Enantioselective addition of terminal alkynes to aldehydes catalyzed by a Cu(I)-TRAP complex

Article abstract of DOI:10.1021/ol701534n

The addition of terminal alkynes to aromatic aldehydes was carried out under mild conditions in the presence of a Cu-phosphine complex, which was prepared in situ from Cu(O-t-Bu) and TRAP chiral bisphosphine, to yield enantiomerically enriched propargyl alcohols with moderate enantioselectivities. Furthermore, according to stoichiometric reactions, the reaction presumably involves the addition of a TRAP-coordinated Cu(I) acetylide to an aldehyde.

Full text of DOI:10.1021/ol701534n

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3901-3904
Enantioselective Addition of Terminal
Alkynes to Aldehydes Catalyzed by a
Cu(I)−TRAP Complex
Yohsuke Asano, Kenji Hara, Hajime Ito, and Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido UniVersity,
Sapporo 060-0810, Japan
sawamura@sci.hokudai.ac.jp
Received June 29, 2007
ABSTRACT
The addition of terminal alkynes to aromatic aldehydes was carried out under mild conditions in the presence of a Cu−phosphine complex,
which was prepared in situ from Cu(O-t-Bu) and TRAP chiral bisphosphine, to yield enantiomerically enriched propargyl alcohols with moderate
enantioselectivities. Furthermore, according to stoichiometric reactions, the reaction presumably involves the addition of a TRAP-coordinated
Cu(I) acetylide to an aldehyde.
The addition of terminal alkynes to aldehydes serves as an
important carbon-carbon bond formation reaction in the
synthesis of complex molecules.1 Given the recent demand
for highly efficient and environmentally friendly processes,
the direct alkynylation of aldehydes that avoids the use of a
stoichiometric amount of a reagent has become highly
desirable. While recent efforts on this subject have led to
the discovery of various catalytic reactions that involve metal
species such as Cs,2 Zn,3 In,4 Ru-In,5 Rh,6 and Ag,7 reactions
that feature the catalysis of Cu, to the best of our knowledge,
have yet to be reported. Although Cu is the first transition-
metal element that was shown to promote carbonyl alkynyl-
ations, the catalytic use of a Cu species was hampered by
the low reactivity of Cu(I) acetylides.8 Herein, we report the
direct addition of terminal alkynes to aromatic aldehydes
under mild conditions catalyzed by a Cu-phosphine com-
plex, which was prepared in situ from Cu(O-t-Bu) and TRAP
chiral bisphosphine,9,10 to produce enantiomerically enriched
propargyl alcohols with moderate enantioselectivities. Fur-
thermore, this is the first application of TRAP to Cu catalysis.
Recently, we have reported on the significant rate-
accelerating effects of Xantphos ligands11 in the Cu(I)-
catalyzed dehydrogenative silylation of alcohols12 and in the
(8) Reppe, W. Liebigs Ann. Chem. 1955, 596, 25-32.
(9) For the synthesis, see: (a) Kuwano, R.; Sawamura, M. In Catalysts
for Fine Chemical Synthesis, Volume 5: Regio- and Stereo-Controlled
Oxidations and Reductions; Roberts, S. M., Whittall, J., Eds.; John Wiley
& Sons: West Sussex, 2007; pp 73-86. (b) Sawamura, M.; Hamashima,
H.; Sugawara, M.; Kuwano, R.; Ito, Y. Organometallics 1995, 14, 4549.
(c) Kuwano, R.; Sawamura, M.; Okuda, S.; Asai, T.; Ito, Y.; Redon, M.;
Krief, A. Bull. Chem. Soc. Jpn. 1997, 70, 2807.
(10) For selected papers for the application of TRAP ligands, see: (a)
Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653. (b) Kuwano, R.;
Sawamura, M.; Ito, Y. Bull. Chem. Soc. Jpn. 2000, 73, 2571. (c) Kuwano,
R.; Sawamura, M.; Shirai, J.; Takahashi, M.; Ito, Y. Bull. Chem. Soc. Jpn.
2000, 73, 485. (d) Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc.
1996, 118, 3309. (e) Goeke, A.; Sawamura, M.; Kuwano, R.; Ito, Y. Angew.
Chem., Int. Ed. Engl. 1996, 35, 662. (f) Sawamura, M.; Hamashima, H.;
Ito, Y. J. Am. Chem. Soc. 1992, 114, 8295.
(11) (a) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14,
3081. (b) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Acc.
Chem. Res. 2001, 34, 895.
(1) For reviews, see: (a) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N.
Eur. J. Org. Chem. 2004, 4095. (b) Pu, L. Tetrahedron 2003, 59, 9873.
(2) Tzalis, D.; Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 1463.
(3) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
(4) (a) Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. Org.
Lett. 2005, 7, 1363. (b) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M.
J. Am. Chem. Soc. 2005, 127, 13760.
(5) Wei, C.; Li, C.-J. Green Chem. 2002, 4, 39.
(6) Dhondi, P. K.; Chisholm, J. D. Org. Lett. 2006, 8, 67.
(7) Yao, X.; Li, C.-J. Org. Lett. 2005, 7, 4395.
10.1021/ol701534n CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/25/2007

reaction of a diboron and allylic carbonates to produce
allylboron compounds.13 The high catalytic activities are
attributable to the large P-Cu-P bite angle that induces large
distributions of active monomeric Cu species, such as
(Xantphos)Cu-X [X ) OR, H, B(OR)2], in the aggregation
equilibriums. Consequently, the results prompted us to
examine large bite-angle phosphines for the activation of Cu
catalysis toward the addition of terminal alkynes and
aldehydes via deaggregation of Cu acetylides.
Because higher yield of 3aa was obtained by introducing a
bulky substituent in the P-phenyl groups of Xantphos (entry
10),16 we can assume that the steric congestion around the
metal center exerts an additional effect to the deaggregation
of the Cu acetylide. Accordingly, the use of TRAP chiral
bisphosphine, which feature an extraordinarily large bite
angle, resulted in a significantly higher yield of 3aa (77%,
entry 11). Furthermore, the enantiomeric excess of the
product indicated that the chirality of the (S,S)-(R,R)-TRAP
ligand can exert some influence on the enantioselectivity of
the addition reaction.
A series of Cu(I)-phosphine catalysts were prepared in
situ by mixing Cu(O-t-Bu) with phosphines (Table 1).
It should be noted that only DTBM-Xantphos and Ph-
TRAP gave homogeneous, yellow solution under the reaction
conditions (Table 1, entries 10 and 11). Otherwise, the
reaction mixture was heavily suspended with fluorecent
yellow precipitates, implying the formation of unreactive,
oligomeric copper(I) acetylides (entries 1-9).
Table 1. Ligand Effect in the Cu-Catalyzed Addition of 2a to
1aa
Upon screening other chiral ligands that include bisphos-
phines with various backbone structures and P-substitution
patterns as well as nitrogen-based ligands, our results
revealed that only the TRAP ligand exhibited significant
catalyst-activating effect and enantioselectivity (Figure 1),
entry
phosphine
NMR yieldb (%)
1
2c
3
4
5
none
PPh3
dppe
dppp
dppb
dppf
0
0
0
0
0
0
6
7
DPEphos
trace
8
DBFphos
2
9
Xantphos
10
10
11
DTBM-Xantphos
(S,S)-(R,R)-Ph-TRAP
20
77 (27% ee, R)
a 1a (0.24-0.62 mmol, 1 M)/2a/Cu(O-t-Bu)/phosphine ) 1:2:0.1:0.1
unless otherwise noted. b Unreacted 1a and 2a were quantitatively recovered.
c 1a/2a/Cu(O-t-Bu)/PPh3 ) 1:2:0.1:0.2.
Catalytic activities of the resulting Cu(I) complexes (10 mol
%) were evaluated by the yields of propargylic alcohol 3aa
via reaction of benzaldehyde (1a) and phenylacetylene (2a,
2 equiv) in toluene at 60 °C for 6 h.
Reactions that involve Cu(O-t-Bu) alone or in combination
with PPh3 (Cu/P ) 1:2) or bisphosphines that possess an
ordinary natural bite angle (such as dppe, dppp, dppb, and
dppf) (Table 1, entries 1-6) were unsuccessful. In contrast,
a slight conversion (10%) was observed when Xantphos was
employed (entry 9).14 Reactions that involved DPEphos12a
and DBFphos,12a,15 which are structurally related to Xantphos,
showed traces of conversion (entries 7 and 8, respectively).
Figure 1. Chiral ligands and yields of 3aa (1a/2a/Cu(O-t-Bu)/
ligand ) 1:2:0.1:0.1, toluene, 60 °C, 6 h).
thus confirming the importance of having a large bite angle
for the effectiveness of the Cu catalysts.
To optimize the Cu-TRAP catalytic system, the conver-
sion to 3aa was carried out using various reaction solvents
(14) The reaction in the presence of K(O-t-Bu) (10 mol %) consumed
the aldehyde (1a, 4% recovery) but gave no addition product 3aa. For the
catalysis of K(O-t-Bu) toward the addition of terminal alkynes to ketones,
see: Babler, J. H.; Liptak, V. P.; Phan, N. J. Org. Chem. 1996, 61, 416.
(15) Haenel, M. W.; Jakubik, D.; Rothenberger, E.; Schroth, G. Chem.
Ber. 1991, 124, 1705.
(12) (a) Ito, H.; Watanabe, A.; Sawamura M. Org. Lett. 2005, 7, 1869.
See also (Au catalysis): (b) Ito, H.; Takagi, K.; Miyahara, T.; Sawamura,
M. Org. Lett. 2005, 7, 3001.
(13) Ito, H.; Kawakami, C.; Sawamura, M. J. Am. Chem. Soc. 2005,
127, 16034.
(16) For the synthesis and use of DTBM-Xantphos, see ref 12a.
3902
Org. Lett., Vol. 9, No. 20, 2007

electron-withdrawing p-CF3 (entry 2) substituent resulted in
a substantial drop in the yield. For the reactions of aliphatic
alkynes 2d-f, our catalytic system was also found to be
effective; however, drastically lower yields were observed
with increasing R-branching of the alkyl substituent (entries
3-5). Poor yields were obtained for the reactions of
trimethylsilylacetylene (2g, entry 6).
Table 2. Solvent Effect in the Enantioselective Cu-Catalyzed
Addition of 2a to 1aa
Next, the effect of various aldehydes on the reactivity and
enantioselectivity were examined using the reaction with 2a
(10 mol % of Cu-TRAP, 40 °C, 24 h, Table 4). As shown
in entries 1-3, 6, and 8, electron-donating substituents (alkyl,
-OMe) on the para and meta positions of aromatic aldehydes
decreased the reactivity along with slightly positive effects
on the enantioselectivity. On the other hand, as shown in
entries 4, 5, and 7, electron-withdrawing groups on the para
(-Cl, -F) and meta positions (-CO2Me) enhanced the
reactivity with slightly negative effects on the selectivity. It
is noteworthy that an o-Me group (entry 9) showed activating
effects with slightly negative effect on the selectivity,
whereas a bulky phenyl group in the same position caused
overcrowded conditions (entry 10). Similar steric effects were
also observed between the isomeric naphthaldehydes (entries
12, 13). In the cases of aliphatic aldehydes such as 1o and
1p, the Cu-TRAP catalyst did not exhibit any activity
(entries 14 and 15).
entry
solvent
toluene
benzene
CH2Cl2
THF
DMI
MeOH
EtOH
T (°C) time (h) isolated yieldb (%) ee (%)
1
2
3
4
5
6
7
8
9
60
60
60
60
60
60
60
60
60
60
40
6
6
6
6
6
6
6
6
6
74
69
0
27
23
N.A.
33
31
25
29
30
35
42
51
50
24
91
83
87
81
91
87
i-PrOH
(i-Pr)2CHOH
t-BuOH
10
6
24
11c t-BuOH
a 1a (0.24-0.62 mmol, 1 M)/2a/Cu(O-t-Bu)/Ph-TRAP ) 1:2:0.1:0.1.
b Unreacted 1a and 2a were quantitatively recovered. c [1a] ) 0.5 M.
(60 °C, 6 h). As shown in Table 2 (entries 1-10), alcohols
were more effective as solvents; furthermore, higher enan-
tiomeric excesses of 3aa corresponded to larger alcohols
(entries 6-10). Based on entry 10, which afforded (R)-3aa
with 42% ee in 91% yield, the optimal solvent was identified
as t-BuOH. Additionally, the use of t-BuOH allowed a lower
reaction temperature (40 °C) that afforded 3aa with a higher
enantiomeric excess (51% ee, entry 11).
The influence of various alkyne substrates on the reactivity
and enantioselectivity were examined using the reaction with
1a under constant conditions (10 mol % Cu-TRAP, 40 °C,
24 h, Table 3). Whereas the electron-donating p-MeO
To gain insight into the mechanism of the Cu-TRAP
catalysis, stoichiometric reactions were carried out. A yellow,
homogeneous mixture of equimolar amounts of Ph-TRAP
and Cu(O-t-Bu) in C6D6 showed several broad signals in the
31P NMR spectrum. Upon addition of 2a (1 equiv), the
yellow color intensified, while the 31P NMR signals con-
verged into a major singlet (δ 10.1) accompanied by two
minor broad signals (δ 8.51 and 13.1). Based on the similarity
to that of [CuCtCPh]n and Ph-TRAP (Cu/TRAP ) 1:1, 60
°C, 3 h), the major signal was assigned to the TRAP-
coordinated Cu(I) acetylide species [Cu(η1-CtCPh)(Ph-
TRAP)] (A) (see the Supporting Information).
Table 3. Enantioselective Cu-Catalyzed Addition of Various
Alkynes to 1aa
To investigate the reactivity of acetylide A, a solution
containing A and t-BuOH, which was released from Cu(O-
t-Bu), was treated with 1a (1 equiv) and heated at 60 °C for
15 h. According to the 1H NMR spectrum, both complex A
and 1a were intact. Furthermore, changes in the spectrum
were not observed even upon treatment of 5 equiv of t-BuOH
(as a possible proton source) and heating at 60 °C for an
Scheme 1. Proposed Mechanism for Cu-TRAP-Catalyzed
Alkynylation of Aldehydes
a 1a (0.20-0.22 mmol, 0.5 M)/2/Cu(O-t-Bu)/Ph-TRAP ) 1:2:0.1:0.1.
b Unreacted aldehyde 1a and alkyne 2 were quantitatively recovered unless
otherwise noted. c Recovery of alkyne was not quantitative.
substituent on the aromatic ring of phenylacetylene (entry
1) did not affect the yield or the enantiomeric excess, the
Org. Lett., Vol. 9, No. 20, 2007
3903

Table 4. Enantioselective Cu-Catalyzed Addition of 2a to Various Aldehydesa
a 1 (0.2-0.22 mmol)/2a/Cu(O-t-Bu)/Ph-TRAP ) 1:2:0.1:0.1. b Isolated yield. Unreacted aldehyde and alkyne 2a were quantitatively recovered.
additional 3 h (except for the increased t-BuOH signals).
Addition product 3aa was produced when the mixture was
treated with 19 equiv of 2a (56% conversion, 60 °C, 14 h).
On the basis of these results, a possible reaction mecha-
nism (Scheme 1) can be described as follows: first, (pro-
pargyl alcoholato) Cu(I) (B) is formed from acetylide A and
aldehyde 1 through a reversible process with a strong
preference toward the starting materials. Next, propargylic
alcohol 3 is formed through metathesis between Cu(I)
alkoxide B and alkyne 2, which is irreversibly driven by the
stability of Cu(I) acetylide A.
alcohols can increase the enatioselectivity. Such solvent
effects imply that the alcohols can directly participate in the
C-C bond formation, as shown in Scheme 2.
We demonstrated the catalytic activity of a Cu(I) complex
with TRAP chiral bisphosphine for the direct addition of
terminal alkynes to aldehydes to produce enantiomerically
enriched propargyl alcohols, under mild conditions, with
moderate enantioselectivities. Furthermore, our studies show
that the TRAP ligand is crucial for the Cu catalytic system.
Insight into the reaction mechanism was gained via stoichio-
metric reactions and may help in the design of more advanced
catalysts.
Acknowledgment. This work was supported by Grant-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy.
Scheme 2. Possible Participation of Alcohol
Supporting Information Available: Experimental pro-
cedures and NMR spectra for stoichiometric reactions. This
material is available free of charge via the Internet at
http://pubs.acs.org.
As mentioned above, our studies have revealed that the
use of alcohols can accelerate the reaction, and bulkier
OL701534N
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Org. Lett., Vol. 9, No. 20, 2007