Asymmetric addition of terminal acetylenes to aldehydes, catalyzed by Zn(OTf)2-cinchona alkaloid complexes

Article abstract of DOI:10.1055/s-2006-939049

Cinchona alkaloids in combination with zinc triflate catalyze the addition of acetylenes to aldehydes at room temperature with ee up to 89% for aliphatic aldehydes. Cinchonidine has proven to be the ligand of choice for the addition reaction whose outcome

Full text of DOI:10.1055/s-2006-939049

LETTER
885
Asymmetric Addition of Terminal Acetylenes to Aldehydes, Catalyzed by
Zn(OTf) –Cinchona Alkaloid Complexes
2
A
J
symmetr
e
ic
A
ddition
s
of Termi
p
nal
A
cetylen
e
es to
A
lde
h
r
ydes Ekström, Alexey B. Zaitsev, Hans Adolfsson*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Fax +46(8)154908; E-mail: hansa@organ.su.se
Received 12 January 2006
Although the price of Zn(OTf) is slightly higher as com-
2
Abstract: Cinchona alkaloids in combination with zinc triflate
catalyze the addition of acetylenes to aldehydes at room tempera-
ture with ee up to 89% for aliphatic aldehydes. Cinchonidine has
2
pared to ZnEt , the in situ generation of acetylenides is
2
much more promising, especially in its catalytic versions.
proven to be the ligand of choice for the addition reaction whose Moreover, recent stoichiometric modifications of this
outcome is demonstrated to be very sensitive to the alkaloid struc- method have proven efficient for the addition of acetyl-
18
ture. Aromatic aldehydes are less reactive and give adducts of low
optical purity. The more sterically hindered 2-bromo- and 2-nitro-
benzaldehydes are considerably more reactive in the reaction as
compared to their 4-substituted congeners.
enes to the keto functionality of a-keto esters.
The most successful ligands used for the zinc triflate
mediated addition of acetylenes to aldehydes are based on
N,N-dialkylated a,b-amino alcohols, and particularly,
high stereocontrol (up to 99% ee) is obtained with N-
methylephedrine (Figure 1).6
Key words: addition reactions, aldehydes, alkaloids, alkynes,
asymmetric catalysis
,15–17
Ph
Me
Ph
Me
The addition of acetylenes to carbonyl compounds re-
presents the most straightforward and atom economical
approach to propargyl alcohols known so far. The impor-
HO
NMe2
HO
NMe2
tance of these compounds in academic research and in Figure 1
industrial applications is the major driving force for the
constant development of this reaction. Among recent
Cinchona alkaloids (Figure 2) readily available from the
chiral pool are among the least expensive representatives
of N,N-dialkylated a,b-amino alcohols, and they have
already found extensive use in various asymmetric cata-
achievements in the field is the development of catalytic
1
–8
versions of this process. However, most of these proto-
9
cols still employ stoichiometric amounts of organometal-
lic reagents (mainly dimethyl or diethyl zinc) in order to
19
lytic applications.
3
,4,6–8
generate the reactive metal acetylenides.
A break-
Although these alkaloids contain several stereogenic
centers, the couples cinchonidine–cinchonine [1–2] and
quinine–quinidine [3–4] are sometimes called pseudo-
enantiomers due to the opposite configurations of the
amino alcohol moieties. Recently, compounds 1–3 were
through in this field was made by Carreira and coworkers
who used zinc acetylenides generated in situ from zinc
triflate and acetylenes for the addition to aldehydes.1
0–15
Soon afterwards catalytic versions of this reaction were
6
,15–17
realized.
The use of the latter method does not only
employed as ligands in the ZnEt -mediated addition of
eliminate the inconvenient employment of already manu-
factured organometallic compounds, it also allows for a
considerable decrease of the amounts of metal precursor.
2
3,5,20
phenylacetylene to carbonyl compounds.
In the case
of benzaldehyde 1 and 3 gave low enantioselectivity3
,5
R
N
N
N
N
(S)
(R)
(S)
(S)
(R)
OH
HO
OH
HO
(R)
(R)
(S)
MeO
MeO
N
N
N
N
1
2
3
4 R = CH=CH2
R = Et
5
Figure 2
SYNLETT 2006, No. 6, pp 0885–0888
0
4.
0
4.
2
0
0
6
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939049; Art ID: G00506ST
Georg Thieme Verlag Stuttgart · New York
©

8
86
J. Ekström et al.
LETTER
which, however, was dramatically improved by the addi- Table 1 Different Cinchona Alkaloids as Ligands in the Addition of
3
Phenylacetylene to 2-Methylpropionaldehyde (Scheme 1)
tion of titanium isopropoxide. The triethylaluminum-
promoted addition of phenylacetylene to acetophenone in
Entry
Liganda Temp (°C) Time (h)
Yield (%) ee (%)b
the presence of 3 as a ligand was reported to give up to
2
0
8
9% ee.
1
2
3
4
5
6
7
8
9
2
4
5
4
3
2
1
1
1
1
1
1
1
1
1
60
60
r.t.
r.t.
r.t.
r.t.
60
60
r.t.
4
6
6
70
48
16
–
–34
–26
2
In this communication we present results on the use of
cinchona alkaloids as ligands in the Zn(OTf) -catalyzed
2
2
1
24
24
24
24
6
addition of acetylenes to aldehydes.
In an initial screening of ligands in the reaction between
-methylpropionaldehyde and phenylacetylene
Scheme 1) catalyzed by Zn(OTf) , we found that ligand
n.d.
29
2
2
3
(
2
1
gave the best result with respect to yield and enantio-
71
71
82
83
61
56
42
69
60
53
selectivity (Table 1).
63
61
74
73
72
69
70
67
67
OH
O
24
24
27
24
24
24
24
6
Zn(OTf)2, L*
+
Ph
Et3N
PhMe
H
Ph
1
1
0
Scheme 1
1c
r.t.
r.t.
r.t.
r.t.
r.t.
The influence of temperature on the reaction outcome 12d
strongly depended on the alkaloid structure. For instance,
1
1
1
3e
when 1 was employed as ligand, a decrease in reaction
temperature from 60 °C to room temperature increased
the enantiomeric excess of the product from 63% to 74%.
Performing the reaction at 4 °C did not improve the selec-
tivity. In contrast, alkaloids 2, 4 and hydroquinidine (5)
gave relatively poor enantioselectivity at 60 °C, and, more
4f
5
a
2
0 mol% Zn(OTf) and 22 mol% ligand unless otherwise stated.
2
b
Excess of the enantiomer with higher retention time was accepted
surprisingly, only racemic product was obtained with as positive.
c
Double loadings of substrates (i.e., 10 mol% of the catalyst).
Fourfold loadings of substrates (i.e., 5 mol% of the catalyst).
THF as a solvent.
these ligands at room temperature. Interestingly, ligands 1
and 3, differing only by the presence of a methoxy group
in the quinoline ring, gave dramatically different results
even though the substituent is positioned relatively distant
from the amino alcohol moiety. These observations de-
monstrate an apparent high sensitivity in the chiral molec-
ular recognition of the substrate by the catalytic complex,
an effect, which must origin from the other stereogenic
centers and/or the distal substituents.
d
e
f
CH Cl as a solvent.
2
2
less distinguishable from hydrogens by the chiral catalytic
complex as compared to the alkyl chains of aliphatic alde-
hydes. Thus, the more sophisticated three-dimensional
architecture of the Zn–cinchona alkaloid complex has a
stronger influence on the molecular recognition of the
substrates as compared to the corresponding N-methyl-
ephedrine complex, which gives more or less similar
Reduction of the catalyst loadings from 20 mol% to 10
mol% and 5 mol%, respectively, resulted in a consider-
able drop of yield, however, the enantioselectivity was
almost unaffected (entries 11 and 12, Table 1). In contrast
to the results obtained by Carreira and coworkers, who
observed a significant drop of enantioselectivity when
toluene was replaced by THF or dichloromethane,11 we
noticed only a small deterioration of the ee upon the
change of reaction media (entries 13 and 14, Table 1).
stereochemical results for aliphatic and aromatic ke-
tones.11–13,17
The addition of phenylacetylene to benzaldehyde
(
Table 2, entry 4) employing ligand 2 resulted in a modest
enantiodifferentiation (26% ee). However, in comparison
to the low enantiocontrol (2% ee) obtained in the same
reaction with 2-methylpropionaldehyde (Table 1, entry 6)
the former result is most instructive. The close to racemic
product mixture obtained in the reaction with 2-methyl-
propionaldehyde is clearly a result of poor discrimination
between the enantiofaces of the substrate, rather than a
difficulty in the formation of the catalytically active com-
plex. The reactivity of different benzaldehydes was
strongly influenced by the nature and position of the sub-
stituents on the aromatic ring. Surprisingly, the addition of
phenylacetylene to the sterically more hindered carbonyl
Further, using 1 as a ligand, the reaction was extended to
other aldehydes and acetylenes (Table 2). The increased
steric encumbrance in 2,2-dimethylpropionaldehyde rela-
tive to 2-methylpropionaldehyde allowed for a significant
improvement of the enantioselectivity in the phenyl-
acetylene addition to the former aldehyde (entry 1,
Table 2). Phenylacetylene addition to aromatic aldehydes
gave lower yields and enantioselectivities as compared to
their aliphatic counterparts. This might be due to the flat
nature of the aromatic substituents, which makes them
Synlett 2006, No. 6, 885–888 © Thieme Stuttgart · New York

LETTER
Asymmetric Addition of Terminal Acetylenes to Aldehydes
887
Table 2 Addition of Phenylacetylene to Different Aldehydes Catalyzed by Zn(OTf) –Cinchona Alkaloid System
2
OH
O
H
Zn(OTf)2, L*
R1
R2
+
R1
Et3N
PhMe
R2
Entry
R1
R2
Ligand
Time (h)a
Yield (%)
ee (%)
89
1
2
3b
4
5
6
7
8
9
t-Bu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-Bu
Ph
Ph
1
1
1
2
1
1
1
1
1
1
1
1
1
24
24
24
24
24
24
61
Ph
26
27
Ph
16
12
Ph
7
–26
n.d.
n.d.
n.d.
n.d.
25
4-MeO-C H -
Traces
Traces
Traces
–
6
4
2-MeO-C H -
6
4
4-Me-C H -
6
4
4-NO -C H -
24
24
24
24
24
24
2
6
4
3-NO -C H -
30c
68c
38c
–
2
6
4
1
1
1
1
0
1
2
3
2-NO -C H -
22
2
6
4
2-NO -C H -
56
2
6
4
4-Br-C H -
n.d.
64
6
4
2-Br-C H -
48c
6
4
a
b
c
All the reactions were run at r.t.
The reaction in the presence of 1 equiv Ti(i-PrO) .
4
1
Conversion determined by H NMR.
group in 2-bromo- and 2-nitrobenzaldehydes proceeded Acknowledgment
much easier than in their 4-substituted congeners. This be-
We thank the Swedish Research Council and the Wenner-Gren
Foundation for financial support.
havior could be explained by a strong inductive effect
from the 2-substituents. However, chelation assistance
enforcing coordination of carbonyl oxygen to zinc, and
hence activating the carbonyl group, is probably the main
reason why 2-substituted derivatives are more reactive.
Expectedly, due to the lower acidity of the acetylenic hy-
drogen, 1-hexyne showed considerably poorer reactivity
as compared to phenylacetylene (cf. entries 10 and 11,
Table 2). On the other hand, significantly higher enantio-
selectivity was obtained employing the alkyl-substituted
References and Notes
(
1) (a) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757.
(b) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855.
(2) Xu, M.-H.; Pu, L. Org. Lett. 2002, 4, 4555.
(3) Kamble, R. M.; Singh, V. K. Tetrahedron Lett. 2003, 44,
5347.
(
(
4) Pu, L. Tetrahedron 2003, 59, 9873.
5) Dahmen, S. Org. Lett. 2004, 6, 2113.
acetylene. In contrast to the ZnEt -based alkynylation of
2
(6) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org.
Chem. 2004, 4095.
aldehydes, the addition of Ti(i-PrO) to the reaction
4
mixture only deteriorated the reaction outcome (entry 3,
Table 2).
(7) Cozzi, P. G.; Alesi, S. Chem. Commun. 2004, 2448.
(8) Zhou, Y.; Wang, R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.;
Han, Z. Org. Lett. 2004, 6, 4147.
In conclusion, we have demonstrated that cinchona
alkaloids in combination with zinc triflate catalyze the
addition of acetylenes to aldehydes, and the formed prop-
argyl alcohols were obtained in up to 89% enantioselec-
tivity. The activity and selectivity of the catalysts is very
dependent on slight variations in the alkaloid structure.
Distal stereogenic centers play a dramatic role in the
enantiocontrol, making matched–mismatched behavior
strongly pronounced. In addition, the enantiodifferen-
tiation is apparently highly sensitive to the nature of the
aldehydes and acetylenes.
(
9) It should be noted that addition of acetylenes to aldimines in
contrast to aldehydes can be efficiently catalyzed by
complexes of copper with chiral ligands, affording chiral
propargyl amines in high yields and enantioselectivity. See:
(
(
a) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638.
b) Rosa, J. N.; Santos, A. G.; Afonso, C. A. M. J. Mol.
Catal. A: Chem. 2004, 214, 161. (c) Benaglia, M.; Negri,
D.; Dell’Anna, G. Tetrahedron Lett. 2004, 8705.
(
10) Boyall, D.; López, F.; Sasaki, H.; Frantz, D.; Carreira, E. M.
Org. Lett. 2000, 2, 4233.
(11) Frantz, D. E.; Fässler, R.; Tomooka, C. S.; Carreira, E. M.
Acc. Chem. Res. 2000, 33, 373.
Synlett 2006, No. 6, 885–888 © Thieme Stuttgart · New York

8
88
J. Ekström et al.
LETTER
(
(
(
12) Frantz, D. E.; Fässler, R.; Carreira, E. M. J. Am. Chem. Soc.
000, 122, 1806.
13) Sasaki, H.; Boyall, D.; Carreira, E. M. Helv. Chim. Acta
001, 84, 964.
14) (a) El-Sayed, E.; Anand, N. K.; Carreira, E. M. Org. Lett.
001, 3, 3017. (b) Boyall, D.; Frantz, D. E.; Carreira, E. M.
Org. Lett. 2002, 4, 2605. (c) Diez, R. S.; Adgerc, B.;
Carreira, E. M. Tetrahedron 2002, 58, 8341.
15) Fässler, R.; Tomooka, C. S.; Frantz, D. E.; Carreira, E. M.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5843.
(20) Liu, L.; Wang, R.; Kang, Y.-F.; Chen, C.; Xu, Z.-Q.; Zhou,
Y.-F.; Ni, M.; Cai, H.-Q.; Gong, M.-Z. J. Org. Chem. 2005,
70, 1084.
2
2
(21) In a typical experiment the reactions were run under
conditions employed by Carreira and coworkers for catalytic
1
6
2
addition of acetylenes to aldehydes in toluene. Zn(OTf)2
(0.036 g, 0.10 mmol, 20 mol%) was heated in a standard
Radley reaction carousel test tube at 125 °C in vacuo (<1
mbar) for 5 h. After cooling the tube to r.t. and releasing
vacuum the cinchona alkaloid was added (0.11 mmol, 22
mol%) and the mixture was evacuated for 0.5 h. To it was
(
(
16) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687.
added dry toluene (0.5 mL) and Et N (0.025 g, 0.25 mmol),
3
(
(
17) Chen, Z.; Xiong, W.; Jiang, B. Chem. Commun. 2002, 2098.
18) (a) Jiang, B.; Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451.
and the tube content was stirred for 2 h at r.t. Subsequent
addition of acetylene (0.60 mmol) and stirring for 0.25 h at
r.t. was followed by addition of aldehyde (0.50 mmol). The
reaction was performed at r.t. or 60 °C (temperature and time
are presented in Table 1 and Table 2). After the required
reaction time, the reaction mixture was filtered through a
plug of silica, using EtOAc as eluent, and the filtrate was
evaporated in vacuo to give the product. The ee of the
products was determined by chiral-phase HPLC analysis.
(
b) Jiang, B.; Si, Y.-G. Angew. Chem. Int. Ed. 2004, 43, 216.
(
19) For recent reviews, see: (a) Lygo, B.; Andrews, B. I. Acc.
Chem. Res. 2004, 37, 518. (b) Tian, S.-K.; Chen, Y.; Hang,
J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37,
621. (c) Kacprzak, K.; Gawroński, J. Synthesis 2002, 961.
Synlett 2006, No. 6, 885–888 © Thieme Stuttgart · New York