Asymmetric direct alkynylation catalyzed by chiral ru-bis(oxazolinyl)phenyl complexes

Article abstract of DOI:10.1021/ol1015338

Propargylic alcohols were obtained with excellent enantioselectivities in the asymmetric direct alkynylation of aldehydes using 5 mol % of chiral ruthenium complexes containing the chiral bis(oxazolinyl)phenyl ligand.

Full text of DOI:10.1021/ol1015338

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3860-3862
Asymmetric Direct Alkynylation
Catalyzed by Chiral
Ru-Bis(oxazolinyl)phenyl Complexes
Jun-ichi Ito, Ryosuke Asai, and Hisao Nishiyama*
Department of Applied Chemistry, Graduate School of Engineering,
Nagoya UniVersity, Chikusa Nagoya, Japan
hnishi@apchem.nagoya-u.ac.jp
Received July 7, 2010
ABSTRACT
Propargylic alcohols were obtained with excellent enantioselectivities in the asymmetric direct alkynylation of aldehydes using 5 mol % of
chiral ruthenium complexes containing the chiral bis(oxazolinyl)phenyl ligand.
Transition-metal complexes containing anionic meridional
ligands, namely, PCP and NCN pincer ligands, are of interest
in homogeneous catalysts for transformation of organic
molecules.1 In recent years, several optically active pincer
complexes with chiral meridional ligands have been inves-
tigated as asymmetric catalysts.2 Among these chiral pincer
complexes, our and other groups have reported the chiral
bis(oxazolinyl)phenyl (phebox) ligands for constructing
transition-metal NCN complexes.3 In this context, we
demonstrated that the Rh-phebox complexes have multiple
potentials in catalytic asymmetric reactions: allylation, hetero-
Diels-Alder, Michael addition, hydrosilylation, conjugate
reduction, reductive aldol reaction, direct aldol reaction, and
ꢀ-boration with high enantiomeric induction.4,5 As an
extension of our research on the phebox complex, we recently
reported the Ru analogue, which was successfully utilized
in catalytic asymmetric hydrogenation, transfer hydrogena-
tion, and cyclopropanation with excellent enantioselectivity.6
These results promoted us to investigate further application
of the Ru-phebox complexes.
(1) (a) Albrecht, M.; van Koten, G. Angew. Chem., Int. Ed. 2001, 40,
3750. (b) van der Boom, M. E.; Milstein, D. Chem. ReV. 2003, 103, 1759.
(c) The Chemistry of Pincer Compounds; Morales-Morales, D., Jensen,
C. M., Eds.; Elsevier: Oxford, 2007.
Asymmetric alkynylation with terminal alkynes can pro-
vide optically active propargylic alcohols that are useful for
materials science or pharmaceutical chemistry.7-10 Recently,
catalytic direct asymmetric alkynylation with chiral Zn,11
(2) For recent examples: (a) Medici, S.; Gagliardo, M.; Williams, S. B.;
Chase, P. A.; Gladiali, S.; Lutz, M.; Spek, A. L.; van Klink, G. P. M.; van
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van Koten, G. J. Organomet. Chem. 2001, 624, 271. (e) Gosiewska, S.;
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17, 674. (f) Longmire, J. M.; Zhang, X. Organometallics 1998, 17, 4374.
(g) Gorla, F.; Togni, A.; Venanzi, L. M. Organometallics 1994, 13, 1607.
(h) Baber, R. A.; Bedford, R. B.; Betham, M.; Blake, M. E.; Coles, S. J.;
Haddow, M. F.; Hursthouse, M. B.; Orpen, A. G.; Pilarski, L. T.; Pringle,
P. G.; Wingad, R. L. Chem. Commun. 2006, 3880. (i) Wallner, O. A.;
Olsson, V. J.; Eriksson, L.; Szabo´, K. J. Inorg. Chim. Acta 2006, 359, 1767.
(j) Aydin, J.; Kumar, K. S.; Sayah, M. J.; Wallner, O. A.; Szabo´, K. J. J.
Org. Chem. 2007, 72, 4689. (k) Takenaka, K.; Minakawa, M.; Uozumi, Y.
J. Am. Chem. Soc. 2005, 127, 12273.
(3) (a) Motoyama, Y.; Makihara, N.; Mikami, Y.; Aoki, K.; Nishiyama,
H. Chem. Lett. 1997, 951. (b) Denmark, S. E.; Stavenger, R. A.; Faucher,
A.-M.; Edwards, J. P. J. Org. Chem. 1997, 62, 3375. (c) Stark, M. A.;
Richards, C. J. Tetrahedron Lett. 1997, 38, 5881.
(4) (a) Nishiyama, H. Chem. Soc. ReV. 2007, 36, 1133. (b) Nishiyama,
H.; Ito, J. Chem. Commun. 2010, 46, 203. (c) Nishiyama, H.; Ito, J. Chem.
Rec. 2007, 7, 159
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Chem. Commun. 2009, 5987
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(6) (a) Ito, J.; Ujiie, S.; Nishiyama, H. Chem. Commun. 2008, 1923. (b)
Ito, J.; Ujiie, S.; Nishiyama, H. Organometallics 2009, 28, 630. (c) Ito, J.;
Ujiie, S.; Nishiyama, H. Chem.sEur. J. 2010, 16, 4986.
10.1021/ol1015338  2010 American Chemical Society
Published on Web 08/10/2010

In,12 and Cu13 catalysts was developed by Carreira et al.,
Shibasaki et al., and Sawamura et al., respectively. Here we
report a new ruthenium-catalyzed alkynylation reaction by
use of chiral Ru-phebox complexes (Figure 1).
Table 1. Asymmetric Alkynylation of Benzaldehyde 6a with
Phenylacetylene 5a Catalyzed by Ru-Bis(oxazolinyl)phenyl
Complexes 1-4a
entry
cat.
base
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1
1
2
3
4
4
1
1
1
1
1
1
1
-
0
75
57
74
74
71
69
73
73
72
70
89
83
-
92
60
93
92
92
94
92
90
82
72
93
93
NaOAc
NaOAc
NaOAc
NaOAc
-
PhCO2Na
LiOAc
KOAc
NaOMe
K2CO3
NaOAc
NaOAc
Figure 1. Chiral Ru-bis(oxazolinyl)phenyl complexes.
9
10
11
12d
13e
The addition of phenylacetylene 5a to benzaldehyde 6a
was investigated using the Ru-phebox complex 16b as a
catalyst (Table 1). Initially, the addition reaction under
heating at 60 °C for 96 h in 2-propanol did not proceed (entry
1). However, addition of NaOAc (10 mol %) promoted the
reaction to give the corresponding propargylic alcohol 7aa
in 75% yield and 92% ee (entry 2). The substituents on the
ligand affected the outcome of the addition reaction. Thus,
the use of isopropyl catalyst 2 decreased both the yield and
the enantioselectivity (entry 3). Next, we utilized mononuclear
complexes 3 and 4 as catalysts. The aqua complex 3 and the
acetate complex 4 with NaOAc afforded the propargylic alcohol
a Reaction conditions: 5a (2 mmol), 6a (1 mmol), Ru-phebox (5 mol
% Ru), base (0.1 mmol), 2-propanol (5 mL), 60 °C, 96 h. b Isolated yield.
c Determined by HPLC. d 5a (4 mmol). e 5a (4 mmol), 60 °C, 48 h.
7aa with excellent enantioselectivity of up to 93% ee (entries
4 and 5). Notably, 4 did not require extra NaOAc to give 7aa
in a similar yield and enantioselectivity (entry 6). Other
carboxylate reagents were also effective for the addition reaction
to produce 7aa with up to 94% ee (entries 7-11). In contrast
to the carboxylate derivatives, other bases, such as NaOMe and
K2CO3, decreased the enantioselectivity. The use of an excess
amount (4 equiv) of the alkyne increased the yield of 7aa to
89% for 96 h and 83% for 48 h (entries 12 and 13).14 We also
verified that the enantioselectivity of 7aa was not changed during
the catalytic reaction (Figure S1 in Supporting Information).
The use of THF showed yields similar to that of 2-pro-
panol, but the enantioselectivity was slightly decreased (Table
2, entry 1). In this case, the formation of unidentified
byproducts was observed. The reaction in 1,2-dichloroethane
was not efficient (entry 2). Use of toluene afforded 7aa in
good enantioselectivity but moderate yield (entry 3). To
elucidate the solvent effect, the reaction was monitored by
1H NMR spectroscopy in both toluene-d8 and 2-propanol-
d8. In toluene-d8, decay of 7aa was observed after reaching
(7) (a) Trost, B. M.; Weiss, A. H. AdV. Synth. Catal. 2009, 351, 963.
(b) Pu, L. Tetrahedron 2003, 59, 9873. (c) Cozzi, P. G.; Hilgraf, R.;
Zimmermann, N. Eur. J. Org. Chem. 2004, 4095. (d) Lu, G.; Li, Y.-M.;
Li, X.-S.; Chan, A. S. C. Coord. Chem. ReV. 2005, 249, 1736. (e) Tyrrell,
E. Curr. Org. Chem. 2009, 13, 1540.
(8) Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937.
(9) Selected examples; (a) Corey, E. J.; Cimprich, K. A. J. Am. Chem.
Soc. 1994, 116, 3151. (b) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am.
Chem. Soc. 2000, 122, 1806. (c) Li, X.; Lu, G.; Kwok, W. H.; Chan, A. S. C.
J. Am. Chem. Soc. 2002, 124, 12636. (d) Gao, G.; Xie, R.-G.; Pu, L. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5417. (e) Trost, B. M.; Weiss, A. H.;
von Wangelin, A. J. J. Am. Chem. Soc. 2006, 128, 8. (f) Wolf, C.; Liu, S.
J. Am. Chem. Soc. 2006, 128, 10996. (g) Gao, G.; Wang, Q.; Yu, X.-Q.;
Xie, R.-G.; Pu, L. Angew. Chem., Int. Ed. 2006, 118, 128. (h) Trost, B. M.;
Chan, V. S.; Yamamoto, D. J. Am. Chem. Soc. 2010, 132, 5186.
(10) Examples of achiral catalysts; (a) Tzalis, D.; Knochel, P. Angew.
Chem., Int. Ed. 1999, 38, 1463. (b) Babler, J. H.; Liptak, V. P.; Phan, N.
J. Org. Chem. 1996, 61, 416. (c) Miyamoto, H.; Yasaka, S.; Tanaka, K.
Bull. Chem. Soc. Jpn. 2001, 74, 185. (d) Ishikawa, T.; Mizuta, T.; Hagiwara,
K.; Aikawa, T.; Kudo, T.; Saito, S. J. Org. Chem. 2003, 68, 3702. (e) Takita,
R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. Org. Lett. 2005, 7,
1363. (f) Sakai, N.; Kanada, R.; Hirasawa, M.; Konakahara, T. Tetrahedron
2005, 61, 9298. (g) Yao, X.; Li, C.-J. Org. Lett. 2005, 7, 4395. (h) Dhondi,
P. K.; Chisholm, J. D. Org. Lett. 2006, 8, 67. (i) Jiang, B.; Si, Y.-G.
Tetrahedron Lett. 2002, 43, 8323.
(14) Typical procedure for 7aa (Table 1, entry 13): To a mixture of 1
(31 mg, 0.025 mmol Ru) and NaOAc (8.2 mg, 0.10 mmol) in iPrOH (5
mL), 5a (408 mg, 4.0 mmol) and 6a (106 mg, 1.0 mmol) were added at
room temperature, and the mixture was stirred at 60 °C for 48 h. Then, the
reaction mixture was concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography with hexane/
ethyl acetate (10:1) as eluent to give 7aa (173 mg, 0.83 mmol) in 83%
(11) (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687. (b) Jiang, B.; Chen, Z; Xiong, W. Chem. Commun. 2002, 1524. (c)
Chen, Z.; Xiong, W.; Jiang, B. Chem. Commun. 2002, 2098. (d) Yamashita,
M.; Yamada, K.-i.; Tomioka, K. AdV. Synth. Catal 2005, 347, 1649. (e)
Emmerson, D. P. G.; Hems, W. P.; Davis, B. G. Org. Lett. 2006, 8, 207.
(12) (a) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 13760. (b) Harada, S.; Takita, R.; Ohshima, T.; Matsunaga,
S.; Shibasaki, M. Chem. Commun. 2007, 948.
1
yield and 93% ee as determined by HPLC analysis. H NMR (300 MHz,
CDCl3): δ 2.33 (d, J ) 5.9 Hz, 1H, OH), 5.71 (d, J ) 5.9 Hz, 1H, CH),
7.28-7.51 (m, 8H, CH), 7.68-7.64 (m, 2H, CH). 13C NMR (75 MHz,
CDCl3): δ 65.0, 86.5, 88.6, 122.2, 126.5, 128.0, 128.2, 128.3, 128.4, 131.5,
140.3. IR (KBr): ν 3363, 3061, 3031, 2228 cm-1. HRMS: m/z 208.0902
[M+], 208.0888 [C15H12O]; chiral HPLC (Daicel CHIRALCEL OD, hexane:
iPrOH ) 80:20, 254 nm): tr ) 8.2 (major), 12.1 (minor) min, 93% ee;
(13) (a) Asano, Y.; Hara, K.; Ito, H.; Sawamura, M. Org. Lett. 2007, 9,
3901. (b) Asano, Y.; Ito, H.; Hara, K.; Sawamura, M. Organometallics
2008, 27, 5984.
9a
20
23
[R]D ) +7.5 (c ) 1.0 in EtOH) {lit. [R]D ) +7.0 [c ) 1.0 in EtOH,
96% ee (R)]}.
Org. Lett., Vol. 12, No. 17, 2010
3861

yields than those with electron-donating groups (entries 1-5).
In each case, the enantioselectivity of the propargylic alcohols
7ab-7af showed excellent values (up to 95% ee). Other
aromatic aldehydes, 3-bromobenzaldehyde and 1- and 2-naph-
thaldehydes, exhibited high yields and excellent enantiose-
lectivity (entries 6, 8, and 9). Although the reaction of 5a
with cyclohexanecarboxaldehyde as a aliphatic aldehyde also
gave the corresponding propargylic alcohol 7ak in a high
yield, the decrese in the ee value was observed (entry 10).
Addition of other alkynes 5b-5e to benzaldehyde 6a
proceeded with high enantioselectivity (entries 11-14).
However, use of 5c-e resulted in low yields of the
corresponding alcohols (entries 12-14). It is noteworthy that
the Ru-phebox complex 1 could be recovered as the acetate
complex 4 in 49% yield after separation by silica gel column
chromatography (entry 7).
Table 2. Alkynylation of 6a with 5a Catalyzed by 1 in Various
Solventsa
entry
solvent
yieldb (%)
eec (%)
1
2
3
4
5
THF
1,2-dichloroethane
toluene
methanol
ethanol
72
48
51
60
64
87
78
90
95
94
a Reaction conditions: 5a (2 mmol), 6a (1 mmol), 1 (5 mol % Ru),
NaOAc (0.1 mmol), solvents (5 mL), 60 °C, 96 h. b Isolated yield.
c Determined by HPLC.
its maximum value probably due to a consecutive reaction
(Figure S2 in Supporting Information). In contrast, such a
phenomenon was not observed in 2-propanol-d8. Interest-
ingly, other alcohols also provided higher enantioselectivity
(up to 95% ee, entries 4 and 5). However, the yields of 7aa
in methanol and ethanol were lower than those in 2-propanol.
Next, the addition reaction of several alkynes to aromatic
or aliphatic aldehydes was examined using the Ru-phebox
complex 1 (5 mol % Ru) and NaOAc (10 mol %) in
2-propanol at 60 °C (Table 3). Benzaldehyde derivatives with
electron-withdrawing groups at the para-position gave better
To gain further insight into the catalytic reaction, the
reaction of 5a with Ru-phebox complexes in 2-propanol-
d8 was monitored by 1H NMR spectroscopy at 60 °C
(Scheme 1). Interestingly, it was found that 1 and 4 catalyzed
Scheme 1
.
H/D Exchange of 5a with 2-Propanol-d8 Catalyzed
by Ru-phebox Complexes
Table 3. Asymmetric Alkynylation of Aldehydes 6 with
Alkynes 5 Catalyzed by 1a
the H/D exchange reaction between the C(sp)-H of 5a and
2-propanol-d8 to give 5a-d1 (96% D for 1, 93% D for 4). In
those reactions, an expected ruthenium acetylide complex
was not detected.
In summary, we have developed a highly enantioselective
direct alkynylation reaction of aldehydes mediated by novel
chiral ruthenium complexes bearing phebox ligands. Further
investigation on the scope and limitations of the substrates
and the reaction mechanism are underway in our laboratory.
product
R1; R2
time
(h)
yieldb
(%)
eec
entry
(%)
1
2
3
4
5
6
7
8
Ph; 4-CF3C6H4 (7ab)
Ph; 4-BrC6H4 (7ac)
Ph; 4-NO2C6H4 (7ad)
Ph; 4-MeC6H4 (7ae)
Ph; 4-MeOC6H4 (7af)
Ph; 3-BrC6H4 (7ag)
Ph; 2-BrC6H4 (7ah)
Ph; 1-naphthyl (7ai)
Ph; 2-naphthyl (7aj)
Ph; C6H11 (7ak)
48
48
24
96
96
48
48
48
48
96
96
96
96
96
94
93
88
70
42
95
95
86
82
98
93
53
24
21
90
93
89
95
95
94
77
94
95
73
93
94
89
95
Acknowledgment. This research was partly supported by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan
(Concerto Catalysis; 460:18065011), and the Japan Society
for the Promotion of Science (18350049, 20750073).
9
10
11
12
13
14
4-MeC6H4; Ph (7ba)
4-CF3C6H4; Ph (7ca)
C6H11; Ph (7da)
Supporting Information Available: Experimental details
and characterization for products. This material is available
free of charge via the Internet at http://pubs.acs.org.
SiMe3; Ph (7ea)
a Reaction conditions: 5 (4 mmol), 6 (1 mmol), 1 (0.025 mmol), NaOAc (0.1
mmol), 2-propanol (5 mL), 60 °C. b Isolated yield. c Determined by HPLC.
OL1015338
3862
Org. Lett., Vol. 12, No. 17, 2010