Second-generation N,O-[2.2]paracyclophane ketimine ligands for the alkenylzinc addition to aliphatic and aromatic aldehydes: Scope and limitations

Article abstract of DOI:10.1002/adsc.200606193

Second generation N,O-[2.2]paracyclophane ketimine ligands were investigated for their ability to catalyze the 1,2-addition of alkenyl-zinc reagents to aliphatic and aromatic aldehydes with special focus on functionalized substrates. For aliphatic aldehydes, which have always been challenging in this field, remarkably high enantiomeric excesses could be determined (50-95% ee). However, alkenylzinc reagents bearing heteroatoms proved to be demanding substrates for this system.

Full text of DOI:10.1002/adsc.200606193

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DOI: 10.1002/adsc.200606193
Second-Generation N,O-[2.2]Paracyclophane Ketimine Ligands
for the Alkenylzinc Addition to Aliphatic and Aromatic
Aldehydes: Scope and Limitations
Frank Lauterwasser,a Julia Gall,a Sebastian Hçfener,a and Stefan Bräsea,*
a
Institut für Organische Chemie, Universität Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax : (+49)-721-608-8581; e-mail: braese@ioc.uka.de
Received: April 20, 2006; Accepted: August 21, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Second generation N,O-[2.2]paracy-
clophane ketimine ligands were investigated for
their ability to catalyze the 1,2-addition of alkenyl-
zinc reagents to aliphatic and aromatic aldehydes
with special focus on functionalized substrates. For
aliphatic aldehydes, which have always been chal-
lenging in this field, remarkably high enantiomeric
excesses could be determined (50–95% ee). How-
ever, alkenylzinc reagents bearing heteroatoms
proved to be demanding substrates for this system.
cesses for aliphatic aldehydes.[4] The alkenylzinc trans-
fer is even less investigated; however, interest in this
reaction has increased throughout the last years.[5–12]
One method elaborated by Oppolzer and Radinov
produces mixed alkyl-alkenylzinc species in situ using
a transmetalation protocol involving hydroboration of
alkynes.[5] Dahmen et al. showed that N,O-
[2.2]para-
G
cyclophane-based ligands produce results ranging
from good to excellent for this type of reaction,
whereas the scope is limited to aromatic aldehydes
and fully branched aliphatic aldehydes.[11] Wipf et al.
also reported the preparation of alkenylzinc reagents
via transmetalation but using zirconium as metal.[9]
A comprehensive survey of [2.2]paracyclophane-
based ligands can be found in recent reviews.[13] The
use of planar-chiral and central-chiral ligands based
on paracyclophane systems has emerged en masse
since the disclosures by Belokon, Rozenberg
Keywords: alkenylzinc reagents; asymmetric cataly-
sis; chiral allylic alcohols; N,O ligands; paracyclo-
phanes
Chiral allylic alcohols are important targets in organic et al.,[14,15] the Berkessel group,[16] and most notably
synthesis, especially in natural product synthesis. As the Hopf group.[17] Within the last years, various new
intermediates they can be used in further reactions paracyclophane ligands have been used for asymmet-
such as allylic substitution, dihydroxylation, ene reac- ric catalysis.[18–20] In particular, the asymmetric 1,2-ad-
tion, cyclopropanation, bromination, or epoxidation. dition reaction of organozinc compounds such as
However, the lack of a powerful ligand system im- alkyl-,[21] alkenyl-,[11] and alkynylzinc[22] reagents with
pedes the use of the 1,2-addition of alkenylzinc re- aldehydes or imines,[21] respectively, can be efficiently
agents to aldehydes as a key step in natural product controlled by the use of hydroxy[2.2]paracyclophane
G
synthesis because highly functionalized substrates ketimine ligands. We recently reported the synthesis
must be tolerated and high enantiomeric excesses of the N,O-[2.2]paracyclophane-based ligands (RP,S)-
must be achieved.[1] The rare examples in the litera- 1, (SP,S)-1, (RP,S)-2, and (SP,S)-2 (Figure 1) and their
ture show mostly the use of divinylzinc and substrate- application in asymmetric catalysis.[23,24] In addition,
induced diastereoselectivity.[2]
we carried out non-linear-like effect and activity stud-
In the case of substrate toleration, the catalyzed al- ies for this class of ligands.[25]
kenylzinc addition could be an appropriate method
Here we present an extension on the highly selec-
because of the relatively low reactivity of zinc di- tive alkenyl transfer onto aliphatic and aromatic alde-
organyls towards aldehydes and ketones in compari- hydes using the second generation of these N,O-
son to other organometal compounds.[3] However, in- [2.2]paracyclophane-based ligands 1 and 2. Our goal
vestigations in this field are few. In contrast, alkyl was to investigate whether our ligands which showed
transfer to aromatic aldehydes is one of the most the best activity and selectivity in the diethylzinc ad-
studied enantioselective catalytic reactions, yet there dition[23,24] also catalyze the alkenylzinc addition and
are only a few examples with high enantiomeric ex- to investigate which substrates are tolerated. There-
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Second-Generation N,O-[2.2]Paracyclophane Ketimine Ligands
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The ligands (SP,S)-1 and (RP,S)-1 catalyzed the addi-
tion of alkenylzinc to various aliphatic aldehydes
ranging from moderate to good yields and good to ex-
cellent enantiomeric excesses (up to 95% ee, Table 1).
Functionalized aldehydes, such as a,b-unsaturated al-
dehydes[26] (entries 18–20) or benzyloxyacetaldehyde
(entries 21, 22), were also tolerated.
The a-branched aldehydes 4a and d gave enantio-
meric excesses from 94% to 95% ee. The diastereo-
meric pair (SP,S)-1 and (RP,S)-1 showed the same se-
lectivity for each substrate (matched pair).
We also studied the difference in selectivity of the
BHPCligands 2 compared with AHPCligands 1 to il-
lustrate the importance of a ligand screening. In some
cases, the selectivity with (RP,S)-1 differed by up to
20% ee in comparison with (RP,S)-2 (entries 1, 3 and
11, 13), which was quite remarkable. However, the
(SP,S)-2 ligand showed nearly the same selectivity as
(SP,S)-1, since the difference was only 2–4% ee.
Linear aliphatic aldehydes have been difficult sub-
strates in this kind of reaction. Here, even the linear
Figure 1.
hexanal (4c) showed
a reasonable enantiomeric
excess with 72% ee. However, it was not possible to
determine the selectivity in the case of undecanal
fore, we used various functionalized aldehydes as well (4b), either by GCon chiral stationary phase, or by
as alkynes bearing a heteroatom to generate the al- 13CNMR spectroscopy of the ( S)-(À)-camphanic acid
kenyl species.
ester for de determination. Overall, we saw a general
The active alkyl-alkenylzinc species was generated trend that the AHPC-based ligands 1 gave better re-
via transmetalation by following the Oppolzer proto- sults than ligands 2 derived from BHPC, and in the
col.[5] Starting from borane-dimethyl sulfide complex latter case the (SP,S)-configurated ligand showed
and cyclohexene which in situ gave the dicyclohexyl- better selectivity than the (RP,S)-diastereomer.
borane, followed by treatment with a 1-alkyne, the
[(E)-1-alkenyl]borane was obtained. Transmetalation b-Branched 3-methylbutyraldehyde (4e) affirmed the
previous results. Methacrolein (4f) as an a,b-unsatu-
Additionally, three further aldehydes were tested.
occurred after addition of diethylzinc at À788Cto
yield the alkyl-alkenylzinc species. The ratio of the al- rated aldehyde was chosen to examine whether 1,2-
dehyde to the active alkenylzinc species (2:3) was or 1,4-addition was favored under the given condi-
adapted to the modified Oppolzer protocol intro- tions. We found that exclusively the 1,2-addition prod-
duced by Dahmen et al.[11]
uct 5f was formed. This is an important difference to
The first investigation focused on the scope of sub- the alkyl transfer with [2.2]paracyclophane ligands ex-
strates for aliphatic aldehydes using an [(E)-1-octe- amined earlier.[26] The yields were quite moderate for
nyl]borane. It is important to note that both enantio- this special substrate, which correlated with the in-
mers of the resulting allylic alcohols can be generated creased formation of condensation side products.
with similar enantiomeric excesses by using diastereo- Moreover, benzyloxyacetaldehyde (4g) could be ap-
mers of the AHPC-based ketimines 1 with a different plied in this reaction, but the enantiomeric excesses
planar-chiral type stereochemistry and the same ste- were not determinable although induction took place.
reogenic center (matched pair). On the basis of our This was shown by measurement of the optical rota-
experience with the 1,2-addition of diethylzinc to aro- tion (see Experimental Section).
matic and aliphatic aldehydes,[24] the BHPC-based To draw a comparison between the first[11] and the
ketimines 2 are known to be a mismatched pair of li- second generation of our ligands, we chose benzalde-
gands. hyde (4h, entries 23 and 24) as an aromatic substrate
For our experiments we chose a relatively low load- and we could achieve better yields and higher enan-
ing of ligands of 2 mol% and a reaction temperature tioselectivities (91% ee compared to 86% ee) under
of À308C. Preliminary screenings had shown that the given conditions.
these are reasonable conditions to observe high enan-
After the successful application of the asymmetric
tiomeric excesses and good yields.[11] The detailed re- addition of octenylzinc onto aliphatic aldehydes, the
sults of the substrate screening are summarized in next step was the extension to heteroatom functional-
Table 1.
ized alkenylzinc species. These are interesting targets
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Table 1. Scope of substrates for the alkenyltransfer to several functionalized aliphatic aldehydes.
Entry
Aldehyde
Ligand
Product[a]
Yield [%][b]
ee [%][c]
1
2
3
4
4a
4a
4a
4a
N
(+)-5a
(À)-5a
(+)-5a
(À)-5a
59
35
51
38
94
95
74
91
5
6
4b
4b
C
(+)-5b
(À)-5b
53
48
nd[d]
nd
7
8
9
10
4c
4c
4c
4c
U
(+)-5c
(À)-5c
(+)-5c
(À)-5c
55
56
58
78
72[e]
72[e]
60[e]
69[e]
11
12
13
14
4d
4d
4d
4d
N
(+)-5d
(À)-5d
(+)-5d
(À)-5d
70
49
63
56
94
94
74
92
15
16
17
4e
4e
4e
C
(+)-5e
(+)-5e
(À)-5e
65
70
42
58
50
68
18
19
20
4f
4f
4f
C
(+)-5f
(+)-5f
(À)-5f
23
23
20
63
48
74
21
22
4g
4g
C
(+)-5g
(À)-5g
55
38
nd
nd
23
24
4h
4h
C
(+)-5h
(À)-5h
77
82
91[f]
90[f]
[a]
Configuration determined either by measurement of optical rotation or by GC (see Experimental Section); in the latter
case indicators (+/À) were assigned in analogy to other experiments.
Isolated yields.
[b]
[c]
[d]
[e]
[f]
Determined by GC(CP-chirasil-dex).
nd: not determinable by GCor NMR spectroscopy of the camphanic acid ester.
The ee was determined after esterification with Ac2O, room temperature, 24 h.
Determined by HPLC(Chiracel OD)
regarding a future implementation of the method in 1,2-addition reaction. Instead, dimerization of the al-
natural product synthesis. As a test system, benzalde- kenyl species to dienes 11 was observed.[27] This was
hyde (4h) was chosen and the experiments were per- earlier rationalized by Walsh,[28] who found that a
formed according to the protocol described above borane formed as a by-product was responsible
using w-functionalized alkynes 12. Despite extensive (Figure 2). The reactive alkyl-alkenylzinc species 6
experimentation, we were not able to conduct a clean was converted into the dialkenyl species 8, which un-
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Second-Generation N,O-[2.2]Paracyclophane Ketimine Ligands
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Unfortunately with these substrates and this
method, the enantioselectivity remains on a low level
(3–13% ee with 5 mol % ligand). One reason could
be that the heteroatom in the alkenylzinc reagent im-
pedes stereocontrol by the N,O ligand, irrespective of
whether a halogen, an ether, or a silyl ether substitu-
ent was used. Alternatively, the Wipf method with zir-
conium was unsuitable for this special catalyst system.
Even with higher catalyst loading (10 and 20 mol%)
we could not observe better induction; on the contra-
ry the yields decreased and the amount of side prod-
uct resulting from the ethyl addition grew. Therefore
two further sets of experiments were carried out.
We conducted the reaction following the usual pro-
tocol but in absence of a ligand and found that the al-
lylic alcohols were formed nevertheless. Obviously,
the uncatalyzed addition reaction proceeds at least as
fast as the reaction with participation of a ligand. This
finding corresponds to the observation of the previous
experiments that only the 1,2-addition of diethylzinc
is accelerated by the application of more ligand and
provided an explanation for the weak stereocontrol.
The direct cause was found by using 1-ocytne (3) as
precursor for the alkenylzinc species. Following the
hydroboration protocol, we had achieved excellent re-
sults with about 90% ee, however, with zirconium as
Figure 2.
derwent reductive coupling catalyzed by an unknown co-metal the isolated allylic alcohols were virtually
boron species. This proposed mechanism follows the racemic, even though the reagent did not bear any
investigations published by Walsh et al.[28]
heteroatom. Thus the low enantioselectivity must be
Therefore, we switched to a method elaborated by attributed to the reaction conditions of the Wipf
Wipf et al.[9] involving a hydrozirconation step instead method, possibly due to the presence of zirconium
of hydroboration.
compounds.
The alkyne 12 was treated first with the Schwartz
Within this article we have presented a highly selec-
reagent. After transmetalation with diethylzinc, the tive access to aliphatic allylic alcohols producing rea-
mixed alkenylzinc species was utilized in the reaction sonable to good yields and high enantiomeric excess-
with benzaldehyde (4h). With this protocol the 1,2-ad- es. Using the method developed by Oppolzer, various
dition proceeded well with reasonable to good yields aliphatic aldehydes – including challenging linear,
(Table 2). As a minor side product from the 1,2-addi- branched, a,b-unsaturated and a-substituted – were
tion of diethylzinc to the aldehyde, 1-phenyl-propan- tested and proved to be suitable substrates with dis-
1-ol could be identified. This was quite surprising, tinguished stereocontrol. As a powerful ligand set we
since alkenylzinc species are usually more reactive used the second generation of N,O-[2.2]paracy-
than alkylzinc species, even though in our case there clophanes. In the catalyzed asymmetric alkenylzinc
were examples for the ethyl group being competitive- addition, both enantiomers of the resulting allylic al-
ly transferred with the vinyl group.[29,30]
cohols could be obtained depending on which diaste-
Our first experiments with 1.1 equivalents of alke- reomer of the ligand was used. With the AHPC-based
nylzinc reagent gave only moderate yields (Table 2, ligand 1 we observed a matched pair with 58–95% ee,
entry 4) with a poor ratio of by-product to desired whereas with BHPC-based ligands 2 different stereo-
product. This effect could be repressed by using 1.5 selectivities (mismatched pair) were achieved. As we
equivalents of the alkyne 12 as well as diethylzinc. It switched to heteroatom-substituted alkenylzinc re-
should be emphasized that the yields and product agents, the desired 1,2-addition product could not be
ratio were consistently higher in the experiments per- obtained with the Oppolzer hydroboration method.
formed with the [2.2]paracyclophane ligands 1 than in We were obliged to use the Wipf protocol with the
the racemic control experiments performed with N,N- Schwartz reagent. However, under the given reaction
dimethylethanolamine. For linear alkynes of varying conditions stereocontrol was suppressed and the unca-
length and terminal group, good yields were also ob- talyzed background reaction took place, even though
tained, regardless of the size of the protective group the yields were satisfying.
used.
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Table 2. Substrates tested with the hydrozirconation protocol.
Entry
1
Alkyne
Ligand
(RP,S)-1
C
Product
Yield [%][a]
88
12a
A
13a
2
3
12b
12b
C
5
5
(+)-13b
(À)-13b
78
88
4
12c
A
5
13c
54[b]
5
6
7
8
9
10
12d
12d
12d
12d
12d
12d
U
5
5
10
10
20
20
(+)-13d
(À)-13d
(+)-13d
(À)-13d
(+)-13d
(À)-13d
69
68
46
47
39
38
11
12
12e
12f
C
5
5
13e
77
64
13f
13
14
15
16
3
3
3
3
N
5
5
10
10
(+)-5h
(À)-5h
(+)-5h
(À)-5h
75
71
67
66
[a]
Isolated yields.
1.1 equivalents of alkyne.
[b]
a Perkin–Elmer 241 polarimeter (Na, 589 nm). All charac-
terization data are available in the Supporting Information.
ExperimentalSection
GeneralRemarks
General Procedure A for Alkenylzinc Addition to
Aldehydes (Hydroboration-Transmetalation Protocol)
All catalyses were performed in 10-mL vials under an argon
atmosphere. Aldehydes, 1-octyne (3), 5-chloro-pent-1-yne
(12e), and TBDMS-protected alkynols (12b and d) were
purchased from commercial sources and were used without
further purification. O-Protected prop-2-yn-1-ols, but-3-yn-
1-ols and pent-4-yn-1-ols were prepared using standard pro-
cedures[31,32] and purified by distillation (benzyl compounds
12a and f) or recrystallization (trityl compounds 12c), re-
spectively. Diethylzinc was purchased as a 1M solution in
hexanes from Fluka. Ligands were synthesized according to
literature procedures.[23] Enantiomeric excesses were deter-
mined by GCon chiral stationary phase (Varian with CP-
Chirasil-Dex CB, 25 m”0.25 mm, 0.25 mm), or by HPLC
(Agilent with Diacel Chiracel OD, 250”4.00 mm, 10 mm).
1H and 13CNMR spectra were recorded on Bruker AC
250 (250 MHz/62.5 MHz), Bruker AM 400 (400 MHz/
100 MHz) and Bruker DRX 500 (500 MHz/125 MHz) spec-
trometers using CDCl3 as the solvent and shift reference
(7.26 ppm/77.00 ppm). Optical rotations were determined on
In a 10-mL vial under an argon atmosphere 0.75 mL of
borane-dimethyl sulfide complex solution (1.50 mmol, 2M
in toluene) were cooled to 08C, 304 mL (246 mg, 3.00 mmol)
of cyclohexene were added, and the reaction mixture was
stirred for 2 h at 08C. Then 223 mL (165 mg, 1.50 mmol) of
1-octyne (3) were added. After stirring at room temperature
for 1 h, the reaction mixture was cooled to À788Cand a so-
lution of the ligand (2 mol%) in diethylzinc solution (2 mL,
2.00 mmol, 1M in hexane) was added slowly. After warming
from À78 to À308Cover a period of 1 h, the aldehyde
4
(1.00 mmol) was added and the mixture was stirred for 14 h
at À308C. The reaction mixture was quenched with water,
diethyl ether was added and the organic layer was subse-
quently extracted with 5% acetic acid, 1M HCl, and satu-
rated NaHCO3 solution. After washing with water the or-
ganic layer was dried over MgSO4 and the solvent was re-
moved under vacuum. Chromatography on silica gel (pen-
tane/diethyl ether) yielded the allylic alcohol 5.
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Second-Generation N,O-[2.2]Paracyclophane Ketimine Ligands
COMMUNICATIONS
The racemic control experiments were performed either
with 3.70 mg (0.01 mmol, 1 mol%) of a mixture of diaste-
[3] P. Knochel, M. I. Calaza, E. Hupe, in: Metal-Catalyzed
Cross-Coupling Reactions, (Eds.: A. de Meijere, F. Die-
derich), Wiley-VCH, Weinheim, 2004, pp. 619–670.
[4] For a recent review, see: a) L. Pu, Tetrahedron 2003,
59, 9873–9886; b) L. Pu; H.-B. Yu, Chem. Rev. 2001,
101, 757–824.
reomers (rac)-(RP,S)/
A
G
N
phenylethylimino)-ethyl]-[2.2]paracyclophane or with 20 mL
(18.0 mg, 0.20 mmol, 20 mol%) of N,N-dimethylethanol-
amine.
[5] a) W. Oppolzer, R. N. Radinov, Helv. Chim. Acta 1992,
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polzer, R. N. Radinov, Tetrahedron Lett. 1988, 29,
5645–5648.
General Procedure B for Alkenylzinc Addition to
Aldehydes (Hydrozirconation-Transmetalation
Protocol)
To a suspension of 387 mg of zirconocene hydrochloride
(Schwartz reagent, 1.50 mmol) in 3 mL of dry dichlorome-
thane at room tempertaure under argon, the alkyne 12
(1.50 mmol) was added dropwise (crystalline compounds
were dissolved in 1 mL of dichloromethane). The mixture
was allowed to stir at room temperature for 15 min, giving a
clear, light yellow solution, before all volatiles were re-
moved under vacuum. The resulting yellow solid was dis-
solved in 3 mL of dry toluene, cooled to À658C, and then
treated with 18.8 mg of chiral ligand 1 (0.05 mmol, 5 mol%)
in 1.50 mL of diethyl zinc solution (1M in hexanes,
1.50 mmol). The mixture was warmed to À208Cduring a
period of 2 h, followed by the addition of 102 mL of benzal-
dehyde (4h, 106 mg, 1.00 mmol) in 1 mL of dry toluene. The
reaction was allowed to proceed overnight before quenching
with saturated NaHCO3 solution. The mixture was extracted
with diethyl ether; the organic layer was washed with satu-
rated NH4Cl solution, dried over NaSO4, filtered, and sol-
vents removed under vacuum. The crude product was chro-
matographed on silica gel.
[6] T. Shibata, K. Nakatsui, K. Soai, Inorg. Chim. Acta
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The racemic control experiments were performed with
30 mL (26.7 mg, 0.30 mmol, 30 mol%) of N,N-dimethyletha-
nolamine.
Acknowledgements
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We would like to thank the DFG (SFB 380) and the Fonds
der Chemischen Industrie (Fellowship for Julia Gall) for fi-
nancial support. Cyclohexylethylamine (ChiProsꢀ) used for
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