[2,2]paracyclophane-based N,O-ligands in alkenylzinc additions to aldehydes

Article abstract of DOI:10.1021/ol016954r

(matrix presented) The application of planar and central chiral [2,2]paracyclophane-based N,O-ligands in asymmetric alkenylzinc additions to various aldehydes is described, which gives rise to very high ee's especially for difficult substrates. A fine-tuning of the alkenylzinc species by employing different transmetalation reagents is reported, allowing control of the steric bulk of the alkenylzinc species and thus the selectivity of the catalysis.

Full text of DOI:10.1021/ol016954r

ORGANIC
LETTERS
2001
Vol. 3, No. 25
4119-4122
[2,2]Paracyclophane-Based N,O-Ligands
in Alkenylzinc Additions to Aldehydes
,‡
Stefan Dahmen† and Stefan Bra1se*
Kekule´-Institut fu¨r Organische Chemie und Biochemie der Rheinischen
Friedrich-Wilhelms-UniVersita¨t Bonn, Gerhard-Domagk-Strasse 1,
D-53121 Bonn, Germany, and Institut fu¨r Organische Chemie der
Rheinisch-Westfa¨lischen Technischen Hochschule Aachen,
Professor-Pirlet-Strasse 1, D-52074 Aachen, Germany
braese@uni-bonn.de
Received October 24, 2001
ABSTRACT
The application of planar and central chiral [2,2]paracyclophane-based N,O-ligands in asymmetric alkenylzinc additions to various aldehydes
is described, which gives rise to very high ee’s especially for difficult substrates. A fine-tuning of the alkenylzinc species by employing
different transmetalation reagents is reported, allowing control of the steric bulk of the alkenylzinc species and thus the selectivity of the
catalysis.
Asymmetric organozinc additions to carbonyl compounds
are among the most extensively studied catalytic reactions
in modern organic synthesis. In a recent review, Pu and Yu
summarized the results of diethylzinc additions carried out
with approximately 600 individual catalysts in the past
decade.1 Very recent developments in this field are asym-
metric arylation reactions, namely, the addition of phenylzinc
reagents to carbonyl compounds, which gives rise to di-
phenylmethanols and related compounds.2
However, the application of alkenylzinc reagents in
asymmetric catalysis has so far been limited to very few
examples, and the methodology is far from being general.
The addition of alkenylzincs to carbonyl compounds affords
the synthetically very useful chiral allyl alcohols, which are
key intermediates in various reactions.3
protocols. Oppolzer and Radinov prepared diethenylzinc by
the reaction of ethenyl Grignard reagents with ZnCl2 and
alkenylzinc bromides from alkenyllithium and ZnBr2.4 Later,
the same authors reported the preparation of alkenylzinc
reagents for the asymmetric addition to aldehydes by reaction
of terminal alkynes with dicyclohexylborane followed by
boron-zinc exchange. By using Noyori’s DAIB ligand,5
good enantioselectivities were achieved for certain aromatic
and aliphatic aldehydes.6,7 In the same paper,6 the authors
also screened a couple of amino alcohols, which are usually
successfully applied in diethylzinc additions to aldehydes,
(3) Allyl alcohols are substrates for, e.g., cyclopropanation reactions,
aziridination reactions, ene-reactions, epoxidations, dihydroxylations, meth-
oxy selenations, iodo hydroxylations, brominations, and allylic substitution
reactions.
(4) (a) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988, 29, 5645.
(b) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777.
(5) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49. (b) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem.
Soc. 1986, 108, 6071.
(6) (a) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75. 10.
This reaction was recently extended to intramolecular cyclization reac-
tions: (b) Oppolzer, W.; Radinov, R. N.; El-Sayed, E. J. Org. Chem. 2001,
66, 4766.
Generally, alkenylzinc reagents are not temperature-stable
and are therefore prepared in situ using transmetalation
† Institut fu¨r Organische Chemie der RWTH Aachen.
‡ Kekule´-Institut der Rheinischen Friedrich-Wilhelms-Universita¨t Bonn.
(1) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757.
(2) For a recent review, see: Bolm, C.; Hildebrand, J. P.; Muniz, K.;
Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284.
10.1021/ol016954r CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/20/2001

but with these ligands, only moderate selectivities were
obtained.
Scheme 1. Generation and Reaction of Alkenylzinc Reagents
Wipf et al. developed a method to prepare alkenylzinc
reagents by in situ transmetalation of alkenylzirconocenes
synthesized by hydrozirconation of alkynes using Cp2ZrHCl
(Schwartz reagent).8 However, relatively large amounts of
ligand had to be employed (10%) to suppress the background
reaction catalyzed by zirconocene byproducts.
During a ligand screening employing various hydroxy
imine, hydroxy ketimine, and amino alcohol ligands based
on the [2,2]paracyclophane backbone, we discovered that
ketimines such as 1 and 2 (Figure 1) showed superior
initially only employed diethylzinc as a 1 M stock solution
in hexane. Addition of the ligand and the aldehyde furnishes
the chiral allyl alcohol product 7.
Although the original Oppolzer protocol essentially em-
ploying equimolar amounts of borane, alkyne, diethylzinc,
and aldehyde gave rise to the correct products, in our hands
the yields were poor (usually below 50%). Increasing the
amount of borane 4 to 1.5 equiv and employing an excess
of diethylzinc (2 equiv with regard to the aldehyde)
substantially improved the isolated yield to around 80%.
Also, addition of 1 mL of toluene was beneficial, as it
obviously improves the solubility of certain substrates at low
temperatures.10
The four paracyclophane ligands depicted in Figure 1 were
tested using these optimized conditions with 1-octyne as the
alkenylzinc precursor and benzaldehyde at -10 °C (Table
1, entries 1-4). At 2% catalyst loading, good enantioselec-
Figure 1. [2,2]Paracyclophane-based ketimine ligands.
selectivity and activity in the diethylzinc addition to benz-
aldehyde and revealed cooperative effects arising from the
combination of the different chirotopic elements of the
ligands (chiral cooperativity). The ketimines 1 and 2 have
first been synthesized by Rozenberg and Belokon, who used
them for the resolution of the corresponding racemic hy-
droxyketones.9 Here, we will report on the application of
these ligands in the asymmetric alkenylzinc addition to
aldehydes.
Table 1. Optimization of Reaction Conditions and Ligand
Screening
The protocol we used relies on the method initially
developed by Oppolzer et al.6 Hydroboration of alkynes with
dicyclohexylborane, prepared in situ from borane dimethyl
sulfide complex and cyclohexene, gives rise to the [(E)-1-
alkenyl]boranes 4, which were directly treated with diethyl-
zinc (Scheme 1). The transmetalation to give the alkenylzinc
species 5 takes place even at -78 °C and is complete within
a couple of minutes (vide infra).
entry
ligand (mol %)
temp (°C)
yield (%)
ee (%)a
1
2
3
4
5
6
(Rp,S)-1 (2)
(Sp,S)-1 (2)
(Rp,S)-2 (2)
(Sp,S)-2 (2)
(Rp,S)-2 (5)
(Rp,S)-2 (2)
-10
-10
-10
-10
-20
-30
64
70
62
69
57
71
68 (S)
81 (R)
86 (S)
85 (R)
90 (S)
86 (S)
a Determined by HPLC (Chiracel OD). See ref 12.
As Oppolzer et al.6 and Wipf et al.8 did not find significant
differences between the use of diethyl- or dimethylzinc, we
tivities ranging from 68% to 86% were obtained. The
diastereomers 2 gave essentially the same selectivities while
producing the opposite enantiomers. The level of selectivity
(7) The addition of vinylzinc has also been studied: (a) von dem Bussche-
Hu¨nnefeld, J. L.; Seebach, D. Tetrahedron 1992, 48, 5719. (b) Soai, K.;
Takahashi, K. J. Chem. Soc., Perkin Trans. 1 1994, 1257. (c) Shibata, T.;
Nakatsui, K.; Soai, K. Inorg. Chim. Acta 1999, 296, 33.
(8) (a) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197. (b) Wipf, P.;
Xu, W. Org. Synth. 1996, 74, 205. (c) Wipf, P.; Ribe, S. J. Org. Chem.
1998, 63, 6454.
(9) Rozenberg, V.; Danilova, T.; Sergeeva, E.; Vorontsov, E.; Starikova,
Z.; Lysenko, K.; Belokon, Y. Eur. J. Chem. 2000, 3295.
(10) Using these modifications, the aldehyde could be added in one
portion, which is a significant practical improvement over the original
Oppolzer protocol, where the aldehyde had to be added over a period of 20
min to obtain high enantioselectivities.
4120
Org. Lett., Vol. 3, No. 25, 2001

achieved for the benzaldehyde substrate with the ligands 2
is comparable to the results of the diethylzinc addition to
benzaldehyde with these ligands.11 Despite the use of excess
diethylzinc, no 1-phenylpropanol, the product of the diethyl-
zinc addition to benzaldehyde, was observed, which is
consistent with the findings in the literature.6,8 The conditions
for the best ligand (Rp,S)-2 were further optimized by varying
reaction temperature and catalyst loading (Table 1).
Decreasing the reaction temperature to -20 or -30 °C
did not change the enantioselectivity of the catalysis.
However, at -20 °C using 5 mol % of ligand (Rp,S)-2,
selectivity rose to 90% ee but with a diminished isolated
yield of 57% (Table 1, entry 5). Hence, all further catalyses
were carried out at -30 °C with 2 mol % of ligand as a
compromise between selectivity and yield.
systems. To the best of our knowledge, in the alkenylzinc
addition to aldehydes there has been no report of a highly
enantioselective addition to these substrates. However, these
aldehydes are excellent substrates for the paracyclophane
ligands, giving virtually complete enantioselection for cy-
clohexylcarbaldehyde and pivalaldehyde (entries 4 and 5).
Bulky alkynes were examined next, and at first glance they
seemed to limit the wide applicability of the paracyclophane
ligands. Thus, with the internal alkyne 3-hexyne only 75%
ee was obtained (entry 6) and the sterically even more
demanding tert-butyl ethyne lead to the desired product in a
disappointing 64% ee (entry 7).
At this point, the other ligands (Figure 1) were reexamined
with the sterically demanding tert-butyl ethyne, but no
improvement could be made (entries 8-10). Obviously, the
greater steric bulk of the zinc species resulting from tert-
butyl ethyne substantially diminishes the stereoselection of
the catalyst. In a final attempt to decrease the steric demand
of the zinc species, dimethylzinc (3 equiv) was employed
as the transmetalation reagent. This should result in the
formation of the somewhat less demanding zinc species 5
(R′′ ) methyl in Scheme 2). Gratifyingly, this brought the
The scope of the asymmetric addition of alkenylzinc
reagents to aldehydes with 2 mol % of ligand (Rp,S)-2 is
illustrated in Table 2. Electron-withdrawing substituents on
Table 2. Alkenylzinc Addition to Various Aldehydes to Give
the Allyl Alcohols 7 According to Scheme 1a
entry
alkyne 3
aldehyde 4, R ) yield (%) ee (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
1-octyne
phenyl
71
88
62
80
89
86
78
90
88
83
88
84
48
86 (S)
97 (S)
91 (S)
>98 (R)c
>98 (R)d
75 (S)
Scheme 2. Equilibrium of Zinc Species
1-octyne
1-octyne
1-octyne
1-octyne
3-hexyne
tert-butyl ethyne 4-Cl-phenyl
tert-butyl ethyne 4-Cl-phenyl
tert-butyl ethyne 4-Cl-phenyl
tert-butyl ethyne 4-Cl-phenyl
tert-butyl ethyne 4-Cl-phenyl
4-Cl-phenyl
4-MeO-phenyl
cyclohexyl
tert-butyl
phenyl
64 (S)
62 (R)e
67 (R)f
54 (S)g
89 (S)h
88 (S)g
76 (S)g
3-hexyne
1-octyne
phenyl
phenyl
breakthrough for bulky alkynes. For tert-butyl ethyne now
89% ee was achieved with ligand (Rp,S)-2 (entry 11), and
also for the symmetrical internal alkyne 3-hexyne 88% ee
could be obtained under the changed reaction conditions
(entry 12).
However, the use of dimethylzinc was only beneficial for
the aforementioned bulky alkynes. Its application in the
reaction of the hydroborated 1-octyne with benzaldehyde lead
to diminished enantioselectivity and yield (76% ee and 48%
isolated yield, entry 13) as compared to the already men-
tioned results with diethylzinc (Table 1 and Table 2, entry
1).
a In the presence of 2 mol % of chiral ligand (Rp,S)-2 (unless otherwise
stated) at -30 °C. b Determined by HPLC (Chiracel OD column, entries
1-3, 13; Chiracel AD column entries 7-11; (S,S)-Welk-O 1 column entries
6, 12). See ref 12. c Determined by GC (Chirasil-dex). The other enantiomer
was not observed. d Determined by NMR of the camphanic ester derivative.
The other enantiomer was not observed. e (Sp,S)-1 was used as ligand.
f (Sp,S)-2 was used as ligand. g (Rp,S)-1 was used as ligand. h Dimethylzinc
was used instead of diethylzinc.
aromatic aldehydes are well tolerated and lead to increased
enantioselecivity of 97% ee for p-chlorobenzaldehyde (entry
2). The electron-rich p-methoxybenzaldehyde, which is a
difficult substrate for many ligands in the diethylzinc1 as well
as alkenylzinc8c addition, also provides a very good ee of
91% although with a diminished yield of 62% (entry 3).
Aliphatic and especially R-branched aliphatic aldehydes
belong to the most problematic substrates for nearly all ligand
We rationalize these results with the slow equilibration
of zinc species at temperatures below 0 °C. Oppolzer et al.
1
already mentioned H NMR studies of the species formed
by reaction of hydroborated alkynes with dimethylzinc.6a
Although the transmetalation proceeds quickly at -65 °C
to give two equilibrating alkenylzinc species (which they
assigned as monomeric and dimeric species), no equilibrium
between mixed (5 in Scheme 2) and symmetrical species
(5′ in Scheme 2) was observed up to 0 °C, where the zinc
species begin to decompose. Thus, the active zinc species 5
can be tuned by the choice of the transmetalation reagent.
(11) Dahmen, S.; Bra¨se, S. Chem. Commun. 2001, in press.
(12) The absolute configuration was assigned by comparison of the
optical rotation with the literature known compounds (S)-1-(4-chloro-
phenyl)-hept-2-en-1-ol [ref c, Supporting Information] and (S)-1-phenyl-
non-2-en-1-ol [ref a], respectively, and the assumption of a unanimous
reaction pathway for all other aldehyde substrates. The absolute configu-
ration of the allyl alcohol products 7 is consistent with the induction observed
in the diethylzinc addition to aldehydes with the ligands 1 and 2.
Org. Lett., Vol. 3, No. 25, 2001
4121

In the case of the paracyclophane ligands, a smaller R-group
is obviously beneficial when sterically demanding alkynes
are employed.
and especially R-branched aliphatic aldehydes can now be
applied with very high levels of enantioselection. In contrast
to the prior results in this field,6,8 we could observe a severe
influence of the applied transmetalation agent on the
selectivity of the catalysts, especially with sterically demand-
ing substrates. A fine-tuning of enantioselectivity, depending
on the steric demand of the substrates was successfully
carried out by varying the transmetalation agent.
The ruling out of an equilibrium as depicted in Scheme 2
is not self-evident. At room temperature, mixed organozinc
compounds ZnR1R2 with similar R1 and R2 groups are in
equilibrium with the corresponding symmetrical species
ZnR1 and ZnR2 .13 The same applies for dialkyl- and
2
2
diarylzinc species.14 Organozincates, however, do not inter-
change at low temperatures.15
In conclusion, we have demonstrated the successful
application of [2.2]paracyclophane-based N,O-ligands in the
alkenylzinc addition to aldehydes. The use of these ligands
substantially extends the scope of this reaction, as aliphatic
Acknowledgment. Our work was supported by the
Deutsche Forschungsgemeinschaft (BR1750-1) and the Fonds
der Chemischen Industrie. We thank K. Hennig and T. Beck
for technical assistance and the BASF and Bayer AG for
the donation of chemicals.
(13) (a) Nehl, H.; Scheidt, W. J. Organomet. Chem. 1985, 289, 1. (b)
Mynott, R.; Gabor, B.; Lehmkuhl, H.; Doering, I. Angew. Chem., Int. Ed.
Engl. 1985, 24, 335.
(14) (a) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Muniz, K. Angew.
Chem., Int. Ed. 2000, 39, 3465. (b) Blacker, J. In Proceedings of the 3rd
International Conference on the Scale Up of Chemical Processes; Laird,
T., Ed.; Scientific Update: Mayfield, East Sussex, Great Britain, 1998; p
74.
Supporting Information Available: Experimental pro-
cedures and characterizations for the compounds 7. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Alvaro, G.; Pacioni, P.; Savoia, D. Chem. Eur. J. 1997, 3, 726.
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