,14]
A plausible mechanism for the ruthenium-catalyzed hy-
drative conjugate addition is presented in Scheme 4. The
catalytic cycle may be initiated with coordination of the
alkyne with a ruthenium complex derived from 7. Among
the viable complexation modes of a terminal alkyne, the for-
mation of vinylidene complex A can lead to anti-Markovni-
kov hydration, while s-complex B and p-complex C undergo
Figure 1. X-ray single crystal structure of [RuCl2ACHTNUTRGNENU(G dppm)ACHTUNGTERN(NUNG NCCH3)2](7).
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C. Lee et al.
COMMUNICATION
Table 1. Ruthenium-catalyzed hydrative addition of alkynes to enones
and enals.
Table 2. Ruthenium-catalyzed hydrative conjugate addition of alkyne to
acrylates.
Entry[a]
Acrylate (8)
g-Keto ester 9[b]
g-Keto acid 10[b]
Entry[a] Alkyne
1
Alkene 3[b]
4[b]
1
2
3
4
methyl acrylate
G
41%
45%
30%
31%
A
17%
19%
32%
37%
ethyl acrylate
phenyl acrylate
tert-butyl acrylate
E
ACHTUNGTRENNUNG
1a 2a
1b 2a
65% (3aa) 6% (4aa)
E
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a] All reactions were performed with 0.15 mmol of 4-phenylbutyne,
0.75 mmol of acrylate, 6.0 mmol of H2O, 10 mol% [RuCl2A(dppm)-
(NCCH3)2] in 0.5 mL of 1,4-dioxane at 1008C for 12 h. [b] Isolated yield.
2
54% (3ba)
–
CHTUNGTRENNUNG
AHCTUNGTRENNUNG
3
4
1c 2a
1d 2a
53% (3ca) 15% (4ca)
simple conjugate addition and Markovnikov hydration path-
ways to give rise to alkynyl adduct 4 and methyl ketone 5,
respectively. The ruthenium acyl complexes D and E ema-
nating from hydration of A then add to the a,b-unsaturated
carbonyl compound 2 to form ruthenium enolate F, which
upon protonation furnishes 1,4-dicarbonyl product 3.[15]
The novel mechanism involving a ruthenium acyl com-
plex, arising from regioselective hydration of a vinylidene
complex, is consistent with a series of observations. First,
performing the reaction with a less reactive, b-substituted
enone acceptor leads to the formation of a noticeable
amount (>5%) of an alkene with one less carbon (e.g. 11),
probably through b-hydride elimination of G derived from
decarbonylation of E.[16] Second, it has been shown by a
control experiment that 1,4-diketone 3 is not produced from
hydration of alkynone 4 (Scheme 5),[17] thereby indicating
the distinctive mechanistic feature associated with the pres-
ent three-component reaction as compared with the known
synthesis of 1,5-dicarbonyls through a ruthenacycle path-
way.[18] Third, an additional test has been performed to ex-
clude the possibility of forming 3 by ruthenium-catalyzed
hydroacylation of 2 with aldehyde 6,[19] or through a Stetter-
type mechanism.[20]
28% (3da)
–
5
6
1e 2a
1 f 2a
–
70% (4ea)
13% (3 fa) 44% (4 fa)
7
1g 2a
9% (3ga)
72% (4ga)
8
1h 2a
1i 2a
1j 2a
1k 2a
73% (3ha) 11% (4ha)
54% (3ia) 20% (4ia)
71% (3ja) 0% (4ja)
61% (3ka) 29% (4ka)
9
10
11
12[c]
1l 2a
44% (3la)
–
55%
13%
13
14
1m 2a
1n 2a
(3ma)
(4ma)
–
63% (4na)
In summary, we have developed a new ruthenium-cata-
lyzed three-component coupling reaction of alkynes, al-
kenes, and water. This process enables terminal alkynes to
undergo hydration and conjugate addition to a,b-unsaturat-
ed carbonyl compounds in tandem to form synthetically
15
1o 2b
50% (3ob) 11% (4ob)
useful 1,4-dicarbonyl products. The catalyst [RuCl
(NCCH3)2], synthesized from commercial materials in one
2ACHTUNGTRENNUNG(dppm)-
16
17
1a 2c
1a 2d
49% (3ac)
–
AHCTUNGTRENNUNG
step, has proved to be effective in promoting both anti-Mar-
kovnikov hydration and Michael addition, while minimizing
other alkyne activation pathways. Mechanistic studies sug-
gest that the reaction occurs through a sequence involving
formation and hydration of a ruthenium vinylidene complex,
and an umpolung carbon–carbon bond-forming process of
the resulting ruthenium acyl species. The unique mechanism
and synthetic potential of the reaction, together with its
high atom economy, should serve as a useful platform for
further exploration in alkyne functionalization.
22% (3ad) 37% (4ad)
[a] All reactions were performed with 0.15 mmol of alkyne, 0.75 mmol of
methyl vinyl ketone, 6.0 mmol of H2O, 10 mol% [RuCl2A(dppm)-
ACHTUNGTRENNUNG(NCCH3)2] in 0.5 mL of 1,4-dioxane at 1008C for 12 h. [b] Isolated yield.
[c] A Markovnikov hydration adduct, methyl ketone 5l, was formed in
15% yield, see the Supporting Information.
CTHUNGTRENNUNG
2002
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Chem. Asian J. 2011, 6, 2000 – 2004

Conjugate Addition of Alkynes to Alkenes
Keywords: 1,4-dicarbonyl
compounds
catalysis
multicomponent reactions
ruthenium
·
homogeneous
·
ligands
·
·
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Scheme 5. Control experiments for mechanistic studies.
Experimental Section
General Procedure for the Ruthenium-Catalyzed Three-Component
Coupling Reaction
An alkyne substrate (0.15 mmol),
a Michael acceptor (0.75 mmol),
[RuCl2A(dppm)(NCCH3)2] (7, 0.015 mmol, 10 mol%), H2O (0.10 mL,
C
ACHTUNGTRENNUNG
6.0 mmol), and dioxane (0.25 mL) were added to a vial equipped with a
screw-cap. After sealing the vial, the resulting yellow solution was heated
at 1008C. No special precautions were taken to exclude air or moisture,
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Acknowledgements
This work was supported by BRL program through KRF funded by
MEST. Y. Chen was supported by a graduate fellowship from Bristol-
Myers-Squibb at Princeton University. We thank Dr. Doug M. Ho for the
X-ray analysis.
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C. Lee et al.
COMMUNICATION
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Received: March 14, 2011
Published online: June 17, 2011
2004
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