Ruthenium-catalyzed regioselective reactions of nitriles and 1,3-dicarbonyl compounds with terminal alkynes 1

Article abstract of DOI:10.1055/s-0029-1218373

RuH₂PPh₃)₄-catalyzed reaction of nitriles with terminal alkynes proceeds highly efficiently under neutral conditions to give the corresponding Michael adducts. Furthermore, 1,3-dicarbonyl compounds react with terminal alkynes at the α-position to afford the exo-methylene compounds with high regioselectivity under neutral conditions. The regioselectivity depends upon the change of substrates. The precise mechanism is presented. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218373

LETTER
3355
Ruthenium-Catalyzed Regioselective Reactions of Nitriles and 1,3-Dicarbonyl
Compounds with Terminal Alkynes1
Reactions of
N
h
itrile
s
and 1,
u
3-Dicarbony
n
l
Compound
-
s
w
ith
T
I
erminal
cA
lkynes hi Murahashi,*a,b Takeshi Naota,a Yoshinori Nakanoa
a
Department of Chemistry, Graduate School of Engineering Science, Osaka University,
1-3, Machikaneyama, Toyonaka, Osaka 560-8531, Japan
b
Department of Applied Chemistry, Faculty of Engineering, Okayama University of Science, 1-1 Ridai-cho, Okayama 700-0005, Japan
Fax +81(86)2564292; E-mail: murahashi@high.ous.ac.jp
Received 23 September 2009
Concerning the latter reaction highly useful regioselective
addition of 1,3-dicarbonyl compounds to terminal alkynes
have been reported using indium,7 gold,8 rhenium,9 and
nickel10 catalysts. The present ruthenium-catalyzed reac-
Abstract: RuH2(PPh3)4-catalyzed reaction of nitriles with terminal
alkynes proceeds highly efficiently under neutral conditions to give
the corresponding Michael adducts. Furthermore, 1,3-dicarbonyl
compounds react with terminal alkynes at the a-position to afford
the exo-methylene compounds with high regioselectivity under neu- tion is compatible to these reactions.
tral conditions. The regioselectivity depends upon the change of
substrates. The precise mechanism is presented.
The catalytic activity of various metal complexes was ex-
amined with respect to the reaction of ethyl 2-cycanopro-
panoate (2) with methyl propiolate (3) in dry THF at room
temperature for five minutes. RuH2(PPh3)4 (1) gave the
best result for the formation of 2-cyano-2-methyl-3-pen-
tenedioate (4). The other transition-metal catalysts such as
RhH(PPh3)4, RhH(CO)(PPh3)3, IrH(CO)(PPh3)3, and
Pd(PPh3)4 gave satisfactory results.
Key words: ruthenium catalyst, regioselective addition, nitriles,
1,3-dicarbonyl compounds, alkynes
The activation of a-C–H bond adjacent to heteroatoms by
a-heteroatom effect leads to find a series of catalytic
methods for selective carbon–carbon bond formation.2
Transiton-metal polyhydride complexes such as
RuH2(PPh3)4 and IrH5(Pi-Pr)2 are excellent catalysts for
the activation of a-C–H bond of various substrates. The
reactions of nitriles,3 isocyanates,4 trifluoromethylated
compounds,5 and carbonyl compounds6 with electrophiles
proceed catalytically under neutral conditions highly effi-
ciently.
Representative results of the reactions of nitriles with ter-
minal alkynes in the presence of the catalyst 1 are shown
in Table 1. Interestingly, the regioselectivity of the reac-
tion of nitriles to alkynes changes dramatically depending
on the structure of nitriles. We obtained a contrast result
depending on the presence of a-substituent of nitriles. The
ruthenium-catalyzed reactions of a-disubstituted aceto-
nitriles with terminal alkynes gave the products 6–10 as
shown in Table 1. The ratios of the Z- and E-isomers are
also listed in Table l. Typically, the reaction of a-methyl-
substituted pivaloyl acetonitrile (11) with methyl propi-
olate 3 in the presence of the catalyst 1 gave methyl 4-
cyano-4,6,6-trimethyl-5-oxo-2-heptenoate (12) in 82%
yield. In contrast, the reaction of pivaloyl acetonitrile (13)
that has no substituent at the a-position with 3 gave a mix-
ture of methyl 3-cyano-5,5-dimethyl-2-methylene-4-oxo-
hexanoate (14) and methyl (2Z)-3-cyano-2,5,5-trimethyl-
4-oxo-2-hexanoate (15) in 78% yield exclusively. Both
compounds were derived from the a-attack to the carbon–
R2
RuH2(PPh3)4
(cat.)
R1
R1
C(O)R3
+
R2
NC
C(O)R3
THF, r.t.
R1 = H
NC
Equation 1
R1(O)C
R2(O)C
RuH2(PPh3)4
R1
R2
(cat.)
C(O)R3
+
THF, 80 °C
C(O)R3
O
O
Equation 2
H
R1
R2
C
R2
C
α
H
H
C CN
H
EWG
We wish to report that ruthenium-catalyzed reactions of
nitriles with alkynes bearing electron-withdrawing sub-
stituents give the corresponding adducts highly efficiently
(Equation 1) and that similar ruthenium-catalyzed reac-
tions of 1,3-dicarbonyl compounds with alkynes give exo-
methylene compounds regioselectively (Equation 2).
R1
C N
R1
C N
M
C
C
– M
R2 = H
EWG
H
M
H
α
-adduct
M = RuLn
C-bonded (16)
R2
R1
R2
β
NC
C
H
H
EWG
R1
C C N
MH
C
C
– M
R2 = H
SYNLETT 2009, No. 20, pp 3355–3359
x
x
.x
x
.2
0
0
9
H
EWG
N-bonded (17)
Advanced online publication: 18.11.2009
DOI: 10.1055/s-0029-1218373; Art ID: U09709ST
© Georg Thieme Verlag Stuttgart · New York
β-adduct
Scheme 1

3356
S.-I. Murahashi et al.
LETTER
carbon triple bond of the alkyne. The ratio of the product goes isomerization to give the N-bonded ruthenium com-
14/15 is 4:96. The structure of 15 was determined by plex 17.11 The structures of these two complexes are
NOESY. Under the reaction conditions the product 14 un- dependent on the cone angle of the phosphine ligands. The
derwent isomerization to give the product 15. In this reac- phosphine bearing larger cone angle forms N-bonded
tion the product derived from the b-attack could not be complexes, while phosphine with smaller cone angle
detected. The compounds 14 would be derived from the a- forms the C-bonded complex because of steric effect. In
attack of alkyne, and then subsequent isomerization of 14 the reaction, the N-bonded complex 17 undergoes reac-
under the reaction conditions would give the product 15.
tion with terminal alkynes at the b-position to give the
Michael-type addition products 6–10 and 12. In contrast,
nitriles bearing no a-substituent undergo addition reaction
via the C-bonded complex 16. Addition of the ruthenium
hydride of 16 to alkynes gives the opposite orientation of
the addition as shown in Scheme 1.
These reactions can be rationalized by assuming the
mechanism shown in Scheme 1. We have found that the
C-bonded ruthenium complex 16, which derived from the
C–H activation a to nitrile by heteroatom effect, under-
Table 1 Ruthenium-Catalyzed Reaction of Nitriles with Alkynesa
Entry
Nitrile
Alkyne
Product
Yield (%)b (Z/E)
EtO2C
Me
Me
CO2Me
1
94 (59:41)
NC
CO2Et
NC
CO2Me
C(O)Me
3
5
2
4
EtO2C
Me
Me
Ph
2
81 (76)c (65:35)
C(O)Me
NC
NC
NC
CO2Et
CO2Et
6
EtO2C
Ph
3
4
5
82d (35:65)
54 (69:31)
79 (56:44)
C(O)Me
C(O)Me
C(O)Me
NC
C(O)Me
C(O)Me
7
Ph
Me
Me
Me
NC
NC
NC
Ph
Ph
8
NC
Me
NC
C(O)Me
9
NC
O
Me
Me
O
6
7
71 (95:5)
NC
O
NC
Ph
O
10
Me
t-Bu(O)C
Me
t-Bu
CO2Me
82 (45:55)
NC
NC
12
CO2Me
3
O
11
t-Bu(O)C
Me
NC
CO2Me
t-Bu
14
NC
8
78 (14/15 = 4:96)
CO2Me
O
t-Bu(O)C
NC
13
Me
CO2Me
15
a A mixture of nitrile (2.0 mmol), alkyne (2.2 mmol), and catalyst 1 (0.06 mmol) in dry THF (0.5 mL) was stirred at r.t. for 24 h under argon.
b Isolated yield based on the nitrile. The E/Z ratio of the product, determined by 1H NMR analysis, was shown in parenthesis.
c Pd(PPh3)4 catalyst was used instead 1.
d RhH(PPh3)4 (0.06 mol) was used instead of 1.
Synlett 2009, No. 20, 3355–3359 © Thieme Stuttgart · New York

LETTER
Reactions of Nitriles and 1,3-Dicarbonyl Compounds with Terminal Alkynes
3357
Similar regioselectivity was observed for the ruthenium- at the a-position with alkynes are summarized in Table 2.
catalyzed reaction of 1,3-dicarbonyl compounds with Various 1,3-dicarbonyl compounds such as 1,3-diketones,
alkynes. 1,3-Dicarbonyl compounds attack at the a-posi- b-keto esters, and b-keto amides underwent the reaction
tion of alkynes with high regioselectivity to afford the cor- with various alkynes at the a-positions selectively. No ad-
responding exo-methylene compounds (Equation 2). duct derived from the b-attack was observed.
Typically, the reaction of acetylacetone with 3-butyn-2- RuH2(PPh3)4 and IrH(CO)(PPh3)3 have proved to be ef-
one in the presence of RuH2(PPh3)4 catalyst in dry THF in fective catalysts. Other transition-metal hydride complex-
a sealed tube at 80 °C for one hour, 3-acetyl-4-methylene- es,
such
as
RuH2(CO)(PPh3)3,
RhH(PPh3)4,
2,5-hexanedione (18) was obtained in 71% yield. The RhH(CO)(PPh3)3, and Pd(PPh3)4 also showed high cata-
keto/enol ratio is 9:91.
lytic activity.
Representative results of the ruthenium-catalyzed reac-
tion of 1,3-dicarbonyl compounds bearing no substituent
Table 2 Ruthenium-Catalyzed Addition of 1,3-Dicarbonyl Compounds to Alkynesa
Entry
1,3-Dicarbonyl Compound Alkyne
Product
Yield (%)b
71
Keto/enol
9:91
Me(O)C
Me
Me
Me
Me
1
Me(O)C
C(O)Me
CO2Me
O
O
O
O
C(O)Me
CO2Me
18
Me(O)C
2
3
73 (83)c
6:94
8:92
Me(O)C
19
Me(O)C
O
MeOC
O
Me
Me
O
79
O
O
O
O
O
20
Me(O)C
O
MeOC
O
Me
Ph
Me
4
5
86
7:93
OEt
OEt
O
O
21
C(O)Me
Me
70d
72:28
C(O)Me
O
O
O
C(O)Me
22
23
C(O)Me
Me
6
7
8
90
34:66
52:48
56:44
O
CO2Me
CO2Me
CO2Me
O
O
CO2Me
O
O
C(O)Me
Me
Me
NH2
53d
55e
H2NOC
O
O
O
O
CO2Me
24
C(O)Me
OMe
MeO2C
CO2Me
25
Synlett 2009, No. 20, 3355–3359 © Thieme Stuttgart · New York

3358
S.-I. Murahashi et al.
LETTER
Table 2 Ruthenium-Catalyzed Addition of 1,3-Dicarbonyl Compounds to Alkynesa (continued)
Entry
9
1,3-Dicarbonyl Compound Alkyne
Product
Yield (%)b
85
Keto/enol
0:100
C(O)Me
Me
CO2Me
O
CO2Me
O
O
26
C(O)Me
Me
Me
C(O)Me
O
Me
27
27/
28 = 70:30
10
51
Me
Me
C(O)Me
C(O)Me
Me
O
O
Me
O
C(O)Me
28
a A mixture of 1,3-dicarbonyl compound (1.0 mmol), alkyne (2.0 mmol), and catalyst 1 (0.03 mmol) in dry THF (2.0 mL) was heated at 80 °C
for 1 h under argon.
b Isolated yield based on the 1.3-dicarbonyl compound.
c IrH(CO)(PPH3)4 (0.03 mmol) was used instead of 1.
d Reaction time 12 h.
e Reaction temperature: 60 °C.
The products are sensitive even to column chromatog- uct 32. To confirm this, the reaction of Ru(ethy-
raphy. The products obtained are mixtures of keto and lene)(PPh3)3 with acetyl acetone was carried out, and the
1
enol isomers. This was confirmed by H NMR and 13C complex 35 was obtained. The reaction of acetyl acetone
NMR analyses and DEPT. The ratios of the keto/enol are with methyl propiolate in the presence of catalyst 35 gave
also shown in Table 2.
methyl 3-acetyl-2-methylene-4-oxopentanoate (19) in
The reaction can be rationalized by assuming the mecha-
nism shown in Scheme 2.
H
PPh3
O
Ph3P Ru
Ph3P
Insertion of low-valent ruthenium species to the a-C–H
bond of 1,3-dicarbonyl compounds would give the ruthe-
nium hydride intermediate 29, which undergoes isomer-
ization to the hydrido(enolate)ruthenium intermediate 30.
Insertion of ruthenium hydride species of 29 to alkynes
would give the intermediate 31, and subsequent reductive
elimination of the ruthenium species would give the prod-
O
35
(cat.)
Me(O)C
Me(O)C
+
CO2Me
THF, 80 °C, 1 h
O
O
CO2Me
74%
19
Equation 3
H
H
R1
R2
R2
R3(O)C
H
R1
H
C(O)R3
O
O
O
O
[Ru]
[Ru]
[Ru]
H
[Ru]
R1
R2(O)C
R1(O)C
H
O
R2
29
O
31
H
C(O)R3
32
R3(O)C
R2
R2
O
H
C(O)R3
O
O
[Ru]
H
H
[Ru]
H
[Ru]
O
R1
R2(O)C
R1(O)C
R1
30
33
C(O)R3
H
34
Scheme 2
Synlett 2009, No. 20, 3355–3359 © Thieme Stuttgart · New York

LETTER
Reactions of Nitriles and 1,3-Dicarbonyl Compounds with Terminal Alkynes
3359
(0.27 D)
MeOC
MeOC
H
RuH2(PPh3)4 (cat.)
THF, 60 °C
+
D
CO2Me
H
(0.27 D)
O
O
94% deuterated
CO2Me
72% conv.
Equation 4
74% yield (Equation 3). In addition, we investigated the References and Notes
reaction of acetyl acetone with deuterated methyl propio-
(1) Presented at the 40th Symposium on Organometallic
Chemistry, 1995, Osaka, Japan.
late (94% deuterated). The result of the deuterium distri-
bution is shown in Equation 4. This may be due to the
addition–elimination of the ruthenium hydride species to
the product 19.
(2) (a) Murahashi, S.-I. In Handbook of C–H Transformation,
Vol. 2; Dyker, G., Ed.; Wiley-VCH: Weinheim, 2005, 319.
(b) Murahashi, S.-I.; Takaya, H. Acc. Chem. Res. 2000, 33,
225. (c) Murahashi, S.-I.; Naota, T. Bull. Chem. Soc. Jpn.
1996, 69, 1805.
(3) (a) Naota, T.; Taki, T.; Mizuno, M.; Murahasi, S.-I. J. Am.
Chem. Soc. 1989, 111, 5954. (b) Murahashi, S.-I.; Naota,
T.; Taki, H.; Mizuno, M.; Takaya, H.; Komiya, S.; Mizuho,
Y.; Oyasato, N.; Hiraoka, M.; Hirano, H.; Fukuoka, A.
J. Am. Chem. Soc. 1995, 117, 12436. (c) Takaya, H.;
Murahashi, S.-I. Synlett 2001, 991. (d) Takaya, H.; Naota,
T.; Murahashi, S.-I. J. Am. Chem. Soc. 1998, 120, 4244.
(e) Takaya, H.; Yoshida, K.; Isozaki, K.; Terai, H.;
Murahshi, S.-I. Angew. Chem. Int. Ed. 2003, 42, 3302.
(4) Takaya, H.; Kojima, S.; Murahashi, S.-I. Org. Lett. 2001, 3,
421.
It is noteworthy that the contrast regioselectivity was ob-
tained for the reactions of a-substituted 1,3-dicarbonyl
compounds with alkynes likewise the reaction of nitriles
as above mentioned. Thus, the reaction of 3-methyl-2,5-
pentanedione with 3-butyn-2-one in the presence of cata-
lyst 1 in THF in a sealed tube at 80 °C gave a mixture of
3-acetyl-3-methyl-4-heptene-2,6-dione (27) and 3-acetyl-
3-methyl-4-methylenehexane-2,5-dione (28; 27/28 =
70:30) in 51% yield. In this reaction the reaction of the
carbon nucleophile of 30 to the b-position of the alkyne
would give the intermediate 33, which undergoes reduc-
tive elimination of ruthenium species to give the product
34.
(5) Guo, Y.; Zhao, X.; Zhang, D.; Murahashi, S.-I. Angew.
Chem. Int. Ed. 2009, 48, 2047.
(6) Takaya, H.; Ito, M.; Murahashi, S.-I. J. Am. Chem. Soc.
2009, 131, 10824.
The contrast regioselectivity observed in the reactions of
nitriles and 1,3-dicarbonyl compounds with terminal
alkyne depends on the change in substrate structure at the
a-position. This is due to the structure of the intermediate
derived from the C–H activation of the substrates. It is
noteworthy that low-valent ruthenium catalyst
RuH2(PPh3)4 plays an important role, which may corre-
spond to Lewis acid catalysts such as indium catalysts.7
Work is in progress to determine the structure of the reac-
tive ruthenium species and to apply this new catalytic sys-
tem to the other reactions.
(7) (a) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem.
Soc. 2003, 125, 13002. (b) Endo, T.; Hatakeyama, T.;
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Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research,
the Ministry of Education, Culture, Sports, Science, and Technolo-
gy, Japan.
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Synlett 2009, No. 20, 3355–3359 © Thieme Stuttgart · New York

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