Highly chemoselective nickel-catalyzed three-component cross-trimerization of three distinct alkynes leading to 1,3-dien-5-ynes

Full text of DOI:10.1002/anie.200902099

Communications
DOI: 10.1002/anie.200902099
Synthetic Methods
Highly Chemoselective Nickel-Catalyzed Three-Component Cross-
Trimerization of Three Distinct Alkynes Leading to 1,3-Dien-5-ynes
Kenichi Ogata,* Jun Sugasawa, and Shin-ichi Fukuzawa*
The transition-metal-catalyzed coupling reaction of alkynes is
a highly attractive synthetic method for p-conjugated com-
pounds because of its atom economy. Among its various
applications in the field of dimerization of alkynes, the cross-
dimerization of two different alkynes has been recognized as a
versatile method in the formation of 1,3-enynes.[1] Recently,
investigations of this reaction have been extended to involve
bulky silyl-substituted terminal alkynes.[2] In contrast, the
selective linear cross-trimerization of alkynes leading to 1,3-
dien-5-ynes has yet to be studied in detail[3] even though much
research on the two-component cross-cyclotrimerization
reaction, which has been recognized as a versatile method
for the synthesis of multisubstituted benzene rings, has been
reported.[4] Moreover, such reactions have been limited to a
two-component reaction involving two different alkynes, that
is, 1:2 or 2:1 cross-trimerization between terminal and internal
alkynes. The three-component linear cross-trimerization of
three distinct alkynes has yet to be developed [Eq. (1)]. The
three-component reaction is challenging because of the need
to control the chemoselectivity of each alkyne.[5]
isopropylsilylacetylene (1), the ether-functionalized internal
alkyne 2a, and 3-hexyne (3a), as shown in Table 1. In the
presence of the [Ni(cod)2]/2PPh3 catalyst (10 mol%), the
Table 1: Screening of phosphine ligands for the three-component cross-
trimerization between 1, 2a, and 3a.[a]
Entry
Phosphine
Yield [%][b]
A/B[c]
1
2
3
4
5
6
7
PPh3
92
61
0[d]
51
16
22
65
93:7
83:17
–
81:19
85:15
89:11
87:13
P(nPr)3
P(o-tolyl)3
P(nBu)3
P(iPr)3
PCy3
dppe
[a] Reaction
conditions:
[Ni(cod)2]
(0.10 mmol),
phosphine
(0.20 mmol), 1 (1.0 mmol), 2a (1.0 mmol), 3a (2.0 mmol), and toluene
(3 mL) were employed. [b] Yield of isolated product. [c] Determined by
1H NMR analysis. [d] Homodimer of 1 was formed; see reference [7].
Cy =cyclohexyl, dppe=bis(1,2-diphenylphosphinoethane).
three-component cross-trimerization reaction proceeded
smoothly at 808C to afford 4aa in high yield with complete
chemoselectivity (Table 1, entry 1); the ratio between the
major (4aa-A) and minor (4aa-B) isomers was determined to
be A/B = 93:7 by integrating the 1H NMR signals for the
alkene proton of each isomer.[6] In comparison, 4aa was
obtained in a lower yield using the [Ni(cod)2]/P(nPr)3 catalyst,
which was previously shown to be effective for the two-
component 1:2 cross-trimerization between 1 and two mole-
We have previously achieved the effective and highly
regio- and stereoselective 1:2 cross-trimerization involving
triisopropylsilylacetylene and two internal alkynes using
[Ni(cod)2]/P(nPr)3 (cod = 1,5-cyclooctadiene) as the cata-
lyst.[3d] In this report, we demonstrate the first highly
chemo-, regio-, and stereoselective 1:1:1 three-component
cross-trimerization leading to 1,3-dien-5-ynes by the combi-
nation of triisopropylsilylacetylene, an ether-functionalized
unsymmetrical internal alkyne, and a symmetrical internal
alkyl alkyne in the presence of [Ni(cod)2]/PPh3 as a catalyst.
First, the effect of phosphine was investigated for the
three-component cross-trimerization reaction involving tri-
cules containing an internal alkyne (Table 1, entry 2).[3d]
A
homodimer of 1 and the 1:2 cross-trimer between 1 and 2a
were also detected as byproducts by using GC-MS methods.
In the case of a bulky arylphosphine, P(o-tolyl)3, the cross-
trimerization reaction was not observed (Table 1, entry 3).[7]
Other alkylphosphines such as P(nBu)3, P(iPr)3, and PCy3
were not effective (Table 1, entries 4–6) in the reaction, and
the [Ni(cod)2]/dppe-catalyzed reaction resulted in a moderate
product yield (Table 1, entry 7). On the basis of a screen of
phosphine ligands, the highest yield and regioselectivity for
the formation of the three-component cross-trimer 4aa was
achieved using PPh3. For reactions using other bulky silyl-
acetylene such as tert-butyldimethylsilylacetylene under these
conditions, the corresponding three-component cross-trimer
was obtained in lower yield and regioselectivity.[8]
[*] Dr. K. Ogata, J. Sugasawa, Prof. Dr. S.-i. Fukuzawa
Department of Applied Chemistry
Institute of Science and Engineering, Chuo University
1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551 (Japan)
Fax : (+81)3-3817-1916
E-mail: orgsynth@kc.chuo-u.ac.jp
Homepage: http://www.chem.chuo-u.ac.jp/~fukuzawaweb/
index.html
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902099.
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Chemie
Next, the [Ni(cod)2]/2PPh3-catalyzed three-component
cross-trimerization was examined using various ether-func-
tionalized internal alkynes 2, as shown in Table 2. Ethoxy- and
with good regioselectivity, albeit in a moderate yield (Table 2,
entry 8). In spite of the low-valent nickel catalyst, the p-
chloro-substituted aryl alkyne 2i reacted to selectively afford
the corresponding cross-trimer 4ia in high yield (Table 2,
entry 9). Reactions of 2j and 2k, which possess heteroaryl
groups, also proceeded to form the products 4ja and 4ka in
high yields, albeit the regioselectivity of 4ka is lower than that
of 4ja (Table 2, entries 10 and 11).
Table 2: Nickel-catalyzed three-component cross-trimerization between
1, 2a–k, and 3a.[a]
In addition to the arylacetylenes, cyclohexyl-substituted
asymmetrical acetylene 2m was also effective in affording the
corresponding cross-trimer 4ma with excellent regioselectiv-
ity and in good yield [Eq. (3)]. However, replacement of the
cyclohexyl group with a n-hexyl group resulted in a complex
mixture.
Entry
2
R
Ar
4 (yield [%])[b]
A/B[c]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2 f
2g
2h
2i
Me
Et
Ph
Ph
Ph
4aa (92)
4ba (87)
4ca (85)
4da (88)
4ea (75)
4 fa (74)
4ga (90)
4ha (65)
4ia (92)
4ja (90)
4ka (89)
93:7
91:9
91:9
94:6
88:12
85:15
96:4
82:18
89:11
91:9
MOM
Me
Me
Me
Me
Me
Me
Me
Me
p-MeC6H4
m-MeC6H4
o-MeC6H4
p-MeOC6H4
p-CF3C6H4
p-ClC6H4
3-pyridyl
2-thiophenyl
9
10
11
2j
2k
80:20
[a] Reaction conditions: [Ni(cod)2] (0.10 mmol), PPh3 (0.20 mmol), 1
(1.0 mmol), 2 (1.0 mmol), 3a (2.0 mmol), and toluene (3 mL) were
employed. [b] Yield of isolated product. [c] Determined by 1H NMR
analysis.
Furthermore, two more symmetrical internal alkyl
alkynes, 2-butyne (3b) or 4-octyne (3c), were also shown to
proceed with high regioselectivities and high or good yields
[Eq. (4)].
methoxymethyl (MOM)-substituted alkynes (2b and 2c,
respectively) furnished the corresponding products, 4ba and
4ca, respectively, in good yields with high regioselectivities
(Table 2, entries 2 and 3). In contrast, replacement of ether-
functionalized alkyne 2 with 1-phenyl-1-propyne (2l) resulted
in a lower yield and regioselectivity of the corresponding
cross-trimer 4la [Eq. (2)], whereas substitution with a bis-
As shown in the proposed mechanism of the three-
component cross-trimerization (Scheme 1), the reaction pre-
sumably proceeds through a reaction mechanism similar to
that of the two-component cross-trimerization reactions[3d]
and the nickel-catalyzed dimerization of alkynes.[9] First, the
ꢀ
oxidative addition of the C H bond of triisopropylsilylacety-
lene onto nickel(0) forms the nickel(II)–alkynyl hydride
(ether)-functionalized symmetrical internal alkyne, bis-
(ethoxymethyl)acetylene, resulted in a low yield of the
cross-trimer because of low chemoselectivity (25% yield,
see the Supporting Information). Other functionalized
alkynes including propargylamine and ester-functionalized
alkynes such as diethyl(3-phenyl-2-propynyl)amine and ethyl
phenylpropiolate could not participate in the reaction. These
results indicate that the use of an unsymmetrical internal
alkyne possessing an ether group is essential for the effective
three-component cross-trimerization of alkynes. The use of
electron-donating p-, m-, o-methyl- or p-methoxy-substituted
aryl alkynes also afforded cross-trimer 4 with high regiose-
lectivities in good to high yields (Table 2, entries 4–7), and the
presence of an electron-withdrawing trifluoromethyl-substi-
tuted alkyne resulted in the formation of cross-trimer 4ha
intermediate C.[10] Next, the selective insertion of alkyne 2
ꢀ
into the Ni H bond of intermediate C results in the formation
of intermediate D (C!D), in which the chemoselectivity of
the insertion reaction may be accelerated by the ligation of
the oxygen atom to the nickel center.[11] The regioselectivity
can be attributed to the restriction of the insertion direction of
alkyne 2 to avoid the steric hindrance between the nickel
fragment and the aryl or cyclohexyl group. Next, internal
ꢀ
alkyne 3 bearing a small substituent is inserted into the Ni C
bond of sterically hindered intermediate D (D!E).[12] Lastly,
ꢀ
the formation of 4 is achieved by C C reductive coupling.
In summary, we have demonstrated the first chemo-
selective three-component cross-trimerization of three dis-
tinct alkynes leading to 1,3-dien-5-ynes by combining triiso-
propylsilylacetylene, an ether-functionalized unsymmetrical
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[1] For examples of cross-dimerization between terminal alkyne and
an electron-deficient internal alkyne, see: a) B. M. Trost, M. C.
McIntoshi, J. Am. Chem. Soc. 1995, 117, 7255; b) B. M. Trost,
A. J. Frontier, J. Am. Chem. Soc. 2000, 122, 11727; c) L. Chen, C.
Li, Tetrahedron Lett. 2004, 45, 2771; d) T. Hirabayashi, S.
Sakaguchi, Y. Ishii, Adv. Synth. Catal. 2005, 347, 872.
[2] For examples of cross-dimerization of alkynes involving bulky
silylacetylene, see: a) H. Katayama, H. Yari, M. Tanaka, F.
Ozawa, Chem. Commun. 2005, 4336; b) T. Nishimura, X.-X.
Guo, K. Ohnishi, T. Hayashi, Adv. Synth. Catal. 2007, 349, 2669;
c) T. Katagiri, H. Tsurugi, A. Funayama, T. Satoh, M. Miura,
Chem. Lett. 2007, 36, 830; d) N. Tsukada, S. Ninomiya, Y.
Aoyama, Y. Inoue, Org. Lett. 2007, 9, 2919; e) T. Katagiri, H.
Tsurugi, T. Satoh, M. Miura, Chem. Commun. 2008, 3405; f) K.
Ogata, O. Oka, A. Toyota, N. Suzuki, S.-i. Fukuzawa, Synlett
2008, 2663; g) N. Matsuyama, K. Hirano, T. Satoh, M. Miura, J.
Org. Chem. 2009, 74, 3576.
[3] a) M. Ishikawa, J. Ohshita, Y. Ito, A. Minato, J. Chem. Soc.
Chem. Commun. 1988, 804; b) N. Matsuyama, H. Tsurugi, T.
Satoh, M. Miura, Adv. Synth. Catal. 2008, 350, 2274; c) B. M.
Trost, M. T. Sorum, C. Chan, A. E. Harms, G. Rꢀhter, J. Am.
Chem. Soc. 1997, 119, 698; d) K. Ogata, H. Murayama, J.
Sugasawa, N. Suzuki, S.-i. Fukuzawa, J. Am. Chem. Soc. 2009,
131, 3176.
[4] For recent reviews of transition-metal-catalyzed [2+2+2] cyclo-
trimerization of alkynes, see: a) S. Kotha, E. Brahmachary, K.
Lahiri, Eur. J. Org. Chem. 2005, 4741; b) Y. Yamamoto, Curr.
Org. Chem. 2005, 9, 503; c) P. R. Chopade, J. Louie, Adv. Synth.
Catal. 2006, 348, 2307; d) V. Gandon, C. Aubert, M. Malacria,
Chem. Commun. 2006, 2209; e) B. R. Galan, T. Rovis, Angew.
Chem. 2009, 121, 2870; Angew. Chem. Int. Ed. 2009, 48, 2830.
[5] For chemoselective three-component cycloaddition of three
distinct alkynes leading to an arene, see: a) Y. Yamamoto, J.
Ishii, H. Nishiyama, K. Ito, J. Am. Chem. Soc. 2004, 126, 3712;
b) Y. Yamamoto, J. Ishii, H. Nishiyama, K. Ito, J. Am. Chem. Soc.
2005, 127, 9625.
[6] NOESY spectra of 3aa-A and 3ga-A are shown in the
Supporting Information.
[7] A homodimer of 1 ((E)-1,4-bis(triisopropylsilyl)but-1-en-3-yne)
was obtained in 60% yield.
[8] The corresponding three-component cross-trimer was obtained
in 40% yield (A/B = 86:14) using [Ni(cod)2]/PPh3 as a catalyst.
[9] S. Ogoshi, M. Ueta, M. Oka, H. Kurosawa, Chem. Commun.
2004, 2732.
[10] The formation of a nickel(II)–alkynyl hydride complex from
[Ni(cod)2]/phosphine by reaction with a terminal alkyne is
usually postulated. See: references [3a,b,9].
Scheme 1. Possible pathway for the three-component cross-trimeriza-
tion of alkynes.
internal alkyne, and a symmetrical internal alkyne and using
[Ni(cod)2]/PPh3 as the catalyst. Moreover, our highly chemo-,
regio-, and stereoselective reaction is applicable for various
internal alkynes.
Experimental Section
Representative procedure (Table 2, entry 1): A mixture of [Ni(cod)2]
(28 mg, 0.10 mmol), toluene (3 mL), triphenylphosphine (52 mg,
0.20 mmol), triisopropylsilylacetylene (1) (0.22 mL, 1.0 mmol), 2a
(146 mg, 1.0 mmol) and 3-hexyne (3) (0.24 mL, 2.0 mmol) was
charged in Schlenk tube under nitrogen atmosphere. After stirring
for 6 h at 808C, the solution was filtered though a small amount of
silica gel. The residue was purified by silica gel preparative TLC
(ether/n-hexane 1:5), which furnished 4aa (378 mg, 0.92 mmol, 92%
1
yield) as a pale-yellow oil. H NMR (CDCl3, 300 MHz): d = 1.0–1.2
(m, 27H, SiiPr3, Et-CH3), 2.2–2.4 (m, 4H, Et-CH2), 3.33 (s, 3H, OMe),
=
4.21 (s, 2H, OCH2), 6.70 (s, 1H, C CH), 7.2–7.4 ppm (m, 5H, Ph);
=
OCH2 and C CH protons of minor isomer 4aa-B; d = 3.89 (d, J =
7.0 Hz, 2H, OCH2), 5.87 ppm (t, J = 7.0 Hz, C CH); 13C NMR
=
(CDCl3, 75 MHz): d = 11.3 (s, SiiPr3-CH), 12.9, 13.5 (s, Et), 18.6 (s,
SiiPr3-CH3), 24.4, 25.7 (s, Et), 58.0, 70.0 (s, OMe, OCH2), 92.3, 108.2 (s,
ꢁ
C C), 120.7, 126.8, 127.8, 129.0, 133.6, 136.9, 139.7, 151.0 ppm (s,
+
[11] It was reported that an oxygen atom such as that found in an OR
or OH moiety as a substituent on the alkyne assists the alkyne
coordinate to the nickel metal center; see: a) P. Bhatarah, E. H.
Smith, J. Chem. Soc. Perkin Trans. 1 1990, 2603; b) Y. Sato, K.
Ohashi, M. Mori, Tetrahedron Lett. 1999, 40, 5231.
=
C C, Ph); HRMS (ESI) calcd for C27H42OSi [M+Na] 433.2903,
found 433.2938.
Received: April 20, 2009
Revised: May 27, 2009
Published online: July 7, 2009
ꢀ
[12] Alkyne insertion into the Ni C(alkenyl) was reported in the case
of the [CpNi] system, see: D. A. Malyshev, N. M. Scott, N.
Marion, E. D. Stevens, V. P. Ananikov, I. P. Beletskaya, S. P.
Nolan, Organometallics 2006, 25, 4462.
ꢀ
Keywords: alkynes · C H activation · nickel · synthetic methods
.
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