Nickel- and rhodium-catalyzed addition of terminal silylacetylenes to propargyl amines: Catalyst-dependent complementary regioselectivity

Article abstract of DOI:10.1021/jo900474d

The cross-addition of terminal silylacetylenes to γ-arylated propargyl amines occurs efficiently via C - H cleavage by using either a nickel or rhodium catalyst. Taking advantage of the catalyst-controlled switching of regioselectivity in the reaction, bo

Full text of DOI:10.1021/jo900474d

and internal alkynes.5 Subsequently, ruthenium,6 rhodium,7
iridium,8 titanium,9 and uranium10 complexes were found to
catalyze similar reactions. In most of these processes, however,
the internal alkynes were limited to the activated ones bearing
an electron-withdrawing group such as a carbonyl or sulfonyl
moiety. Recently, some successful examples of the catalytic
cross-addition of terminal silylacetylenes to unactivated terminal
and internal alkynes or weakly activated ones such as propargyl
ethers have been described.11 Our groups also focused on the
catalytic activities of nickel12 and rhodium complexes and
succeeded in the same type of transformation.13 In the course
of our study of this chemistry, we anticipated that our catalyst
systems could be applied to the addition of terminal silylacety-
lenes to propargyl amines. The reaction is, to the best of our
knowledge, unprecedented, while the expected products, 2- or
3-alkynylallylamines, are not only synthetically useful inter-
mediates but also of pharmaceutical interest, especially the
arylated derivatives for treating neurological disorders including
Alzheimer’s disease.14 Herein, we report the nickel- and
rhodium-catalyzed regio- and stereoselective addition of terminal
silylacetylenes to γ-arylated propargyl amines, the regioselec-
tivity being highly catalyst-dependent.
Treatment of tert-butyldimethylsilylacetylene (1a) with di-
methyl(3-phenyl-2-propynyl)amine (2a) in the presence of
Ni(cod)2 (5 mol %) and an excess (to Ni) of 2,6-lutidine in
toluene, which was an effective catalyst system in our previous
work,13a gave the desired adduct 3aa and its regioisomer 4aa
in a ratio of 94:6 with a good combined yield (Table 1, entry
1). The stereochemistry of each product was unambiguously
determined by NOE analysis (see the Supporting Information).
Notably, the corresponding stereoisomers were not detected. In
Nickel- and Rhodium-Catalyzed Addition of
Terminal Silylacetylenes to Propargyl Amines:
Catalyst-Dependent Complementary
Regioselectivity
Naoto Matsuyama, Koji Hirano, Tetsuya Satoh, and
Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering,
Osaka UniVersity, Suita, Osaka 565-0871, Japan
miura@chem.eng.osaka-u.ac.jp
ReceiVed March 3, 2009
The cross-addition of terminal silylacetylenes to γ-arylated
propargyl amines occurs efficiently via C-H cleavage by
using either a nickel or rhodium catalyst. Taking advantage
of the catalyst-controlled switching of regioselectivity in the
reaction, both the 2- and 3-alkynylallylamines are readily
accessible from the same starting materials.
The transition metal-catalyzed addition of terminal alkyne
C-H bonds to carbon-carbon triple bonds ranks as the most
simple and straightforward access to π-conjugated enynes, which
are versatile building blocks in organic synthesis.1 In particular,
the catalytic homodimerization of terminal alkynes directed
toward the selective synthesis of one of the three possible
(E)-,2 (Z)-,3 and gem-4enyne isomers have been extensively
studied. On the other hand, the selective cross-dimerization
between terminal alkynes and internal ones is much more
challenging since the terminal alkynes are prone to undergo the
rapid homodimerization and oligomerization in the presence of
transition metal catalysts. In 1987, Trost reported the highly
selective palladium-catalyzed cross-dimerization with terminal
(6) Yi, C. S.; Liu, N. Organometallics 1998, 17, 3158.
(7) (a) Weng, W.; Guo, C.; Celenligil-cetin, R.; Foxman, B. M.; Ozerov,
O. V. Chem. Commun. 2006, 197. (b) Ito, J.; Kitase, M.; Nishiyama, H.
Organometallics 2007, 26, 6412.
(8) Hirabayashi, T.; Sakaguchi, S.; Ishii, Y. AdV. Synth. Catal. 2005, 347,
872.
(9) Akita, M.; Yasuda, H.; Nakamura, A. Bull. Chem. Soc. Jpn. 1984, 57,
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(10) Wang, J.; Kapon, M.; Berthet, J. C.; Ephritikhine, M.; Eisen, M. S.
Inorg. Chem. Chim. Acta 2002, 334, 183.
(11) Ruthenium: (a) Katayama, H.; Yari, H.; Tanaka, M.; Ozawa, F. Chem.
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Inoue, Y. Org. Lett. 2007, 9, 2919. Iridium: (c) Ogata, K.; Oka, O.; Toyota, A.;
Suzuki, N.; Fukuzawa, S. Synlett 2008, 2663. Rhodium: (d) Nishimura, T.; Guo,
X.-X.; Ohnishi, K.; Hayashi, T. AdV. Synth. Catal. 2007, 349, 2669. See also: (e)
Nishimura, T.; Guo, X.-X.; Hayashi, T. Chem. Asian J. 2008, 3, 1505. (f)
Nshimura, T.; Tsurumaki, E.; Kawamoto, T.; Guo, X.-X.; Hayashi, T. Org. Lett.
2008, 10, 4057.
(12) Pioneering work of nickel-catalyzed cross-dimerization between terminal
and internal alkynes: (a) Ishikawa, M.; Ohshita, J.; Ito, Y.; Minato, A. J. Chem.
Soc., Chem. Commun. 1988, 804. In recent years, Suginome reported nickel-
catalyzed addition of triisopropylsilylacetylene to 1,3-dienes and styrenes. (b)
Shirakura, M.; Suginome, M. J. Am. Chem. Soc. 2008, 130, 5410. (c) Shirakura,
M.; Suginome, M. Org. Lett. 2009, 11, 523. Nickel-catalyzed selective cross-
trimerization: (d) Ogata, K.; Murayama, H.; Sugasawa, J.; Suzuki, N.; Fukuzawa,
S. J. Am. Chem. Soc. 2009, 131, 3176.
(13) Nickel: (a) Matsuyama, N.; Tsurugi, H.; Satoh, T.; Miura, M. AdV. Synth.
Catal. 2008, 350, 2274. Rhodium: (b) Katagiri, T.; Tsurugi, H.; Funayama, A.;
Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 830. (c) Katagiri, T.; Tsurugi, H.;
Satoh, T.; Miura, M. Chem. Commun. 2008, 3405. See also: (d) Satoh, T.;
Tsurugi, H.; Miura, M. Chem. Rec. 2008, 8, 326.
(14) (a) Egle, I.; Frey, J.; Isaac, M. PCT Int. Appl. 2001, WO 2001032602,
A1 20010510 (CAN 134:340706). (b) Egle, I.; Frey, J.; Isaac, M. U.S. Pat. 2002,
US 6426364, B1 20020730 (CAN 137:124979). (c) Woods, S. W. PCT Int. Appl.
2006, WO 2006110724, A2 20061019 (CAN 145:432223).
(1) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259. (b) Tsuji,
J. Transition Metal Reagents and Catalysts; Wiley: Chichester, UK, 2000. (c)
Bustelo, E.; Dixneuf, P. H. Handbook of C-H Transformations; Dyker, G., Ed.;
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3576 J. Org. Chem. 2009, 74, 3576–3578
10.1021/jo900474d CCC: $40.75 2009 American Chemical Society
Published on Web 04/08/2009

TABLE 1. Nickel-Catalyzed Addition of Terminal Silylacetylenes
TABLE 3. Rhodium-Catalyzed Addition of
1 to Propargylamines 2a-ea
tert-Butyldimethylsilylacetylene (1a) to Propargylamines 2a-ca
% yieldb
entry
R1, R2 in 2
4, % yieldb
E/Zc
entry
Si in 1
tBuMe2Si (1a) Me, Me (2a)
R1, R2 in 2
3
4
3:4c
1
2
3
Me, Me (2a)
Et, Et (2b)
iPr, iPr (2c)
4aa, 92
4ab, 99
4ac, 99
91:9
97:3
>99:1
1
2
3
4
5
6
7
3aa, 72 4aa, 6
3ab, 82 4ab, 4
3ac, 90 4ac, trace >99:1
3ad, 82 4ad, 8
94:6
96:4
1a
1a
Et, Et (2b)
i
iPr, Pr (2c)
a Reaction conditions: [1a]:[2]:[{Rh(OH)(cod)}2]:[dCypb] ) 0.75:0.25:
0.0038:0.0075 (in mmol), in o-xylene (2.5 mL) at 150 °C under N2 for
1a
1a
(CH2)5 (2d)
(CH2)2O(CH2)2 (2e) 3ae, 80 4ae, 9
90:10
90:10
92:8
4
h. b Isolated yield. No corresponding regioisomer was detected.
c
1
Me3Si (1b)
2a
2a
3ba, 54 4ba, 6
3ca, 75 4ca, 7
Determined by H NMR.
iPr3Si (1c)
92:8
a Reaction conditions: [1]:[2]:[Ni(cod)2]
mmol), in toluene/2,6-lutidine (2.4:0.1 mL) under N2 at rt for 24 h.
b Isolated yield. The corresponding stereoisomers were not observed.
c Determined by GC analysis in the crude mixture.
)
0.75:0.25:0.0125 (in
TABLE 4. Catalytic Addition of tert-Butyldimethylsilylacetylene
(1a) to Propargylamide 2fa
TABLE 2. Nickel-Catalyzed Addition of
tert-Butyldimethylsilylacetylene (1a) to Propargylamines 2ca-cfa
catalyst/
ligand
% yieldb
entry
Ar in 2
5, % yieldb
entry
1
conditions
(3af/4af)c
1
2
3
4
5
6
4-MeC6H4 (2ca)
4-MeOC6H4 (2cb)
4-CF3C6H4 (2cc)
4-ClC6H4 (2cd)
4-MeO2C (2ce)
4-NCC6H4 (2cf)
5aa, 92
5ab, 87
5ac, 98
5ad, 75
5ae, 97
5af, 82
5 mol % of
toluene, rt, 24 h
21 (81:19)
Ni(cod)2/0.1 mL
of 2,6-lutidine
5 mol % of
Ni(cod)2/5 mol %
of xantphos
1.5 mol % of
[Rh(OH)(cod)]2/3 mol %
of dCypb
2
3
toluene, 120 °C, 3 h
75 (28:72)
o-xylene, 150 °C, 4 h 79 (0:100d)
a Reaction conditions: [1a]:[2]:[Ni(cod)2]
)
0.75:0.25:0.0125 (in
mmol), in toluene/2,6-lutidine (2.4:0.1 mL) under N2 at rt for 24 h.
b Isolated yield. No corresponding regio- and stereoisomer was detected.
a Reaction conditions: a mixture of 1a (0.75 mmol), 2f (0.25 mmol),
and catalyst/ligand was stirred under the indicated conditions. b Isolated
addition, the reaction proceeded smoothly at room temperature,
whereas the addition to propargyl ethers required elevated
temperatures.13a Thus, the result may indicate that the propargyl
amine has higher reactivity under nickel catalysis, compared to
the corresponding ethers. The regioisomeric ratio of 3:4
increased from 94:6 to over 99:1 with increasing the size of
substituents on nitrogen (entries 2 and 3). Piperidine and
morpholine derivatives 2d and 2e also participated in the
reaction without any difficulties (entries 4 and 5). Other terminal
silylacetylenes were available for use. Both smaller trimethyl-
silylacetylene (1b) and bulkier triisopropylsilylacetylene (1c)
reacted with 2a to furnish 3ba and 3ca, respectively, with
compatible regioselectivities (entries 6 and 7).
With tert-butyldimethylsilylacetylene (1a) as the terminal
silylacetylene, we also examined the substituent effect on the
phenyl moiety of 2c (Table 2). Electron-rich 2cb and electron-
deficient 2cc as well as electron-neutral 2ca were converted to
the corresponding enynes 5aa-ac in high yields with excellent
regioselectivities (entries 1-3). The reaction with 2cd produced
5ad in a good yield, leaving the sp2 C-Cl moiety untouched
(entry 4). Ester and nitrile functionalities were also tolerated
under the reaction conditions (entries 5 and 6).15
yield. The ratio was determined by H NMR. d E/Z ) 90:10.
c
1
Next, in order to explore an efficient route to 2-alkynylally-
lamine 4, we attempted to switch the regioselectivity in the
reaction by ligand control. However, the approach was unsuc-
cessful as far as we examined. According to our previous
observation,13b,c we then turned our attention to rhodium-based
processes (Table 3). Gratifyingly, upon treatment of 1a with
2a in the presence of [Rh(OH)(cod)]2/dCypb (dCypb ) 1,4-
bis(dicyclohexylphosphino)butane) catalyst in o-xylene at 150
°C (bath temperature), the corresponding 2-alkynylated product
4aa was obtained as the sole regioisomer in 92% yield with
good stereoselectivity (entry 1). Bulkier substitutions on nitrogen
improved the stereoselectivity (entries 2 and 3).
The catalytic addition to amide 2f containing an acidic proton
on nitrogen was also performed (Table 4). The reaction of 2f
using the Ni(cod)2/2,6-lutidine system resulted in the formation
of an 81:19 mixture of 3af and 4af with only 21% combined
yield (entry 1). After some additional ligand investigation, the
use of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xant-
phos) instead of 2,6-lutidine at 120 °C was found to lead to the
corresponding adducts in 75% combined yield. However, to our
surprise, a different regioselectivity was observed, and thus, the
major regioisomer was enyne 4af (entry 2). Although the exact
(15) Unfortunately, the reaction with alkyl-substituted substrates such as
diethyl(2-heptynyl)amine was unsuccessful. A large amount of the starting
material was recovered intact.
J. Org. Chem. Vol. 74, No. 9, 2009 3577

1
0.011 mmol) in 72% and 6% yields, respectively. 3aa: H NMR
reason is not clear at this stage, the uniquely large bite angle of
xantphos would cause the unusual regioselectivity. It is note-
worthy that the amide 2f was converted successfully to 4af by
using the [Rh(OH)(cod)]2/dCypb system (entry 3).
In summary, we have found the nickel- and rhodium-
catalyzed regio- and stereoselective addition of terminal sily-
lacetylenes to propargyl amines and developed the facile
methods for the preparation of allylamine-moiety-containing
π-conjugated enynes of synthetic value. Notably, both regioi-
somers bearing a versatile silyl function can be selectively
synthesized from the same starting materials by the proper
choice of catalysts.
(400 MHz, CDCl3) δ 0.13 (s, 6H), 0.95 (s, 9H), 2.20 (s, 6H), 3.09
(d, J ) 7.0 Hz, 2H), 6.31 (t, J ) 7.0 Hz, 1H), 7.25-7.38 (m, 5H);
13C NMR (100 MHz, CDCl3) δ -4.6, 16.7, 26.1, 45.7, 57.8, 91.1,
107.0, 125.8, 127.6, 128.0, 128.8, 136.9, 137.7; HRMS m/z (M+)
calcd for C19H29NSi, 299.2069. Found 299.2075. (E)-4aa: 1H NMR
(400 MHz, CDCl3) δ 0.15 (s, 6H), 0.98 (s, 9H), 2.33 (s, 6H), 3.09
(s, 2H), 7.09 (s, 1H), 7.23-7.30 (m, 1H), 7.34 (t, J ) 7.3 Hz, 2H),
7.45 (d, J ) 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ -4.6,
16.8, 26.2, 45.4, 59.7, 92.2, 109.7, 127.7, 128.0, 128.2, 129.6, 136.3,
140.6; HRMS m/z (M+) calcd for C19H29NSi, 299.2069. Found
299.2073.
Typical Procedure for Rhodium-Catalyzed Addition of
Terminal Silylacetylenes to Propargyl Amines. The reaction of
tert-butyldimethylsilylacetylene (1a) with dimethyl(3-phenyl-2-
propynyl)amine (2a) is representative (Table 3, entry 1). In a
glovebox filled with nitrogen, [Rh(OH)(cod)]2 (1.7 mg, 0.0038
mmol), dCypb (3.4 mg, 0.0075 mmol), 1a (105 mg, 0.75 mmol),
2a (40 mg, 0.25 mmol), o-xylene (2.5 mL), and dibenzyl (ca. 50
mg, internal standard) were placed in a Schlenk tube, and the tube
was then taken outside the glovebox. After being heated at 150 °C
for 4 h, the consumption of the starting materials was confirmed
by GC analysis. The solvent was evaporated and purification of
the residue by column chromatography on silica gel produced 4aa
(69 mg, 0.23 mmol, E/Z ) 91:9) in 92% yield.
Experimental Section
Typical Procedure for Nickel-Catalyzed Addition of Termi-
nal Silylacetylenes to Propargyl Amines. The reaction of tert-
butyldimethylsilylacetylene (1a) with dimethyl(3-phenyl-2-propy-
nyl)amine (2a) is representative (Table 1, entry 1). In a glovebox
filled with nitrogen, Ni(cod)2 (0.050 M toluene solution, 0.25 mL,
0.013 mmol), 1a (105 mg, 0.75 mmol), 2a (40 mg, 0.25 mmol),
2,6-lutidine (0.10 mL), toluene (2.4 mL), and dibenzyl (ca. 50 mg,
internal standard) were placed in a Schlenk tube. The tube was
then taken outside the glovebox, and the mixture was stirred at
room temperature for 24 h. After the consumption of the starting
materials was checked by GC analysis, the solvent was evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel with hexane/ethyl acetate (80:20, v/v)
as an eluent to furnish a mixture of (E)-[5-(tert-butyldimethylsilyl)-
3-phenyl-2-penten-4-ynyl]dimethylamine (3aa) and (E)-[2-ben-
zylidene-4-(tert-butyldimethylsilyl)-3-butynyl]dimethylamine [(E)-
4aa]. Further purification by preparative TLC (PTLC) afforded
analytically pure 3aa (54 mg, 0.18 mmol) and (E)-4aa (4.5 mg,
Acknowledgment. This work was partly supported by Grants-
in-Aid from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan.
Supporting Information Available: Characterization data
of compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO900474D
3578 J. Org. Chem. Vol. 74, No. 9, 2009