Ruthenium-catalyzed addition of 1,3-diketones to terminal alkynes

Article abstract of DOI:10.1055/s-0033-1339708

Ruthenium complex [RuCl₂(CO)₃]₂ catalyzes the addition of 1,3-diketones to terminal alkynes. We observed C-addition with acyclic 1,3-diketones, whereas the use of cyclic 1,3-diketones systematically led to O-addition react

Full text of DOI:10.1055/s-0033-1339708

LETTER
▌2287
lRettuer thenium-Catalyzed Addition of 1,3-Diketones to Terminal Alkynes
Addition of 1,3-Diketones to Terminal Alkynes
Benjamin Léotard, Takahide Fukuyama,* Yuki Higashibeppu, Célia Brancour, Hiromi Okamoto, Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
Fax +81(72)2549695; E-mail: fukuyama@c.s.osakafu-u.ac.jp
Received: 04.07.2013; Accepted after revision: 14.08.2013
We first investigated the reaction of acetylacetone (1a)
with phenylacetylene (2a; Equation 1). After a survey of
several Ru complexes as catalyst, we found that
[RuCl2(CO)3]2 effectively catalyzed the addition reaction.
Thus, when a solution of 1a and 2a in benzene was treated
with 5 mol% [RuCl2(CO)3]2 at 70 °C for 12 hours, the ex-
pected reaction indeed took place to give 3a in 49% yield.
Other ruthenium complexes, such as [RuCl2(cod)]2,
[Ru3(CO)12], and RuCl3 were less effective. We found that
an improved yield (59%) could be obtained with a sol-
vent-free reaction in a reduced time of five hours.
Abstract: Ruthenium complex [RuCl2(CO)3]2 catalyzes the addi-
tion of 1,3-diketones to terminal alkynes. We observed C-addition
with acyclic 1,3-diketones, whereas the use of cyclic 1,3-diketones
systematically led to O-addition reactions.
Key words: ruthenium, catalysis, alkynes, 1,3-diketones, vinyl-
ation
The addition of an activated carbonyl compound to an un-
saturated enophile is known as the Conia-ene reaction, the
intramolecular version of which is well documented.1 The
intermolecular addition to unactivated alkynes remains a
challenge and has been the object of several recent re-
ports. The Re complex-catalyzed addition of 1,3-dicar-
bonyl compounds to terminal alkynes was reported by
Takai, Kuninobu, and co-workers.2 In(III) salts effective-
ly catalyze this type of addition reaction, and were inde-
pendently reported by the Nakamura group3 and by the
Kaneda group.4 Takeuchi and co-workers reported that an
Ir complex catalyzes the addition of active methylene
compounds to internal alkynes.5
O
OH
[RuCl2(CO)3]2 (5 mol%)
O
O
Ph
+
benzene, 70 °C, 12 h 49%
neat, 70 °C, 5 h
59%
Ph
1a
2a
3a
Equation 1 Ru-catalyzed addition of acetylacetone (1a) and phenyl-
acetylene (2a) to give 3a
These conditions were then chosen for further investiga-
tion with a range of 1,3-diketones 1 and alkynes 2; the re-
sults are summarized in Table 1. The addition occurred
selectively on the carbon α to the carbonyl moieties. The
reaction of p-methoxy- and p-methyl-substituted alkynyl
arenes 2b and 2c with acetylacetone (1a) resulted in 52
and 48% yields of the products 3b and 3c, respectively
(entries 2 and 3). The reaction of 1a with 4-chlorophenyl-
acetylene (2d) gave 67% yield of the addition product 3d
(entry 4). The reaction was also successful with 2-ethyn-
ylthiophene (2e), which gave 3e in 50% yield (entry 5).
When 1a was treated with ethyl propiolate (2f), we ob-
served inverse regioselectivity, yielding the anti-
Markovnikov product 3f in 45% yield (entry 6). Non-aromatic
alkynes were also examined. Although the reaction of 1a
with 1-octyne was unsuccessful, alkenylacetylene 2g also
reacted with 1a to form 3g, albeit in low yield (27%; entry
7). The reaction of 1a with 6-methyl-2,4-heptanedione
(1b) afforded the desired product 3h in 52% yield (entry
8). When 3-methyl substituted acetylacetone (1c) was
used, the addition product 3i was formed in poor yield
(entry 9).
During the course of our exploration of Ru-catalyzed C–
C bond forming reactions,6 we became interested in the
potential application of Ru catalysts to this type of addi-
tion reaction7 and, herein, we report our results on the ad-
dition of 1,3-diketones to unactivated terminal alkynes in
the presence of [RuCl2(CO)3]2 as catalyst (Scheme 1). In-
terestingly, unlike the previous work, when cyclic 1,3-
diketones were used, O-vinylation took place preferential-
ly. To the best of our knowledge, the intermolecular O-ad-
dition of 1,3-dicarbonyl compounds to alkynes has only
been reported once by Tae and Kim, who used ethyl pro-
piolate as the only alkyne partner in a reaction involving a
stoichiometric amount of N-methylmorpholine.8,9
O
O
O
O
O
OH
Ph
O
Ph
O
Ph
[RuCl2(CO)3]2
C-vinylation
[RuCl2(CO)3]2
O-vinylation
To extend the scope of the addition reaction, we then ex-
amined cyclic 1,3-diketones 4a–d; the results are summa-
rized in Table 2. The reaction of 1,3-cyclohexanedione
(4a) with phenylacetylene (2a) was carried out using ben-
zene as the solvent because 4a was a solid. To our sur-
prise, the reaction gave divinyl ether 5a selectively in 79%
yield, which was obtained through O-vinylation (entry 1).
Scheme 1 Addition of acyclic and cyclic 1,3-diketones to phenyl-
acetylene
SYNLETT 2013, 24, 2287–2291
Advanced online publication: 20.09.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339708; Art ID: ST-2013-U0619-L
© Georg Thieme Verlag Stuttgart · New York

2288
B. Léotard et al.
LETTER
p-Methyl- and p-chloro-substituted phenylacetylenes 2c hexane-1,3-dione (4b) was reacted with 2c, the product 5f
and 2d reacted with 4a to give the corresponding divinyl was obtained in 63% yield (entry 6). On the other hand,
ethers 5b and 5c in 73 and 65% yields, respectively (en- the reaction of 4,4-dimethylcyclohexane-1,3-dione (4c)
tries 2 and 3). The reaction of 4a with 2-ethynylthiophene with 2a gave a mixture of 5g and 5h in 48 and 20% yield,
(2e) gave 5d in 56% yield. The reaction with ethyl propi- respectively (entry 7). The reaction of 1,3-cyclopentane-
olate (2f) gave dialkenyl ether 5e in a 91% yield, but with dione (4d) with 2a gave the anticipated product 5i in 47%
an inverse regioselectivity, which was identical to the re- yield (entry 8).
sults reported by Tae and Kim. When 5,5-dimethylcyclo-
Table 1 C-Addition of Acyclic 1,3-Diketones to Terminal Alkynesa
O
OH
R1
O
O
[RuCl2(CO)3]2 (5 mol%)
neat
R2
+
R1
R2
1
2
3
Entry
1
Diketone 1
Alkyne 2
Product 3
Yield (%)b
O
OH
O
O
Ph
59
2a
Ph
1a
1a
3a
O
OH
OMe
2
3
4
52
48
67
2b
2c
2d
OMe
3b
3c
O
OH
1a
1a
O
OH
Cl
Cl
3d
3e
3f
O
OH
S
S
5
6
1a
1a
50
45
2e
2f
O
OH
O
OEt
CO2Et
Synlett 2013, 24, 2287–2291
© Georg Thieme Verlag Stuttgart · New York

LETTER
Addition of 1,3-Diketones to Terminal Alkynes
2289
Table 1 C-Addition of Acyclic 1,3-Diketones to Terminal Alkynesa (continued)
O
OH
R2
R1
O
O
[RuCl2(CO)3]2 (5 mol%)
neat
R2
+
R1
1
2
3
Entry
Diketone 1
Alkyne 2
Product 3
Yield (%)b
O
OH
7
1a
27
2g
2a
3g
3h
3i
O
OH
O
O
O
O
8
9
52
30
Ph
O
1b
1c
O
2a
Ph
a Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), [RuCl2(CO)3]2 (5 mol%), stirred in a screw-cap test tube, 70 °C, 5 h.
b Isolated yield after silica gel chromatography.
Table 2 O-Addition of 1,3-Cyclodiketones to Terminal Alkynesa
O
O
[RuCl2(CO)3]2 (5 mol%)
benzene
+
R
2
O
R
O
n
n
4
5
Entry
1
Diketone 4
Alkyne 2
Product 5
Yield (%)b
O
O
2a
79
O
Ph
O
4a
5a
5b
O
2
3
4a
4a
2c
73
O
O
2d
65
O
Cl
5c
© Georg Thieme Verlag Stuttgart · New York
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B. Léotard et al.
LETTER
Table 2 O-Addition of 1,3-Cyclodiketones to Terminal Alkynesa (continued)
O
O
[RuCl2(CO)3]2 (5 mol%)
benzene
+
R
2
O
R
O
n
n
4
5
Entry
Diketone 4
Alkyne 2
Product 5
Yield (%)b
O
4
4a
2e
56
S
O
5d
5e
O
5
6
4a
2f
91
63
O
CO2Et
O
O
2c
O
O
4b
5f
O
O
O
+
7
8
2a
2a
48+20
O
O
O
4c
5g
5h
O
O
47
O
O
4d
5i
a Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), benzene (1 mL), [RuCl2(CO)3]2 (5 mol%), stirred in a screw-cap test tube, 70 °C, 5 h.
b Isolated yield after silica gel chromatography.
While the precise mechanism awaits further study, the fol- from the carbon center, which results instead in a reaction
lowing explanation could account for the observed regio- with the proximal oxygen.
selectivity (Scheme 2). When an acyclic 1,3-diketone is
In summary, we have shown that the addition of 1,3-di-
treated with a ruthenium catalyst, the metallic center can
ketones to terminal alkynes can be catalyzed by
form a chelate with the two oxygen atoms. In this case,
[RuCl2(CO)3]2, which leads to alkenylation products.10
when a terminal alkyne approaches the metal, the nucleo-
The addition was regiospecific, depending on the struc-
philic carbon is close enough to react with the alkyne. As
ture of the active methylene compounds. Thus, acyclic
a consequence, C-addition then occurs, leading to a C-vi-
diketones undergo C-vinylation whereas cyclic diketones
nylation product. When a cyclic 1,3-diketone is em-
undergo O-vinylation. This difference could be explained
ployed, the metal cannot form such a chelate by the two
by the formation of two distinct intermediates with differ-
oxygen atoms, leading to coordination of the alkyne away
ent geometries. Further mechanistic studies are in prog-
ress in our laboratory.
Synlett 2013, 24, 2287–2291
© Georg Thieme Verlag Stuttgart · New York

LETTER
Addition of 1,3-Diketones to Terminal Alkynes
2291
(6) (a) Doi, T.; Fukuyama, T.; Minamino, S.; Husson, G.; Ryu,
I. Chem. Commun. 2006, 1875. (b) Fukuyama, T.; Doi, T.;
Minamino, S.; Omura, S.; Ryu, I. Angew. Chem. Int. Ed.
2007, 46, 5559. (c) Omura, S.; Fukuyama, T.; Horiguchi, J.;
Murakami, Y.; Ryu, I. J. Am. Chem. Soc. 2008, 130, 14094.
(d) Omura, S.; Fukuyama, T.; Murakami, Y.; Okamoto, H.;
Ryu, I. Chem. Commun. 2009, 6741. (e) Denichoux, A.;
Fukuyama, T.; Doi, T.; Horiguchi, J.; Ryu, I. Org. Lett.
2010, 12, 1. (f) Fukuyama, T.; Okamoto, H.; Ryu, I. Chem.
Lett. 2011, 40, 1453. (g) Kuwahara, T.; Fukuyama, T.; Ryu,
I. Org. Lett. 2012, 14, 4703.
[Ru]
R
R
O
O
[Ru]
O
1a
[Ru]
O
– H+
O
O
O
O
H+
C-addition
– [Ru]
[Ru]
R
R
O
O
(7) For recent work on Ru-catalyzed C-addition of 1,3-diket-
ones to alkynes, see for TpRu[4-CF3C6H4N(PPh2)2]OTf:
(a) Cheung, H. W.; So, C. M.; Pun, K. H.; Zhou, A.; Lau, C.
P. Adv. Synth. Catal. 2011, 353, 411. (b) For RuCl3/AgPF6,
see: Pennington-Boggio, M. K.; Conley, B. L.; Williams, T.
J. J. Organomet. Chem. 2012, 716, 6.
(8) Tae, J.; Kim, K.-O. Tetrahedron Lett. 2003, 44, 2125.
(9) For examples of intramolecular O-addition, see: (a) Gulías,
M.; Rodríguez, J. R.; Castedo, L.; Mascareñas, J. L. Org.
Lett. 2003, 5, 1975. (b) Nishibayashi, Y.; Yoshikawa, M.;
Inada, Y.; Hidai, M.; Uemura, S. J. Org. Chem. 2004, 69,
3408. (c) Imagawa, H.; Kotani, S.; Nishizawa, M. Synlett
2006, 642. (d) Kusakabe, T.; Kawai, Y.; Shen, R.; Mochida,
T.; Kato, K. Org. Biomol. Chem. 2012, 10, 3192.
R
[Ru]
4a
[Ru]
[Ru]
– H+
O
O
R
O
O
[Ru]
O
O-addition
H+
– [Ru]
R
O
R
Scheme 2 Proposed mechanisms
Acknowledgment
(10) Reaction of Acyclic Diketones; Typical Procedure for
4-Hydroxy-3-(1-phenylvinyl)-3-pentene-2-one (3a):3a
Under an atmosphere of argon, acetylacetone (1a; 50 mg,
0.5 mmol) and phenylacetylene (2a; 102 mg, 1 mmol) were
added to a screw-cap test tube, then [RuCl2(CO)3]2 (12.8 mg,
0.025 mmol) was added. After sealing the tube, the mixture
was stirred by a stirring bar at 70 °C for 5 h. After cooling,
the reaction mixture was separated by column
This work was supported by a Grant-in-Aid for Scientific Research
from the MEXT and the JSPS. B.L. was supported by a Monbuka-
gakusho Scholarship.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
chromatography on silica gel (hexane–Et2O, 98:2), which
allowed the isolation of the desired product 3a (59.6 mg,
59%) as a pale-yellow oil; Rf = 0.48 (hexane–Et2O, 80:20).
1H NMR (CDCl3, 500 MHz): δ = 7.31–7.44 (m, 5 H), 5.91
(d, J = 1.0 Hz, 1 H), 5.24 (d, J = 1.0 Hz, 1 H), 1.99 (s, 6 H);
13C NMR (CDCl3, 125 MHz): δ = 191.3 (2C), 143.4, 139.6,
128.7 (2C), 128.1, 125.8 (2C), 118.3, 113.9, 23.5 (2C).
Reaction of Cyclic Diketones; Typical Procedure for
3-(1-Phenylvinyloxy)-2-cyclohexenone (5a): Under an
atmosphere of argon, 1,3-cyclohexandione (4a; 56 mg,
0.5 mmol) and phenylacetylene (2a; 102 mg, 1 mmol) were
placed in a screw-cap test tube and [RuCl2(CO)3]2 (12.8 mg,
0.025 mmol) and benzene (1 mL) were then added. After
sealing the tube, the mixture was stirred using a stirring bar
at 70 °C for 5 h. After cooling, the reaction mixture was
separated by column chromatography on silica gel (hexane–
EtOAc, 60:40), which allowed the isolation of the desired
product 5a (84.4 mg, 79%) as a pale-yellow oil; Rf = 0.35
(hexane–EtOAc, 60:40). 1H NMR (CDCl3, 500 MHz): δ =
7.30–7.42 (m, 4 H), 5.43 (d, J = 1.9 Hz, 1 H), 5.41 (s, 1 H),
4.97 (d, J = 1.9 Hz, 1 H), 2.60 (t, J = 6.4 Hz, 2 H), 2.29 (t,
J = 6.4 Hz, 2 H), 2.01 (quint, J = 6.4 Hz, 2 H); 13C NMR
(CDCl3, 125 MHz): δ = 199.3, 176.3, 154.7, 133.1, 129.2
(2C), 126.6, 124.9 (2C), 106.3, 101.8, 36.4, 28.1, 21.0; IR
(neat): 1613, 1651 cm–1; MS (EI): m/z (%) = 214 (21) [M]+,
186 (21), 158 (26), 103 (100), 77 (57). HRMS (EI): m/z [M]+
calcd for C14H14O2: 214.0994; found: 214.0988.
References and Notes
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Nakamura, E. Org. Lett. 2005, 7, 3279. (c) Endo, K.;
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© Georg Thieme Verlag Stuttgart · New York
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