Co-metal-free enantioselective conjugate addition reactions of zinc reagents

Article abstract of DOI:10.1002/chem.200801676

Asymmetric conjugate addition of diethylzinc to cinnamaldehyde in a co-metal-free fashion by using N,O-ligands with planar and central chirality is described. Different modulations of the ligand structure, including several combinations of the chiral units, indicate that a [2.2]paracyclophane backbone is essential for the activity and the enantioselectivity of the generated active catalyst. By using the optimized ligand, an isolated yield of 90 % was obtained with up to 99 % ee.

Full text of DOI:10.1002/chem.200801676

FULL PAPER
DOI: 10.1002/chem.200801676
Co-Metal-Free Enantioselective Conjugate Addition Reactions
of Zinc Reagents
Sefer Ay,[a] Martin Nieger,[b] and Stefan Brꢀse*[a]
Abstract: Asymmetric conjugate addition of diethylzinc to cinnamaldehyde in a
co-metal-free fashion by using N,O-ligands with planar and central chirality is de-
scribed. Different modulations of the ligand structure, including several combina-
tions of the chiral units, indicate that a [2.2]paracyclophane backbone is essential
for the activity and the enantioselectivity of the generated active catalyst. By using
the optimized ligand, an isolated yield of 90% was obtained with up to 99% ee.
Keywords: asymmetric catalysis
conjugate addition reactions · enals ·
N,O-ligands · organozinc reagents
·
Introduction
reactions. Beside these lead structures, [2.2]paracyclophanes
have also been employed.[12] This class of compounds gives
rapid access to planar chiral structures. Monosubstituted
[2.2]paracyclophanes are, in fact, already chiral, whereas fer-
rocene derivatives need to be disubstituted (with achiral
substituents) to become chiral. Furthermore, paracyclo-
phanes are very stable[13] and do not racemize easily unlike
some ferrocenes.[14]
The conjugate addition reaction (onto Michael substrates)
of carbon-centered nucleophiles is one of the most impor-
tant and powerful C–C bond-forming reactions in modern
organic chemistry.[1] Catalytic asymmetric versions also play
a significant role in the total synthesis of complex chiral nat-
ural products.[2] Asymmetric 1,4-addition reactions with hard
nucleophiles generally require the presence of a co-metal,
with copper or rhodium being the most used ones.
In particular, asymmetric 1,4-addition reactions of organo-
zinc, organoaluminum, or Grignard reagents to a,b-unsatu-
rated substrates under copper catalysis have been successful-
ly accomplished.[3] Excellent yields and high enantioselectiv-
ities were achieved for cyclic and acyclic enones,[4] amide de-
rivatives,[5] nitro olefins,[6] esters,[7] thioesters,[8] and malo-
nates.[9] However, enals still constitute a challenging class of
substrates since efficient systems allowing a regioselective
addition are rare.
Paracyclophane ligands were successfully used for asym-
metric allylic substitution reactions,[15] sulfoxidation of thio-
ethers,[16] cyclopropanation of olefins,[17] and asymmetric hy-
drogenation reactions.[18] Furthermore, 1,2-addition reactions
of organozinc reagents to different electrophiles, for exam-
ple, aldehydes or imines, were also effectively accomplished
by using ligands bearing
a
paracyclophane scaffold.[19]
Lately, even Morita–Baylis–Hillman reactions have been
catalyzed by [2.2]paracyclophane-derived monophos-
phines.[20]
Recently, our group developed a [2.2]paracyclophane
ligand-based asymmetric Michael-addition reaction of orga-
nozinc reagents to this class of compounds.[21] There is no
need to add any copper salts. This is the key advantage of
this ligand system, which makes it an environmentally
benign process with a potential application in drug synthe-
ses. We have newly reported the scope of this reaction. Now
we present our trials to optimize the ligand structure and
enhance the regioselectivity.
Axial chiral ligands, such as (mostly binaphthyl-based)
phosphoramidites[10] or planar chiral ferrocene-based li-
gands,[11] are broadly used in asymmetric conjugate addition
[a] Dipl.-Chem. S. Ay, Prof. Dr. S. Brꢀse
Institute of Organic Chemistry, University of Karlsruhe (TH)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax : (+49)721-608-8581
E-mail: braese@ioc.uka.de
[b] Dr. M. Nieger
Laboratory of Inorganic Chemistry, University of Helsinki
P.O. Box 55 (A.I. Virtasen aukio 1)
Results and Discussion
FIN-00014 University of Helsinki (Finland)
Nowadays, lots of different ligands are available for copper-
catalyzed asymmetric 1,4-addition reactions. One of the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801676.
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most powerful types developed by Hoveyda is based on pep-
tidic imines bearing a phosphine moiety.[22] These ligands
are particularly effective for copper co-metal catalysis due
to a chelation of the copper ion by the imine and phosphine
moiety. Zinc ions, in contrast, are predominately complexed
by a nitrogen–oxygen chelate. That is why mostly amino al-
cohols are used as ligands for 1,2-addition reactions of orga-
nozinc reagents onto aldehydes.[23] With a,b-unsaturated al-
dehydes, it is likely that a mixture of 1,2- and 1,4-addition
products is obtained, which can, however, in some cases be
limited to a single product depending on whether the reac-
tion is run under thermodynamic or kinetic control. A po-
tential ligand 2 for such reactions is shown in Scheme 1. Its
Scheme 2. General synthesis of potential ligands for zinc catalysis.
Scheme 1. Ligand simplification and variation of ligand
catalysis.
1 for zinc
structure is based on a simplification of Hoveydaꢂs ligand 1.
The latter has a characteristic imine functionality, which is
connected to a peptide. The amino acids (AA) used bear
chiral elements, which are necessary for the asymmetric in-
duction. The N atom of the imine group serves together
with the P atom as donors for the copper ion. Based on this,
we proposed structure 2, composed of an imine bearing a
central chiral group and a phenol, to act as the ligand
during zinc catalysis.
We first synthesized a small library of ligands 3a–h
(Scheme 2), by starting from readily available 2-acetylphe-
nol (3), which was condensed with different enantiopure
amines (compounds a–r are the different amines and hydra-
zines used for ligand synthesis). The obtained yields range
from 40% (for 3a) to 98% (for 3e and 3h).
These potential ligands were then used in an asymmetric
1,4-addition reaction. As a model reaction, we choose the
copper-free Michael-addition reaction of Et2Zn to cinnamal-
dehyde 13 (Scheme 3).[24–26]
We were pleased to observe the formation of 1,4-addition
product 14 in the presence of the ligands 3a–h (Table 1).
The tested ligands led, however, to substandard results in
terms of yield, selectivity, and ee in almost all cases. The
generated catalysts showed quite low activity ranging from
62% recovery of the starting material for 3a (entry 1) to
88% for 3 f (entry 6) after the reaction mixture had been
stirred for three days. In addi-
time either dominated by the 1,2-addition adduct (the a,b-
unsaturated alcohol 15, entries 1, 2, and 5) or is a 1:1 mix-
ture of 14 and 15 (entries 3, 4, 6, and 8).
Because of the high electrophilicity of the aldehyde, a 1,2-
addition competes most of the time with the Michael-addi-
tion reaction. However, the formation of the 1,2-addition-re-
action product should be reduced, even avoided, if the reac-
tion, the observed enantioselec-
tivities for the conjugate addi-
tion products, which give in all
cases (R)-14, are poor, ranging
from 13 to 41%. Moreover, the
desired product is most of the Scheme 3. Addition reaction of diethyl zinc to cinnamaldehyde 13.
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Enantioselective Conjugate Addition Reactions
FULL PAPER
Table 1. Screening of central chiral ligands 3a–h.[a,e]
Entry Ligand Starting mate- 1,4-Product
ee of 14 1,2-Product
rial [%][b]
(14) [%][b]
[%][c]
(15) [%][b]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
62
65
81
67
87
88
80
64
12
5
6
12
4
4
41 (R)
25 (R)
nd[d]
20 (R)
13 (R)
17 (R)
nd[d]
15
22
5
14
7
6
16
15
<0.5
17
30 (R)
[a] Reaction conditions: ligand (2 mol%), diethylzinc (1.10m in toluene,
2.00 equiv), toluene, À308C, 3 d under an argon atmosphere. [b] Deter-
mined by GC analysis after workup. [c] Determined by GC analysis
(chiral, Lipodex-E). [d] nd=not determined. [e] Due to side reactions,
such as aldol reactions, the total amount of material does not always
reach 100%.
tion is conducted at low temperature. Running the reaction
at À308C leads only in one case—in the presence of 3g—to
preferable formation of the kinetic product (Table 1,
entry 7). Almost no 1,2-addition product was observed;
however, the desired Michael adduct 14 was obtained in
only 16% yield.
Interestingly, ligand 3h, which is very similar to 3g again
only provides a nearly equimolar mixture of 14 and 15
(Table 1, entry 8). It might be possible to optimize the activi-
ty of ligand 3g by means of the incorporation of different
substituents onto the naphthalene part, but because of these
ligands leading also to poor enantioselectivities, we did not
continue with further efforts in this direction.
To better control the regioselectivity, we next investigated
substituted (2,6-diphenylphenyl-2-yliminomethyl)phenols 4–
8r as ligands. Due to their steric hindrance, a 1,2-addition
reaction should indeed be discriminated, especially as the
substrate is thought to coordinate via the aldehyde to the
generated zinc catalyst.[27]
Different substituents in the ortho position to the hydroxy
function were tested to evaluate their influence. Therefore,
several substituted a-formylphenols 4–8 were condensed
with 2,6-diphenylaniline r (Scheme 1). Figure 1 shows X-ray
structures of 5r and Figure 2a the X-ray structure of 11r. In
both cases, a hydrogen bond between the phenolic oxygen
Figure 1. Molecular structure of two independent molecules of 5r. Dis-
placement parameters are drawn at the 50% probability level.
atom and the imine nitrogen atom is observable. In the case
of 5r, the formation of rotameric structures could be identi-
fied due to the sterically demanding 2,6-diphenylamine sub-
stituent. In 11r, this substituent is twisted to the plane of the
[2.2]paracyclophane backbone. Compounds 4–8r were then
utilized as ligands during the addition reaction of diethyl
zinc to cinnamaldehyde 13 as before (Scheme 3, Table 2). In
the case of ligand 4r with a free ortho position, an accepta-
ble yield and excellent regioselectivity were obtained
(entry 1). Supplying 4 mol% of ligand 4r, the regioselectivi-
ty and the product yield could even be increased (entry 2).
The reaction mixture became cloudy, however, after the ad-
dition of the zinc reagents, which indicated a precipitation
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11541

S. Brꢀse et al.
Figure 2. A) Top: Molecular structure of 11r. Bottom: Molecular structure of 12n. B) Molecular structure of the two independent molecules of 12o. Dis-
placement parameters are drawn at 50% probability level.
Table 2. Screening of ortho-substituted ligands 4–8r derived from 2,6-di-
ing material is recovered. This can be rationalized by the
fact that complex generation becomes more difficult, so that
less active catalyst will be formed. These results suggest that
by incorporating substituents at the ortho position, the re-
gioselectivity cannot be positively influenced.
We next turned to substituted [2.2]paracyclophanes bear-
ing an imine and phenol function. Ketimines and rac-12n–q
were obtained by Lewis acid catalyzed condensation of rac-
phenylaniline.[a,d]
Entry Ligand Starting material 1,4-Product (14) 1,2-Product (15)
[%][b]
[%][b]
[%][b]
1
2
3
4
5
6
4r
71
52
82
80
88
85
22
40
13
13
3
3
<1
4
<1
7
4r[c]
5r
6r
7r
8r
4
7
[a] Reaction conditions: ligand (2 mol%), diethylzinc (1.10m in toluene,
2.00 equiv), toluene, À258C, 1.5 d under an argon atmosphere. [b] Deter-
mined by GC analysis after workup. [c] 4 mol% ligand used. [d] Due to
side reactions, such as aldol reactions, the total amount of material does
not always reach 100%.
of compounds. Thus, a further optimization seemed not to
be possible by increasing the ligand concentration.
When the ortho position becomes sterically more hin-
dered (Table 2, entries 2–7), the yield drops and more start-
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Enantioselective Conjugate Addition Reactions
FULL PAPER
5-acetyl-4-hydroxyACHTUNGTRENNUNG[2.2]paracyclophane (rac-10) with differ-
ent achiral amines or hydrazines (Scheme 2). Figure 2a
and b show X-ray structures of 12n and 12o. The present
hydrogen bond in these structures makes again sure, that
the ligand structure is conformationally stable. In the case of
rac-11r, which contains a sterically hindered 2,6-diphenyl-
phenyl substituent, 5-formyl-4-hydroxyACTHNUTRGNEUNG[2.2]paracyclophane
(rac-9) was used as the reactant.
Compounds rac-11r and rac-12n–q were then used in the
model 1,4-addition reaction (Scheme 2, Table 3). Compound
Table 3. Screening of planar chiral ligands.[a,e]
Entry
Ligand
Starting
material
[%][b]
1,4-Product (14)
1,2-Product (15)
[%][b]
[%][b]
1
2
3
rac-11r
rac-12n
rac-12o
rac-12p
rac-12q
(Sp)-12q
90
36
35
28
34
35
3
41
38
38
4
17
19
27
18
17
As ligand rac-11r, based on sterically demanding 2,6-di-
phenylaniline, led to very poor results, only sterically less-
demanding chiral amines were employed.[28] Starting from
rac-10,[29] two diastereomeric ketimines 12a–m were ob-
tained that could be separated. These structures combining
a planar and central chiral unit were submitted to the 1,4-
addition model reaction (Scheme 1, Table 4). The diastereo-
meric ligands 12 show mostly good regioselectivities and
yields along with excellent enantioselectivities, which is over
90% ee in nearly all cases (Table 4). As we have already ob-
served for similar cases before, the absolute configuration of
the product is determined by the absolute configuration of
the paracyclophane backbone (Rp or Sp), which seems to
dominate the cooperation of the planar and central chiral
units, present in our ligands. A (Rp)-ligand leads to the S
product, and a (Sp)-ligand generates the R product.[21]
Ligand 12a with its two diastereomers shows remarkable
match/mismatch characteristics. While (Sp,S)-12a produces a
very high regioselectivity along with a good yield and a high
ee (entry 2), ligand (Rp,S)-12a on the other hand has a very
low activity, accompanied by a low ee (entry 1).
Although ligand pair 12a remained the only relevant
match/mismatch case among the whole series, we always
screened both diastereomers. Ligand pair 12m with a cyclo-
hexylethyl substituent stands out under the tested ligands
(Table 4, entries 7 and 8). When considering the yield of the
desired Michael product, it was found that (Rp,S)-12m gives
the highest one, up to 63% with 2 mol% ligand, along with
an excellent ee (>99%; entry 7). Additionally, this type of
ligand has an excellent regioselectivity. Almost no 1,2-addi-
tion product is formed (entries 7 and 8). This means a yield
of 90% based on recovered starting material, which now
provides a synthetically useful transformation. It is interest-
ing to note that this ligand is also the optimal ligand for
other transformations.[19a,b,30]
4[c]
5
39
6
39[d]
[a] Reaction conditions: ligand (2 mol%), diethylzinc (1.10m in toluene,
2.00 equiv), toluene, À308C, 3 d under an argon atmosphere. [b] Deter-
mined by GC analysis after workup. [c] À208C, 3 d. [d] 97% ee for (R)-
14, determined by GC (chiral, Lipodex-E). [e] Due to side reactions, such
as aldol reactions, the total amount of material does not always reach
100%.
rac-11r bearing a bulky N substituent, led to almost no con-
version (entry 1). A 2:1 mixture of 14 and 15 was obtained
in all other cases (entries 2–6), which indicated that the
nature of the imine substituent, as long as it is not too
bulky, has no influence on the outcome of the reaction.
By using rac-12p—one of the few examples for a hydra-
zone based on [2.2]paracyclophane—at À208C instead of
À308C, a higher conversion of the starting material was ob-
served, but a worse regioselectivity was obtained since at
higher temperatures the formation of the 1,2-product is fa-
vored (Table 3, entry 4).
To check if an enantiomerically pure ligand of this type
leads to good enantioselectivities of the 1,4-addition product
14, we tested (Sp)-12q (Table 3, entry 6), which was obtained
by condensation of cyclohexylamine with (Sp)-10.[19b] We
were pleased to note that (R)-14 was obtained with an ex-
cellent enantiomeric excess of 97% ee.
Encouraged by these results, we next investigated keti-
mines obtained by Lewis acid catalyzed condensation of rac-
10 with different enantiomerically pure amines (compounds
12a–m are synthesized planar and central chiral diastereo-
meric ligands based on [2.2]paracyclophanes; Scheme 2).
These compounds offer with their [2.2]paracyclophane
moiety the opportunity to combine the implied planar chiral
unit with a central chiral part. This combination could
indeed affect match–mismatch cases and lead to better
enantioselectivities.
So far, all the tested ligands had a central chiral unit bear-
ing a methyl group. To see whether this group has an influ-
ence on the outcome of the reaction, two diastereomeric li-
gands 12d were tested. The latter are identical to 12i,
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S. Brꢀse et al.
Table 4. Screening of planar and central chiral diastereomeric ligands 12a–m.[a,d]
Thus, high to excellent diaste-
reomeric excesses are ob-
tained.[34] The new stereogenic
centers are, therefore, in all
cases independent of the cen-
tral chiral center.
Entry
Ligand
Starting
1,4-Product (14) [%][b]
ee of 14 [%][c]
1,2-Product (15) [%][b]
material [%][b]
1
2
3
4
5
6
7
8
N
82
30
29
28
37
30
30
23
34
34
34
62
34
35
37
32
44
28
25
25
28
29
39
28
27
28
11
52
46
38
42
44
63
59
39
40
43
26
44
41
47
38
37
42
36
53
39
37
35
41
50
43
86 (S)
98 (R)
94 (S)
98 (R)
96 (S)
97 (R)
>99 (S)
97 (R)
97 (S)
98 (R)
96 (R)
92 (S)
>99 (S)
97 (R)
98 (S)
97 (R)
97 (S)
98 (R)
97 (S)
97 (R)
97 (S)
99 (R)
93 (S)
98 (R)
97 (S)
97 (R)
2
14
20
24
15
21
<1
4
18
18
19
6
17
16
10
17
15
22
25
18
27
23
19
23
18
20
The absolute configuration of
the
ligands
(Rp,S,S)-16m,
(Sp,S,R)-16, (Rp,S,S)-16i, and
(Rp,S,S)-16i was determined by
their X-ray structures, which
are presented in Figure 3. In
our first communication, we as-
signed the structure of (Rp,S,S)-
16i as Rp,S,R.[31,32]
These amine ligands 16m,i
submitted to the 1,4-addition
model reaction deliver, in gen-
eral, lower product yields and a
lower regioselectivity than their
imine analogues and what is
most interesting is that the 1,2-
addition compound becomes
the major product (Scheme 2,
Table 6). As already observed
before, the absolute configura-
tion of the 1,4-addition product
14 seems again to be mainly de-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
[a] Reaction conditions: ligand (2 mol%), diethylzinc (1.10m in toluene, 2.00 equiv), toluene, À258C, 1.5 d
under an argon atmosphere. [b] Determined by GC analysis after workup. [c] Determined by GC analysis
(chiral, Lipodex-E). [d] Due to side reactions, such as aldol reactions, the total amount of material does not
always reach 100%.
except that the benzylic methyl group had been replaced by
an ethyl group. Comparing 12d and 12i, similar results in
terms of yields, regioselectivities, and enantioselectivities
were obtained in both cases (Table 4, entries 25, 26 and 9,
10).
Taking all the results so far obtained together, it becomes
clear that the planar chiral [2.2]paracyclophane unit in com-
bination with a central chiral element is important for the
activity and the selectivity of the ligand. Although, excellent
enantioselectivities were observed with
a [2.2]paracy-
clophane backbone lacking a central chiral unit, the best re-
sults in terms of yields, selectivities, and enantioselectivities
are clearly obtained by combining the two chiral elements.
It still remains, however, unclear as to how and to what
extent a central chiral unit influences the outcome of the re-
action. To further explore this topic, we decided to reduce
the imine double bond of the ligands. This results in the for-
mation of an additional stereogenic center that might help
us to understand the influence of central chiral units.
Reduction of imines 12m and 12i was easily accomplished
by using sodium borohydride in combination with concen-
trated acetic acid in a mixture of methanol and methylene
chloride (Scheme 4).[31,32] The products are isolated in good
yields ranging from 70–79% (Table 5). In all cases, the half
space bearing the [2.2]paracyclophane substituent, is effec-
tively shielded from an attack of the reducing agent, so that
the borohydride anion approaches from the opposite side.[33]
Scheme 4. General reduction conditions for ligands 12m and 12i.
Table 5. Synthesis of ligands 16.
Entry
Ligand
(Rp,S)-12m
(Sp,S)-12m
(Rp,S)-12i
(Sp,S)-12i
Yield[a]
de [%][b]
Configuration[c]
(Rp,S,S)-16m
(Sp,S,R)-16m
(Rp,S,S)-16i
(Sp,S,R)-16i
1
2
3
4
G
73
70
79
79
>99
>99
>99
>99
ACHTUNGTRENNUNG
E
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
[a] Isolated yield. [b] Determined by NMR spectroscopic analysis of the
crude material. de=diastereomeric excess. [c] Determined X-ray struc-
ture analysis.
termined by the chiral planar unit rather than the central
chiral one. The catalyst activity of the generated complexes
is, however, similar to that of the ligands containing the
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Enantioselective Conjugate Addition Reactions
FULL PAPER
only 11% starting material recovery (entry 2). In addition,
high enantiomeric excesses (>90% ee) were obtained in all
cases with ligands 16m being the most selective ones (en-
tries 1 and 2).
Furthermore, ligands with an Sp,S,R configuration seem to
generate a slightly more active catalyst for the 1,2-addition
compared to those containing an Rp,S,S configuration.
Finally, with the different amine-containing ligands 16 in
hand we investigated their ability to act as ligands in the
copper-mediated 1,4-addition reaction. Since secondary or
tertiary amines are commonly used in N,P-ligands[35] for
copper catalysis, ligands 16 should have better chelating
properties than their imine analogues. The model reaction
presented in Scheme 2 was used again, this time run under
optimized conditions for copper catalysis.[36] The results are
summarized in Table 7. 10 mol% CuCN and an equimolar
amount of ligand were used in all cases (entries 1–4). As a
control, identical reaction conditions without the addition of
copper were applied (entries 5–8).
Concerning the copper-mediated catalysis, ligands 16m
generate a more active catalyst than 16i (based on the re-
covered starting material). Ligand (Sp,S,R)-16i is remark-
able, since almost no conversion takes place (Table 7,
entry 4) and (Sp,S,R)-16m seems to be the most active one
(entry 2).
The most dramatic change observed compared to the con-
trol experiments is, however, the pronounced difference in
conversion to the desired product. Without addition of
CuCN, high enantioselectivities, ranging from 70 to 89% ee,
are obtained (Table 7, entries 5–8). But in the presence of
copper, the observed enantioselectivities drop dramatically,
27% on the one hand for ligands (Sp,S,R)-16m and (Sp,S,R)-
16i (entries 2 and 4) and almost no enantiomeric excess on
the other hand for ligands (Rp,S,S)-16m and (Rp,S,S)-16i
(entries 1 and 3).
Another interesting observation is that in the case of li-
gands (Sp,S,R)-16m and (Rp,S,S)-16i, the absolute configura-
tion of 14 is switched depending on the presence or absence
of copper. Even though we cannot rationalize this finding at
this point, one can imagine that in the presence of copper,
two opposite processes may run in parallel. On the one
hand, the generated catalyst promotes the Michael addition
under zinc catalysis with excellent enantioselectivities. On
the other hand, there seems to be a copper-mediated path-
way, which delivers the desired Michael product in high
yields, but as a racemic mixture. If one assumes that the li-
gands do not complex copper, which is apparently the case
(all efforts to obtain copper–ligand crystals by mixing either
copper(I) cyanide, copper(I) iodide, copper(I) bromide, or a
dimethyl sulfide complex with an equimolar amount of
ligand 12i in THF, CH2Cl2, and methyl tert-butyl ether, were
unsuccessful) a transmetalation of diethylzinc to copper is
likely to occur. This would generate an achiral organocopper
species that is able to react in a conjugate addition reaction.
Moreover, in the control experiments without copper salt,
the regioselectivity is in favor of the 1,2-addition product 14
(Table 6). The best results for an asymmetric 1,2-addition
Figure 3. Top: Molecular structure of (Rp,S,S)-16m. Middle: Molecular
structure of (Sp,S,R)-16m. Bottom: Molecular structure of (Rp,S,S)-16i.
Displacement parameters are drawn at 50% probability level.
imine functionality. The use of ligand (Sp,S,R)-16m, which
generates by far the most active catalyst, results even in
Chem. Eur. J. 2008, 14, 11539 – 11556
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11545

S. Brꢀse et al.
Table 6. Screening of amine ligands 16m,i.[a,d]
There are ongoing studies re-
garding this catalyst system and
detailed mechanistic investiga-
tions done by in situ EXAF and
IR techniques will be published
in due course.
Entry
Ligand
Starting
1,4-Product (14) [%][b]
ee of 14 [%][c]
1,2-Product (15) [%][b]
material [%][b]
1
2
3
4
N
19
11
31
30
14
12
13
6
95 (S)
95 (R)
92 (S)
91 (R)
49
55
38
45
[a] Reaction conditions: ligand (2 mol%), diethylzinc (1.10m in toluene, 2.00 equiv), toluene, À258C, 1.5 d
under an argon atmosphere. [b] Determined by GC analysis after workup. [c] Determined by GC analysis
(chiral; Lipodex-E). [d] Due to side reactions, such as aldol reactions, the total amount of material does not
always reach 100%.
Experimental Section
General: All reactions were carried
out under an argon atmosphere with
oven-dried glassware. Solvents were
dried under an argon atmosphere by
using standard methods and were
freshly distilled before use. Diethylzinc
(1.10m in toluene or 1.00m in n-
hexane) were purchased from com-
mercial sources and used without fur-
ther purification. rac-10, (Sp)-10, rac-
9,[19] and 2,6-diphenylaniline[37] were
synthesized according to literature
procedures. The aldehydes used for
the synthesis of the ortho-substituted
salicylaldehyde derivatives were avail-
able from commercial sources or syn-
thesized according to literature proce-
dures. NMR spectra were analyzed ac-
cording to first order and recorded on
a Bruker AM 400 spectrometer. The
chemical shifts (d) are given in parts
per million (ppm) relative to TMS and
are referred to CHCl3 with d=
7.26 ppm. All coupling constants (J)
are given in absolute values in Hertz
Table 7. Copper-mediated and copper-free screening reactions with ligands 16m and 16i.[a,f]
Entry
Ligand
Starting
material
[%][b]
1,4-Product (14)
ee of 14
1,2-Product (15)
ee of 15
[%][b]
[%][c]
[%][b]
[%][d]
1
2
3
4
N
29
24
44
82
36
23
30
40
43
56
34
8
20
27
16
17
1 (S)
27 (S)
2 (R)
27 (R)
89 (S)
89 (R)
88 (S)
70 (R)
19
10
13
6
33
32
45
33
1
À6
1
À2
5[e]
6[e]
7[e]
8[e]
66
À48
75
À63
[a] Reaction conditions: CuCN (10 mol%), ligand (10 mol%), diethylzinc (1.00m in n-hexane, 3.00 equiv), tol-
uene, À308C, 1 d under an argon atmosphere. [b] Determined by GC analysis after workup. [c] Determined by
GC analysis (chiral, Lipodex-E). [d] Determined by GC analysis (chiral; Hydrodex g-TBDAc). [e] No CuCN
is added to the reaction. [f] Due to side reactions, such as aldol reactions, the total amount of material does
not always reach 100%.
(Hz). The description of signals include: s=singlet, brs=broad singlet,
d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of dou-
blets, and ddd=doublet of dd. The signal abbreviations include: Har =ar-
omatic proton and Car =aromatic carbon. The signal structure was ana-
lyzed by DEPT and is described as follows: p=primary C atom, s=sec-
ondary C atom, t=tertiary C atom, and q=quaternary C-atom. Gas
chromatograms were recorded on a Varian CP-3900 (achiral stationary
phase, capillary column Zebron ZB-5mS, 30 mꢃ0.25 mm, 0.50 mm df).
Enantiomeric excesses were determined by GC on a Varian CP-3800
(chiral stationary phase, capillary column Lipodex-E, 25 mꢃ0.25 mm and
Hydrodex g-TBDAc, 25 mꢃ0.25 mm). In both cases, helium was used as
a Carrier gas and nitrogen as the make-up gas. Optical rotations were de-
termined on a Perkin–Elmer 241 polarimeter (Na, 589 nm). Melting
points were measured with a MEL-TEMPII instrument from Laboratory
Devices. IR spectra were recorded on a Bruker FTIR IFS-88. EIMS and
HRMS were recorded on a Finnigan MAT 90 instrument. Elemental
analysis was performed by using an Elementar Vario Microcube or a
Heraeus CHN-O-Rapid. Flash chromatography was performed by using
Machery-Nagel silica gel 60 (230–400 mesh ASTM) with the denoted sol-
vents as the eluent. For TLC, silica-gel-coated aluminum plates (Merck,
silica gel 60 with fluorescence indicator, F254) were employed. All reac-
tions were conducted under an argon atmosphere.
are obtained with (Rp,S,S)-16i in 45% yield and 75% ee,
which makes these reduced ligands promising catalysts to
address the 1,2-position of a,b-unsaturated carbonyl com-
pounds selectively.
Concerning the amine-containing ligands, we were able to
show that our zinc-catalyzed reactions indeed run under
copper-free conditions and that traces of copper (present in
commercially available diethylzinc solutions) mediate a con-
current racemic pathway.
Conclusion
We have demonstrated that substituted planar chiral
[2.2]paracyclophanes bearing a central chiral unit are effec-
tive catalysts for asymmetric 1,4-addition reactions. Al-
though the influence of the central chiral part cannot be
fully rationalized to date, combining both chiralities results
in the best catalysts. In addition, we proved that the zinc-
based catalytic system is concurrently affected by copper
salts and that copper-free conditions are required to obtain
the desired 1,4-addition product selectively.
At this stage, it is interesting to note that depending on
the paracyclophane ligand used, 1,4- or 1,2-regioselectivity is
observed. In both cases with a high degree of enantioselec-
tion.
X-ray crystallographic analysis: The data were collected on a Bruker-
Nonius KappaCCD diffractometer at À1508C by using MoKa radiation
(l=0.71073 ꢄ). The structures were solved by direct methods (SHELXS-
97).[39] The non-hydrogen atoms were refined anisotropically, H atoms
were refined by using a riding model, H (N, O) free (full-matrix least-
squares refinement on F2, SHELXL-97).[37] The absolute structure could
not be determined reliably by refinement of Flackꢂs x parameter.[37] For
(Rp,S,S)-16m, (Sp,S,R)-16m, and (Rp,S,S)-16i, the absolute configuration
was assigned by reference to an unchanging chiral center in the synthetic
procedure. Details of data collection and refinement are given in
11546
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11539 – 11556

Enantioselective Conjugate Addition Reactions
FULL PAPER
Tables 8 and 9. CCDC-696783 (5r),
696784 (11r), 696785 (12n), 696786
(12o), 696787 ((Rp,S,S)-16m), 696788
((Sp,S,R)-16m), and 696789 ((Rp,S,S)-
16i) contain the supplementary crys-
tallographic data for this paper. These
data can be obtained free of charge
from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/
data_request/cif
Table 8. Crystallographic data, structure solution, and refinement of 5r, 11r, 12n, and 12o.
Compound
5r
11r
12n
12o
formula
Mr
C27H23NO
377.46
C35H29NO
479.59
C24H23NO
341.43
C28H31NO
397.54
dimensions [mm]
crystal system
space group
a [ꢄ]
b [ꢄ]
c [ꢄ]
0.20ꢃ0.30ꢃ0.50
monoclinic
P21/c (No.14)
10.503(1)
10.069(1)
38.394(4)
90
0.10ꢃ0.20ꢃ0.50
monoclinic
C2/c (No.15)
30.5348(6)
8.5751(2)
19.1776(3)
90
0.30ꢃ0.40ꢃ0.50
monoclinic
P21/c (No.14)
11.5302(3)
10.2977(3)
15.4454(5)
90
0.10ꢃ0.15ꢃ0.20
orthorhombic
Pca21 (No.29)
16.3542(4)
9.3885(2)
28.4435(7)
90
General procedure A for the conju-
gate addition of diethylzinc: The de-
sired ligand (0.01 mmol, 0.02 equiv)
was placed in a vial, dissolved in a di-
ethylzinc solution (1.00 mL, toluene or
n-hexane, 2.00 equiv) and stirred for
30 min at room temperature. After
this time, the reaction mixture was
cooled to the desired temperature
(À30 or À258C) and cinnamaldehyde
(0.50 mmol, 1.00 equiv) was added
slowly by a syringe. The resulting reac-
tion mixture was stirred at the men-
tioned temperature for the required
time. The reaction was quenched with
a 1m HCl solution and diluted with di-
ethyl ether. After separation of the or-
ganic phase, the mixture was washed
twice with water and then dried over
MgSO4.
a [8]
b [8]
90.95(1)
90
4059.8(10)
8
1.235
0.074
91.581(1)
90
5019.53(17)
8
1.269
0.075
103.463
90
1783.51(9)
4
1.272
0.077
(2
90
90
g [8]
V [ꢄ3]
Z
4367.25(18)
8
1.209
0.072
1712
1 [gcmÀ3
]
]
m [mmÀ1
(000)
F
A
1600
2032
728
2q max. [8]
50
50
55
55
À11ꢀhꢀ12
À11ꢀkꢀ11
À45ꢀlꢀ45
38012
À36ꢀhꢀ36
À10ꢀkꢀ10
À22ꢀlꢀ22
36326
À14ꢀhꢀ14
À13ꢀkꢀ12
À20ꢀlꢀ14
13499
4019
À16ꢀhꢀ21
À12ꢀkꢀ12
À31ꢀlꢀ36
21099
no. of measured reflns
no. of unique reflns
7052
4386
8114
Rint
0.0378
0.0455
0.0281
0.0678
refinement on
F2
F2
F2
F2
no. of parameters/restraints
533/0
337/1
239/1
549/3
x
À1.6(19)
R [for I>2s(I)]
0.0461
0.0484
0.0453
0.0529
wR2 (all data)
0.1038
0.1180
0.1359
0.1197
General procedure
B for conjugate
S
1.18
0.224/À0.174
1.10
0.220/À0.192
1.13
0.248/À0.246
0.90
0.258/À0.209
max./min. difference peak [eꢄÀ3
]
addition with ligands 16m and 16i:
The desired ligand (0.01 mmol,
0.10 equiv) was placed together with
CuCN (0.01 mmol, 0.10 equiv) in
a
Table 9. Crystallographic data, structure solution, and refinement of (Rp,S,S)-16m, (Sp,S,R)-16m, and (Rp,S,S)-
16i.
vial. Then dry toluene (1.00 mL) was
added and the mixture was stirred for
5 min. After this time, cinnamaldehyde
(0.50 mmol, 1.00 equiv) was added.
The resulting mixture was stirred for
10 min and was then cooled to À308C.
Diethylzinc (0.30 mmol, 1.00m solution
in n-hexane, 3.00 equiv) was slowly
added and the reaction mixture was
stirred for 1 d. The reaction was
quenched with a 1m HCl solution and
diluted with diethyl ether. After sepa-
ration of the organic phase, the mix-
ture was washed twice with water and
then dried over MgSO4.
Compound
G
G
ACHTUNGTRENUN(NG Rp,S,S)-16i
formula
Mr
C26H35NO
377.55
C26H35NO
377.55
C26H29NO
371.50
dimensions [mm]
crystal system
space group
a [ꢄ]
b [ꢄ]
c [ꢄ]
0.15ꢃ0.30ꢃ0.50
orthorhombic
P212121 (No.19)
8.030(1)
14.928(3)
17.577(3)
90
0.10ꢃ0.20ꢃ0.40
orthorhombic
P212121 (No.19)
7.750(1)
9.987(2)
26.354(4)
90
0.10ꢃ0.25ꢃ0.35
orthorhombic
P212121 (No.19)
8.245(2)
9.093(2)
29.959(5)
90
a [8]
b [8]
90
90
90
g [8]
90
90
90
V [ꢄ3]
Z
2107.0(6)
4
1.190
0.071
824
2039.8(6)
4
1.229
0.073
824
2021.2(8)
4
1.221
0.073
800
General procedure C for imine con-
densation: The ketone (1.00 equiv)
was dissolved in toluene (50.0 mL)
and the desired amine (3.00 equiv)
was added to the solution at room
1 [gcmÀ3
]
]
m [mmÀ1
(000)
F
A
2q max. [8]
55
55
50
À10ꢀhꢀ10
À19ꢀkꢀ19
À22ꢀlꢀ22
43138
À10ꢀhꢀ10
À12ꢀkꢀ12
À34ꢀlꢀ34
30119
À9ꢀhꢀ9
À10ꢀkꢀ10
À32ꢀlꢀ31
20363
temperature. Then Bu2SnACTHUNGRTNE(NUG OAc)2 (cat.)
was added in one portion and the re-
action mixture was refluxed by using a
Dean–Stark apparatus until no more
starting material was detected by TLC.
The mixture was allowed to cool to
room temperature and the solvent was
completely removed under reduced
pressure. The residue was purified by
flash column chromatography (n-pen-
tane/diethyl ether).
no. of measured reflns
no. of unique reflns
Rint
refinement on
no. of parameters/restraints
x
4798
4629
2036
0.0382
0.0378
0.0573
F2
F2
F2
259/2
0.4(11)
0.0338
0.0872
1.06
259/2
0.0(15)
0.0418
0.0871
1.08
259/2
À2(4)
R [for I>2s(I)]
wR2 (all data)
0.0615
0.1354
1.12
0.278/À0.211
S
Synthesis and characterization of li-
gands 3a–h
max./min. difference peak [eꢄÀ3
]
0.226/À0.170
0.204/À0.187
Chem. Eur. J. 2008, 14, 11539 – 11556
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11547

S. Brꢀse et al.
Synthesis of 3a: Compound 3a was synthesized according to general pro-
cedure C with 2-hydroxyacetophenone (0.220 mL, 297 mg, 2.18 mmol)
and enantiopure (S)-3-3-dimethyl-2-aminobutane (221 mg, 2.18 mmol).
After 36 h stirring at room temperature, the raw material was purified by
flash chromatography (pentane/diethyl ether 10:1). Yield: 191 mg (40%);
yellow oil; [a]2D0 =+101.5 (c=0.850 g/100 mL CHCl3); Rf =0.35 (n-
hexane/ethyl acetate 5:1); 1H NMR (400 MHz, CDCl3): d=0.99 (s, 9H;
pure (S)-phenylpropylamine (270 mg, 2.00 mmol). After 3 d heating at
reflux temperature, the raw material was purified by flash chromatogra-
phy (n-pentane/diethyl ether 10:1). Yield: 269 mg (53%); yellow oil;
[a]2D0 =+363 (c=1.05 g/100 mL CHCl3); Rf =0.36 (n-hexane/ethyl acetate
5:1); 1H NMR (400 MHz, CDCl3): d=0.88 (t, J=7.4 Hz, 3H; CH3CH2),
1.93 (ddq, J=14.5, 7.4, 6.7 Hz, 2H; CH3CH2), 2.24 (s, 3H; CH3CN), 4.61
(t, J=6.7 Hz, 1H; CH2CH), 6.68 (ddd, J=1.1, 1.6, 8.3 Hz, 1H; Har), 6.88
(dd, J=1.1, 8.3 Hz, 1H; Har), 7.13–7.28 (m, 6H; Har), 7.42 (dd, J=1.6,
J=8.3 Hz, 1H; Har), 14.72 ppm (brs, 1H; COH); 13C NMR (100 MHz,
CDCl3): d=10.94 (p; CH3CH2), 14.85 (p; CH3CN), 32.31 (s; CH3CH2),
64.93 (t; CH2CH), 116.92 (t; Car), 118.95 (t; Car), 119.28 (q; Car), 126.91
(t, 2C; Car), 127.20 (t; Car), 128.17 (t; Car), 128.70 (t, 2C; Car), 132.67 (t;
Car), 142.80 (q; Car), 164.58 (q, Car; COH), 171.23 ppm (q; C=N); IR
(KBr): n˜ =3061 (w), 3028 (w), 2966 (m), 2930 (m), 2874 (w), 1949 (vw),
1614 (vs), 1579 (s), 1493 (m), 1450 (s), 1378 (w), 1305 (s), 1256 (m), 1236
(m), 1161 (m), 1134 (vw), 1088 (vw), 1050 (w), 1027 (w), 1005 (w), 937
(w), 838 (w), 754 (vs), 701 (s), 647 (vw), 543 (w), 522 cmÀ1 (vw); EIMS
(70 eV): m/z (%): 253 (100) [M+], 224 (41), 135 (38), 119 (23), 91 (81);
HR-EIMS: calcd for C17H19NO: 253.1466; found: 253.1469; elemental
analysis calcd (%) for C17H19NO: C 80.6, H 7.56, N 5.53; found: C 80.49,
H 7.48, N 5.40.
CACHTUNGTRENNUNG(CH3)3), 1.17 (d, J=6.6 Hz, 3H; CH3CHN), 2.37 (s, 3H; CH3CHN),
3.57 (q, J=6.6 Hz, 1H; NCH), 6.74 (ddd, J=1.1, 1.6, 8.3 Hz, 1H; Har),
6.91 (dd, J=1.1, 8.3 Hz, 1H; Har), 7.28 (ddd, J=1.1, 1.6, 8.3 Hz, 1H),
7.50 ppm (dd, J=1.6, 8.3 Hz, 1H; Har); 13C NMR (100 MHz, CDCl3): d=
13.68 (p; CH3CHN), 16.59 (p; CH3CN), 26.43 (p, 3C; C
ACHTUGNTRENN(UNG CH3)3), 34.50 (q;
CACHTUNGTRENNUNG(CH3)3), 62.95 (t; NCH), 116.37 (t; Car), 118.86 (q; Car), 119.27 (t; Car),
128.07 (t; Car), 132.55 (t; Car), 165.48 (q; Car, COH), 169.35 ppm (q; C=
N); IR (KBr): n˜ =3471 (vw), 2966 (vw), 1615 (w), 1579 (vw), 1501 (vw),
1448 (vw), 1396 (vw), 1372 (vw), 1303 (vw), 1236 (vw), 1203 (vw), 1160
(vw), 1135 (vw), 1112 (vw), 1087 (vw), 1011 (vw), 854 (vw), 837 (vw), 752
(vw), 625 (vw), 568 cmÀ1 (vw); EIMS (70 eV): m/z (%): 219 (15) [M+],
162 (100), 146 (14), 120 (23), 91 (68), 57 (38), 41 (36); HR-EIMS: calcd
for C14H21NO: 219.1623; found: 219.1626.
Synthesis of 3b: Compound 3b was synthesized according to general pro-
cedure C with 2-hydroxyacetophenone (204 mg, 1.50 mmol) and enantio-
pure (S)-1-(4-methoxyphenyl)ethylamine (151 mg, 1.00 mmol). After 3 d
heating at reflux temperature, the raw material was purified by flash
chromatography (n-pentane/diethyl ether 5:1). Yield: 238 mg (59%);
yellow oil; [a]2D0 =+326.6 (c=2 g/100 mL CHCl3); Rf =0.18 (n-hexane/
ethyl acetate 5:1); 1H NMR (400 MHz, CDCl3): d=1.53 (d, J=6.6 Hz,
3H; CH3CH), 2.25 (s, 3H; CH3CN), 3.7 (s, 3H; OMe), 4.82 (q, J=
6.6 Hz, 1H; CH3CH), 6.67 (ddd, J=1.1, 1.6, 8.3 Hz, 1H; Har), 6.77–6.81
(m, 2H; Har), 6.86 (dd, J=1.1, 8.3 Hz, 1H; Har), 7.12–7.22 (m, 3H; Har),
7.41 ppm (dd, J=1.6, 8.3 Hz, 1H; Har); 13C NMR (100 MHz, CDCl3): d=
14.57 (p; CH3CN), 25.24 (p; CH3CH), 55.30 (p; OCH3), 57.78 (t;
CH3CH), 114.19 (t, 2C; Car), 116.91 (t; Car), 118.98 (t; Car), 119.24 (q;
Car), 127.39 (t, 2C; Car), 128.14 (t; Car), 132.66 (t; Car), 136.30 (q; Car),
158.69 (q; COMe), 164.60 (q; Car, COH), 170.33 ppm (q; C=N); IR
(KBr): n˜ =3450 (vw), 2967 (vw), 2928 (vw), 2835 (vw), 1611 (s), 1579 (w),
1511 (m), 1447 (w), 1373 (vw), 1303 (m), 1246 (m), 1177 (w), 1160 (w),
1133 (vw), 1098 (vw), 1033 (w), 972 (vw), 830 (w), 754 (w), 642 (vw), 623
(vw), 551 cmÀ1 (vw); EIMS (70 eV): m/z (%): 269 (36) [M+], 135 (100);
HR-EIMS: calcd for C17H19NO2: 269.1416; found: 269.1412; elemental
analysis calcd (%) for C17H19NO2: C 75.81, H 7.11, N 5.20; found: C
75.48, H 7.11, N 5.23.
Synthesis of 3e: Compound 3e was synthesized according to general pro-
cedure C with 2-hydroxyacetophenone (136 mg, 1.00 mmol) and enantio-
pure (S)-1-aminotetraline (147 mg, 1.00 mmol). After 3 d heating at
reflux temperature, the raw material was purified by flash chromatogra-
phy (n-pentane/diethyl ether 10:1). Yield: 256 mg (98%); yellow solid;
[a]2D0 =+100.6 (c=1.00 g/100 mL CHCl3); m.p. 77–788C; Rf =0.31 (n-
hexane/ethyl acetate 5:1); 1H NMR (400 MHz, CDCl3): d=1.87–2 (m,
2H; CH2), 2.06–2.17 (m, 2H; CH2), 2.56 (s, 3H; CH3), 2.82–3.03 (m, 2H;
CH2), 5–5.07 (m, 1H; NCH), 6.83 (ddd, J=1.1, 1.6, 8.3 Hz, 1H; Har), 6.92
(dd, J=1.1, 8.3 Hz, 1H; Har), 7.08–7.24 (m, 4H; Har), 7.31 (ddd, J=1.1,
1.6, 8.3 Hz, 1H; Har), 7.61 ppm (dd, J=1.6, 8.3 Hz, 1H; Har); 13C NMR
(100 MHz, CDCl3): d=14.27 (p; CH3CN), 20.46, 29.19, 31.01 (s; 3CH2),
57.05 (t; NCH), 117.00 (t; Car), 118.88 (t; Car), 119.43 (q; Car), 126.14 (t;
Car), 127.15 (t; Car), 127.90 (t; Car), 128.20 (t; Car), 129.25 (t; Car), 132.46
(t; Car), 136.77 (q; Car), 137.07 (q; Car), 164.16 (q; Car, COH), 169.79 ppm
(q; C=N); IR (KBr): n˜ =3064 (vw), 3017 (vw), 2933 (w), 2861 (vw), 2555
(vw), 1821 (vw), 1615 (w), 1579 (w), 1508 (w), 1491 (w), 1448 (w), 1374
(vw), 1304 (w), 1240 (w), 1163 (w), 1127 (vw), 1082 (vw), 1011 (vw), 950
(w), 853 (vw), 837 (vw), 775 (vw), 749 (w), 644 (vw), 625 (vw), 564 (vw),
531 (vw), 494 (vw), 478 (vw), 435 cmÀ1 (vw); EIMS (70 eV): m/z (%):
265 (54) [M+], 135 (52), 131 (100), 91 (18); HR-EIMS: calcd for
C18H19NO: 265.1467; found: 265.1465; elemental analysis calcd (%) for
C18H19NO: C 81.47, H 7.22, N 5.28; found: C 81.07, H 7.12, N 5.20.
Synthesis of 3c: Compound 3c was synthesized according to general pro-
cedure C with 2-hydroxyacetophenone (272 mg, 2.00 mmol), enantiopure
Synthesis of 3 f: Compound 3 f was synthesized according to general pro-
cedure C with 2-hydroxyacetophenone (1.31 g, 9.60 mmol) and enantio-
(S)-1-(4-fluorphenyl)ethylamine (278 mg, 2.00 mmol), and
a catalytic
amount of TiCl4. After 5 d stirring at room temperature, the raw material
was purified by flash chromatography (n-pentane/diethyl ether 10:1).
Yield: 352 mg (68%); orange/yellow oil; [a]2D0 =+305.9 (c=1.45 g/
100 mL CHCl3); Rf =0.25 (n-hexane/ethyl acetate 5:1); 1H NMR
(400 MHz, CDCl3): d=1.61 (d, J=6.6 Hz, 3H; CH3CHN), 2.34 (s, 3H;
CH3CN), 4.94 (q, J=6.6 Hz, 1H; NCH), 6.79 (ddd, J=8.3, 1.6, 1.1 Hz,
1H; Har), 6.95 (dd, J=8.3, 1.1 Hz, 1H; Har), 7.03 (tt, J=8.7, 2.1 Hz, 2H;
Har), 7.28–7.36 (m, 3H; Har), 7.51 (dd, J=8.3, 1.6 Hz, 1H; Har),
15.17 ppm (brs, 1H; COH); 13C NMR (100 MHz, CDCl3): d=14.66 (p;
CH3CHN), 25.28 (p; CH3CN), 57.87 (NCH), 115.53 (t; Car), 116.49 (t, d,
pure
1-(S)-trans-(S)-2-phenylmethoxycyclohexylamine
(500 mg,
2.40 mmol). After 4 d heating at reflux temperature, the raw material
was purified by flash chromatography (n-pentane/diethyl ether 10:1).
Yield: 607 mg (78%); orange oil; [a]2D0 =+211.4 (c=1.15 g/100 mL
CHCl3); Rf =0.20 (n-hexane/ethyl acetate 5:1); 1H NMR (400 MHz,
CDCl3): d=1.32–1.51 (m, 3H; c-hexyl), 1.57–1.67 (m, 1H; c-hexyl), 1.74–
1.88 (m, 2H; c-hexyl), 1.88–1.96 (m, 1H; c-hexyl), 2.16–2.27 (m, 1H; c-
hexyl), 2.38 (s, 3H; CH3CN), 3.46–3.53 (m, 1H; c-hexyl), 3.71–3.77 (m,
1H; c-hexyl), 4.46 (d, 2J=11.5 Hz, 1H; CHaHbPh), 4.6 (d, 2J=11.5 Hz,
1H; CHaHbPh), 6.79 (ddd, J=1.1, 1.6, 8.3 Hz, 1H; Har), 6.97 (dd, J=1.1,
8.3 Hz, 1H; Har), 7.19–7.26 (m, 5H; CH2Ph), 7.32 (ddd, J=1.1, 1.6,
8.3 Hz, 1H; Har), 7.53 ppm (dd, J=1.6, 8.3 Hz, 1H; Har); 13C NMR
(100 MHz, CDCl3): d=14.72 (p; CH3CN), 23.97 (s; C-c-hexyl), 24.03 (s;
C-c-hexyl), 30.53 (s; C-c-hexyl), 32.16 (s; C-c-hexyl), 62.18 (t; C-c-hexyl),
71.99 (s; CH2Ph), 81.83 (t; C-c-hexyl), 116.60 (t; Car), 119.10 (t; Car),
119.22 (q; Car), 127.47 (t; Car), 127.78 (t, 2C; Car), 128.26 (t, 3C; Car),
132.49 (t; Car), 138.59 (q; Car), 165.05 (q; Car, COH), 171.10 ppm (q; C=
N); IR (KBr): n˜ =3061 (w), 3030 (w), 2932 (s), 2859 (m), 1812 (vw), 1616
(vs), 1579 (m), 1497 (m), 1449 (s), 1361 (w), 1303 (m), 1259 (m), 1230
(m), 1207 (w), 1161 (m), 1093 (s), 1028 (w), 953 (w), 918 (w), 853 (w),
836 (w), 752 (s), 698 (m), 645 (vw), 620 (vw), 530 (vw), 502 cmÀ1 (vw);
EIMS (70 eV): m/z (%): 323 (5) [M+], 232 (20), 217 (23), 91 (100); HR-
EIMS: calcd for C21H25NO2: 323.1885; found: 323.1883.
J
C,F =151.6 Hz; Car), 118.75 (t; Car), 119.39 (q; Car), 127.87 (t, d, JC,F =
8.0 Hz; Car), 128.18 (t; Car), 132.68 (t; Car), 139.99 (q, JC,F =3.0 Hz, d; Car),
161.85 (q, d, JC,F =245.3 Hz; Car), 163.9 (q; Car, COH), 170.55 ppm (q; C=
N); IR (KBr): n˜ =3472 (vw), 3065 (vw), 2974 (vw), 2928 (vw), 1890 (vw),
1793 (vw), 1701 (vw), 1686 (vw), 1616 (w), 1578 (vw), 1509 (w), 1449
(vw), 1375 (vw), 1305 (vw), 1225 (vw), 1159 (vw), 1134 (vw), 1092 (vw),
1038 (vw), 1014 (vw), 937 (vw), 835 (vw), 755 (vw), 642 (vw), 623 (vw),
573 (vw), 548 (vw), 505 cmÀ1 (vw); EIMS (70 eV): m/z (%): 257(64) [M+
], 135 (43), 123 (100), 103 (19); HR-EIMS: calcd for C16H16FNO:
257.1216; found: 257.1213; elemental analysis calcd (%) for C16H16FNO:
C 74.69, H 6.27, N 5.44; found: C 74.63, H 6.19, N 5.36.
Synthesis of 3d: Compound 3d was synthesized according to general pro-
cedure C with 2-hydroxyacetophenone (272 mg, 2.00 mmol) and enantio-
11548
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11539 – 11556

Enantioselective Conjugate Addition Reactions
FULL PAPER
Synthesis of 3g: Compound 3g was synthesized according to general pro-
cedure C with 2-hydroxyacetophenone (100 mL, 136 mg, 1.00 mmol) and
enantiopure (S)-1-(2-naphthyl)ethylamine (514 mg, 3.00 mmol). After 3 d
heating at reflux temperature, the raw material was purified by flash
chromatography (n-pentane/diethyl ether 10:1). Yield: 191 mg (66%);
yellow solid; [a]2D0 =+494.2 (c=1.15 g/100 mL CHCl3); m.p. 123–1268C;
Rf =0.24 (n-hexane/ethyl acetate 5:1); 1H NMR (400 MHz, CDCl3): d=
1.75 (d, J=6.6 Hz, 3H; CH3), 2.36 (s, 3H; CH3CN), 5.11 (q, J=6.6 Hz,
1H; NCH), 6.79 (ddd, J= <0.5, 1.6, 8.3 Hz, 1H; Har), 7.01 (d, J=8.3 Hz,
1H; Har), 7.33 (ddd, J=1.1, 1.6, 8.3 Hz, 1H; Har), 7.54–7.55 (m, 4H; Har),
7.78–7.87 ppm (m, 4H; Har); 13C NMR (100 MHz, CDCl3): d=14.83 (p;
CH3CN), 25.25 (p; CH3CH), 58.63 (t; CH3CH), 117.08 (t; Car), 118.99 (t;
Car), 119.32 (q; Car), 124.64 (t; Car), 124.77 (t; Car), 125.91 (t; Car), 126.31
(t; Car), 127.72 (t; Car), 127.89 (t; Car), 128.26 (t; Car), 128.80 (t; Car),
132.70 (q; Car), 132.80 (t; Car), 133.47 (q; Car), 141.58 (q; Car), 164.52 (q;
Car, COH), 171.05 ppm (q; C=N); IR (KBr): n˜ =3058 (w), 2980 (w), 2933
(w), 2555 (w), 1904 (vw), 1788 (vw), 1614 (m), 1577 (w), 1506 (w), 1445
(w), 1370 (w), 1300 (w) 1257 (w), 1165 (w), 1132 (w), 1108 (w), 1061 (w),
1011 (w), 951 (w), 898 (w), 863 (w), 836 (w), 824 (w), 751 (m), 663 (vw),
634 (w), 613 (w), 578 (w), 550 (vw), 532 (vw), 480 (w), 449 cmÀ1 (vw);
EIMS (70 eV): m/z (%): 289 (44) [M+], 155 (100); HR-EIMS: calcd for
C20H19NO: 289.1467; found: 289.1468; elemental analysis calcd (%) for
C20H19NO: C 83.01, H 6.62, N 4.84; found: C 83.24, H 6.53, N 4.65.
2906, 2848, 2677, 2655, 1837, 1776, 1604, 1505, 1453, 1405, 1361, 1345,
1316, 1270, 1251, 1220, 1177, 1131, 1113, 1100, 1044, 1034, 977, 933, 891,
828, 806, 771, 743, 711, 672, 648, 638, 539, 494, 450 cmÀ1; EIMS (70 eV):
m/z (%): 284 [M+] (31), 269 (100); HR-EIMS: calcd for C20H28O:
284.2140; found: 284.2137.
Synthesis of 3-adamantyl-5-tert-butyl-2-hydroxybenzaldehyde: 2,6-Luti-
dine (84.0 mL, 0.73 mmol) was added to a solution of 2-adamantan-1-yl-4-
tert-butylphenol (259 mg, 0.91 mmol) in toluene (4.00 mL) at room tem-
perature. Then SnCl4 (1m solution in CH2Cl2, 180 mL, 0.18 mmol) was
added dropwise slowly over 10 min. The resulting reaction mixture was
stirred for 20 min at room temperature and then paraformaldehyde
(109 mg, 3.60 mmol) was added at once. It was stirred for an additional
12 h at room temperature. Then the reaction mixture was stirred for 6 h
at 958C. After cooling to room temperature, the mixture was filtered
over Celite/silica gel 1:1 and washed with ethyl acetate. The filtrate was
washed successively with water, 1m HCl solution, and brine. The organic
layer was then dried over sodium sulfate and evaporated. Purification
was carried out by flash chromatography (n-hexane/ethyl acetate 15:1).[37]
Yield: 251 mg (88%); colorless oil; Rf =0.82 (n-hexane/ethyl acetate
5:1); 1H NMR (400 MHz, CDCl3): d=1.33 (s, 9H; C
ACHTNUGTRNEUNG(CH3)3), 1.76–1.80
(m, 6H; H-Ad), 2.10–2.16 (m, 9H; H-Ad), 7.34 (d, J=2.5 Hz, 1H; Har),
7.54 (d, J=2.5 Hz, 1H; Har), 9.87 (s, 1H; CHO), 11.69 ppm (s, 1H;
COH); 13C NMR (100 MHz, CDCl3): d=28.99 (t, 3C; C-Ad), 31.35 (p,
Synthesis of 3h: Compound 3h was synthesized according to general pro-
cedure C with 2-hydroxyacetophenone (100 mL, 136 mg, 1.00 mmol) and
enantiopure (S)-1-(1-naphthyl)ethylamine (422 mg, 2.50 mmol). After 4 d
heating at reflux temperature, the raw material was purified by flash
chromatography (n-pentane/diethyl ether 10:1). Yield: 328 mg (98%);
brown solid; [a]2D0 =+563.3 (c=1.20 g/100 mL CHCl3); m.p. 1168C; Rf =
0.30 (n-hexane/ethyl acetate 5:1); 1H NMR (400 MHz, CDCl3): d=1.83
(d, J=6.6 Hz, 3H; CH3), 2.26 (s, 3H; CH3CN), 5.71 (q, J=6.6 Hz, 1H;
NCH), 6.78 (ddd, J=1.1, 1.6, 8.3 Hz, 1H; Har), 7 (dd, J=1.1, 8.3 Hz, 1H;
Har), 7.33 (ddd, J=1.1, 1.6, 8.3 Hz, 1H; Har), 7.44 (t, J=7.7 Hz, 1H; Har),
7.48–7.54 (m, 3H; Har), 7.59 (ddd, J=1.5, 1.5, 8.4 Hz, 1H; Har), 7.77 (d,
J=8.1 Hz, 1H; Har), 7.91 (dd, J=1.3, 8.1 Hz, 1H; Har), 8.15 ppm (d, J=
8.4 Hz, 1H; Har); 13C NMR (100 MHz, CDCl3): d=15.19 (p; CH3CN),
24.70 (p; CH3CH), 54.50 (t; CH3CH), 116.95 (t; Car), 119.02 (t; Car),
119.22 (q; Car), 122.42 (t; Car), 123.64 (t; Car), 125.63 (t; Car), 125.89 (t;
Car), 126.34 (t; Car), 127.63 (t; Car), 128.17 (t; Car), 129.23 (t; Car), 130.03
(q; Car), 132.79 (t; Car), 133.90 (q; Car), 140.33 (q; Car), 164.60 (q, Car;
COH), 171.71 ppm (q; C=N); IR (KBr): n˜ =3045 (w), 2976 (w), 2926 (w),
2865 (vw), 2548 (w), 1929 (vw), 1817 (vw), 1613 (m), 1578 (m), 1505 (m),
1450 (w), 1394 (w), 1372 (w), 1356 (w), 1323 (m), 1307 (m), 1257 (w),
1238 (w), 1171 (w), 1159 (w), 1133 (w), 1092 (w), 1016 (w), 968 (w), 938
(w), 866 (w), 834 (w), 798 (w), 779 (m), 765 (m), 659 (vw), 636 (w), 575
(vw), 533 (vw), 503 (w), 470 (vw), 457 (vw), 431 (vw), 406 cmÀ1 (vw);
EIMS (70 eV): m/z (%): 289 (33) [M+], 155 (100); HR-EIMS: calcd for
C20H19NO: 289.1467; found: 289.1469; elemental analysis calcd (%) for
C20H19NO: C 83.01, H 6.62, N 4.84; found: C 83.16, H 6.55, N 4.64.
3Cp; C
(CH2)3), 40.22 (s, 3C; CAd), 119.99 (q; Car-CHO), 127.73 (t; Car), 132.00
(t; Car), 137.82 (q; Car-C(CH2)3), 141.74 (q; C-tBu), 159.39 (q; COH),
197.49 ppm (t; CHO); IR (KBr): n˜ =3881, 3496, 2950, 2904, 2848, 2739,
2677, 2656, 1812, 1741, 1648, 1611, 1456, 1414, 1361, 1327, 1271, 1251,
1211, 1181, 1128, 1104, 1081, 1044, 976, 953, 878, 828, 818, 794, 765, 748,
705, 651, 638, 548, 520, 462, 437 cmÀ1; EIMS (70 eV): m/z (%): 312 [M+]
(68), 297 (100); HR-EIMS: calcd for C21H28O2: 312.2089; found:
312.2092; elemental analysis calcd (%) for C21H28O2: C 80.73, H 9.03;
found: C 80.34, H 9.12.
ACHTUTGNRNEUG(N CH3)3), 34.32 (q; CHCATUNGTRENN(NGU CH3)3), 37.03 (s, 3C; CAd), 37.24 (q; Car-C-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Synthesis of 4-tert-butyl-2-tritylphenol: 4-tert-Butylphenol (3.00 g,
19.97 mmol) and tritylchloride (1.86 g, 6.66 mmol) were heated at 2208C
for 15 min. The resulting mixture was then cooled to room temperature
and the obtained raw product was purified by flash chromatography (n-
hexane/ethyl acetate 20:1). Yield: 527 mg (41%); white solid; m.p. 148–
1538C; Rf =0.76 (n-hexane/ethyl acetate 5:1); 1H NMR (400 MHz,
CDCl3): d=1.07 (s, 9H; C
1H; Har), 7.00 (d, J=2.4 Hz, 1H; Har), 7.11–7.24 ppm (m, 16H; Har);
13C NMR (100 MHz, CDCl3): d=31.46 (p, 3C; C
(CH3)3), 34.23 (q; C-
(CH3)3), 62.93 (C-C(C6H5)3), 117.25 (t; Car), 125.44 (t; Car), 126.75 (t; 3C;
ACHTUGNERTN(NUNG CH3)3), 4.25 (s, 1H; OH), 6.69 (d, J=8.3 Hz,
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
Ctrityl), 127.88 (t, 6C; Ctrityl), 127.93 (t; Car), 131.02 (t, 6C; Ctrityl), 132.29
(q; Car), 142.70 (q; Car), 144.34 (q, 3C; Ctrityl), 152.07 ppm (q; COH); IR
(KBr): n˜ =3488, 3393, 3055, 3027, 2961, 2903, 2865, 1955, 1891, 1816,
1661, 1596, 1490, 1444, 1406, 1363, 1332, 1269, 1208, 1186, 1124, 1082,
1036, 921, 885, 825, 748, 702, 671, 648, 632, 605, 543, 518, 496, 441, 419,
404 cmÀ1; EIMS (70 eV): m/z (%): 392 [M+] (100), 377 (85), 315 (39),
283 (15), 263 (23); HR-EIMS: calcd for C29H28O: 392.2140; found:
392.2143; elemental analysis calcd for C29H28O: C 88.74, H 7.19; found:
C 88.82, H 7.30.
Synthesis and characterization of precursor molecules 7r and 8r
Synthesis of 2-adamantyl-4-tert-butylphenol: 4-tert-Butylphenol (500 mg,
3.30 mmol) and adamantan-1-ol (532 mg, 3.50 mmol) were dissolved in
CH2Cl2 (3.00 mL). Then, concentrated H2SO4 (180 mL) was added drop-
wise slowly to the reaction mixture over 10 min at room temperature.
After 16 h stirring at room temperature, water (3 mL) was added and the
reaction mixture was neutralized by adding a 1m sodium hydroxide solu-
tion. This mixture was then extracted with CH2Cl2 (ꢃ3), and the organic
phase was washed with brine and dried over sodium sulfate. After remov-
ing the solvent, purification was carried out by flash chromatography (n-
hexane/ethyl acetate 10:1).[41] Yield: 400 mg (43%); white solid; Rf =0.58
(n-hexane/ethyl acetate 10:1); 1H NMR (400 MHz, CDCl3): d=1.30 (s,
Synthesis of 5-tert-butyl-2-hydroxy-3-tritylbenzaldehyde: 4-tert-Butyl-2-
tritylphenol (500 mg, 1.27 mmol), dry magnesium chloride (234 mg,
92.20 mmol), and paraformaldehyde (84.0 mg, 2.80 mmol) were suspend-
ed in THF (5.00 mL). Then, Et3N (180 mL, 129 mg, 1.27 mmol) was
added dropwise to the reaction mixture at room temperature and it was
refluxed for 2 d. After complete conversion of the starting material
(TLC-control), the mixture was cooled to room temperature and diluted
with water. It was then extracted with CH2Cl2 (ꢃ3) and the combined or-
ganic layers were washed with water (ꢃ1) and brine (ꢃ2). The organic
phase was dried over MgSO4 and the solvent was removed. Purification
was carried out by flash chromatography (n-hexane/ethyl acetate 40:1).[37]
Yield: 214 mg (40%); white solid; m.p. 162–1688C; Rf =0.68 (n-hexane/
ethyl acetate 20:1); 1H NMR (500 MHz, CDCl3): d=1.24 (s, 9H; C-
9H; CACHTUNGTRENNUNG(CH3)3), 1.76–1.82 (m, 6H; H-Ad), 2.06–2.18 (m, 9H; H-Ad), 4.68
(brs, 1H; COH), 6.58 (d, J=8.2 Hz, 1H; Har), 7.07 (dd, J=2.4, 8.2 Hz,
1H; Har), 7.25 ppm (d, J=2.4 Hz, 1H; Har); 13C NMR (100 MHz,
CDCl3): d=29.10 (t, 3C; CAd), 31.65 (p, 3C; C
(CH3)3), 36.89 (q; Car-C(CH2)3), 37.11 (s, 3C; CAd), 40.61 (s, 3C; CAd),
116.14 (t; Car), 123.31 (t; Car), 124.02 (t; Car), 135.53 (q; Car-C(CH2)3),
143.08 (q; C-tBu), 152.02 ppm (q; COH); IR (KBr): n˜ =3489, 3070, 2961,
ACHTUGNTRENUN(NG CH3)3), 34.36 (q; C-
A
U
ACHTGNURTENUN(NG CH3)3), 7.20–7.29 (m, 15H; Har), 7.48 (d, J=2.4 Hz, 1H; Har), 7.65 (d,
A
J=2.4 Hz, 1H; Har), 9.88 (s, 1H; CHO), 11.22 ppm (s, 1H; COH);
13C NMR (125 MHz, CDCl3): d=31.16 (p, 3C; C
ACHTNUGTRNEUNG(CH3)3), 34.18 (q; C-
Chem. Eur. J. 2008, 14, 11539 – 11556
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11549

S. Brꢀse et al.
A
E
Car), 129.87 (t, 4C; Car), 130.26 (t, 2C; Car), 135.07 (q, 2C; Car), 136.49
(q; Car), 139.69 (q, 2C; Car), 139.78 (q; Car), 145.14 (q; Car), 158.06 (q;
Car, COH), 169.27 ppm (t; CH=N); IR (KBr): n˜ =3057 (w), 3027 (w),
2955 (m), 1947 (vw), 1882 (vw), 1804 (vw), 1618 (m), 1579 (w), 1496
(vw), 1458 (m), 1438 (m), 1411 (w), 1392 (w), 1361 (w), 1319 (w), 1273
(w), 1250 (w), 1194 (w), 1168 (m), 1132 (vw), 1072 (w), 1027 (w), 980
(w), 916 (w), 865 (w), 801 (w), 760 (m), 720 w), 700 (m), 669 (vw), 644
(vw), 613 (w), 602 (vw), 577 (vw), 531 (vw), 505 (vw), 459 cmÀ1 (vw);
EIMS (70 eV): m/z (%): 462 (57) [M+], 446 (16), 256 (29), 234 (23), 219
(100); HR-EIMS: calcd for C33H35NO: 461.2719; found: 461.2716; ele-
mental analysis calcd for C33H35NO: C 85.86, H 7.64, N 3.03; found: C
85.64, H 7.72, N 2.97.
Ctrityl), 127.30 (t, 6C; Ctrityl), 128.89 (t; Car), 130.91 (t, 6C; Ctrityl), 135.02
(q; Car-trityl), 136.22 (t; Car), 141.51 (q; Car), 144.90 (q, 3C; Ctrityl), 158.64
(q; COH), 196.84 ppm (t; CHO); IR (KBr): n˜ =3526, 3053, 3028, 2962,
2869, 1953, 1740, 1650, 1607, 1491, 1446, 1417, 1383, 1363, 1322, 1265,
1216, 1189, 1128, 1085, 1033, 1008, 950, 887, 836, 808, 748, 702, 659, 632,
617, 541, 520 cmÀ1; EIMS (70 eV): m/z (%): 420 [M+] (79), 343 (45), 182
(45), 105 (80), 77 (100); HR-EIMS: calcd for C30H28O2: 420.2089; found:
420.2092; elemental analysis calcd (%) for C30H28O2: C 85.68, H 6.71;
found: C 85.36, H 6.87.
Synthesis and characterization of ligands 4–8r
Synthesis of 4r: Compound 4r was synthesized according to general pro-
cedure C with 5-tert-butyl-2-hydroxybenzaldehyde (83.0 mg, 0.61 mmol)
and 2,6-diphenylamine (100 mg, 0.41 mmol). After 12 h heating at reflux
temperature, the raw material was purified by flash chromatography (n-
hexane/ethyl acetate 20:1). Yield: 155 mg (63%); yellow solid; m.p. 163–
1668C; Rf =0.47 (n-hexane/ethyl acetate 5:1); 1H NMR (400 MHz,
Synthesis of 7r: Compound 7r was synthesized according to general pro-
cedure
C
with 3-adamantan-1-yl-5-tert-butyl-2-hydroxybenzaldehyde
(113 mg, 0.36 mmol) and 2,6-diphenylamine (123 mg, 0.50 mmol). After
20 h heating at reflux temperature, the raw material was purified by flash
chromatography (n-hexane/ethyl acetate 100:1) and afterwards by prepa-
rative TLC (n-pentane/diethyl ether 20:1). Yield: 172 mg (73%); yellow
oil; Rf =0.30 (n-hexane/ethyl acetate 100:1); 1H NMR (400 MHz,
CDCl3): d=1.10 (s, 9H; CACTHNUTRGNEUGN(CH3)3), 6.63 (d, J=2.5 Hz, 1H; Har), 6.72 (d,
J=8.7 Hz, 1H; Har), 7.15–7.19 (m, 1H; Har), 7.24–7.28 (m, 5H; Har),
7.30–7.34 (m, 6H; Har), 7.85 (s, 1H; HC=N), 12.17 ppm (s, 1H; COH);
CDCl3): d=1.20 (s, 9H; CACTHNUTRGNEUNG(CH3)3), 1.79–1.85 (m, 6H; H-Ad), 2.11–2.19
13C NMR (100 MHz, CDCl3): d=31.30 (p, 3C; C
ACHTUNGTRENNUNG
(m, 9H; H-Ad), 6.56 (d, J=2.38 Hz, 1H; Har), 7.24–7.28 (m, 2H; Har),
7.31–7.38 (m, 6H; Har), 7.40–7.45 (m, 6H; Har), 12.99 ppm (s, 1H; OH);
13C NMR (100 MHz, CDCl3): d=29.10 (t, 3C; C-Ad), 31.33 (p, 3C; C-
ACHNUTTGRE(GUNNN CH3)3), 33.99 (q; CACHTNUREGTN(GUNN CH3)3), 37.14 (q; Car-CACTHUNGTRENGUN(N CH2)3), 37.16 (s, 3C; CAd),
40.12 (s, 3C; CAd), 117.77 (q; Car), 125.43 (t; Car), 126.27 (t; Car), 126.74
(t, 2C; Car), 127.67 (t; Car), 128.26 (t, 4C; Car), 129.82 (t, 4C; Car), 130.20
ACHTUNGTRENNUNG
128.34 (t, 5C; Car), 129.84 (t, 4C; Car), 130.29 (t, 2C; Car), 130.34 (t; Car),
135.03 (q; 2C; Car), 139.67 (q, 2C; Car), 141.29 (q; Car), 145.24 (q; Car),
158.49 (q; COH), 168.88 ppm (t; C=N); IR (KBr): n˜ =3056 (w), 3027
(w), 2964 (w), 2869 (w), 1953 (vw), 1887 (vw), 1619 (w), 1580 (w), 1490
(m), 1460 (w), 1440 (w), 1407 (w), 1393 (w), 1365 (w), 1287 (w), 1264
(w), 1174 (w), 1134 (vw), 1074 (w), 1027 (vw), 986 (w), 936 (vw), 921
(vw), 896 (vw), 874 (w), 830 (w), 787 (w), 758 (m), 727 (w), 701 (m), 654
(vw), 621 (w), 593 (vw), 574 (vw), 555 (vw), 512 (vw), 493 (vw), 480 (vw),
463 cmÀ1 (vw); EIMS (70 eV): m/z (%): 405 (46) [M+], 390 (27), 256
(100), 254 (26); HR-EIMS: calcd for C29H27NO: 405.2093; found:
405.2090; elemental analysis calcd (%) for C29H27NO: C 85.89, H 6.71, N
3.45; found: C 85.86, H 7.06, N 3.50.
(t, 2C; Car), 135.05 (q, 2C; Car), 136.74 (q; Car-CACHTNUGTRNEUGN(CH2)3), 139.67 (q, 2C;
Car), 139.82 (q; Car, C-tBu), 145.10 (q, Car), 158.29 (q; Car, COH),
169.27 ppm (t; CH=N); IR (KBr): n˜ =3058 (w), 3027 (w), 2962 (m), 2908
(m), 2849 (m), 2678 (vw), 1946 (vw), 1712 (vw), 1647 (m), 1618 (m), 1580
(m), 1497 (w), 1458 (m), 1413 (w), 1393 (w), 1363 (w), 1317 (w), 1272
(w), 1253 (m), 1214 (w), 1194 (w), 1181 (w), 1105 (w), 1082 (w), 1028
(w), 977 (w), 908 (w), 868 (w), 796 (w), 757 (m), 700 (m), 668 (vw), 650
(vw), 638 (vw), 613 (vw), 548 (vw), 507 cmÀ1 (vw); EIMS (70 eV): m/z
(%): 539 (71) [M+], 524 (12), 312 (53), 297 (100), 256 (38), 245 (8); HR-
EIMS: calcd for C39H41NO: 539.3188; found: 539.3187.
Synthesis of 5r: Compound 5r was synthesized according to general pro-
cedure C with 2-hydroxy-3,6-dimethylbenzaldehyde (70.0 mg, 0.47 mmol)
and 2,6-diphenylamine (137 mg, 0.56 mmol). After 12 h heating at reflux
temperature, the raw material was purified by flash chromatography (n-
hexane/ethyl acetate 20:1). Yield: 163 mg (92%); yellow solid; m.p. 119–
1218C; Rf =0.46 (n-hexane/ethyl acetate 5:1); 1H NMR (400 MHz,
CDCl3): d=1.62 (s, 3H; CH3), 1.99 (s, 3H; CH3), 6.24 (d, J=7.5 Hz, 1H;
Har), 6.84 (d, J=7.5 Hz, 1H; Har), 7.11–7.15 (m, 2H; Har), 7.19–7.31 (m,
11H; Har), 8.20 (s, 1H; HC=N), 13.13 ppm (s, 1H; COH); 13C NMR
(100 MHz, CDCl3): d=15.44 (p; CH3), 18.09 (p; CH3), 115.82 (q; Car),
119.77 (t; Car), 124.04 (q; Car), 125.67 (t; Car), 126.94 (t, 2C; Car), 128.38
(t, 4C; Car), 129.97 (t, 4C; Car), 130.48 (t, 2C; Car), 134.02 (t; Car), 135.30
(q, 2C; Car), 137.18 (q; Car), 139.88 (q, 2C; Car), 145.60 (q; Car), 160.27
(q; COH), 167.31 ppm (t; C=N); IR (KBr): n˜ =3398 (vw), 3053 (w), 3027
(w), 2948 (w), 2926 (w), 1948 (vw), 1899 (vw), 1808 (vw), 1606 (m), 1578
(w), 1496 (w), 1461 (w), 1427 (w), 1413 (w), 1380 (w), 1358 (w), 1307
(vw), 1282 (w), 1254 (w), 1197 (w), 1158 (vw), 1073 (w), 1052 (w), 1027
(w), 982 (w), 917 (vw), 855 (w), 809 (w), 768 (w), 754 (m), 723 (w), 702
(m), 613 (vw), 596 (vw), 566 (vw), 535 (vw), 513 cmÀ1 (vw); EIMS
(70 eV): m/z (%): 377 (100) [M+], 256 (63); HR-EIMS: calcd for
C27H23NO: 377.1779; found: 377.1776; elemental analysis calcd (%) for
C27H23NO: C 85.91, H 6.14, N 3.71; found: C 85.82, H 6.05, N 3.65.
Synthesis of 8r: Compound 8r was synthesized according to general pro-
cedure
C
with 5-tert-butyl-2-hydroxy-3-tritylbenzaldehyde (100 mg,
0.24 mmol) and 2,6-diphenylamine (49.0 mg, 0.20 mmol). After 20 h heat-
ing at reflux temperature, the raw material was purified by flash chroma-
tography (n-hexane/ethyl acetate 20:1). Yield: 110 mg (71%); yellow oil;
Rf =0.50 (n-hexane/ethyl acetate 20:1); 1H NMR (400 MHz, CDCl3): d=
0.97 (s, 9H; C
Har), 7.77 (s, 1H; CH=N), 12.71 ppm (s, 1H; OH); 13C NMR (100 MHz,
CDCl3): d=31.15 (p, 3C; C(CH3)3), 33.93 (q; C(CH3)3, 63.30 (q; CPh3),
ACHTUGNERTN(NGNU CH3)3), 6.63 (d, J=2.43 Hz, 1H; Har), 7.05–7.31 (m, 29H;
A
ACHTUNGTRENNUNG
117.88 (q; Car), 125.53 (t, 2C; Car), 126.69 (t, 3Car; C-trityl), 127.06 (t,
6Car; C-trityl), 127.44 (t; Car), 127.62 (t; Car), 128.11 (t, 4C; Car), 129.77
(t, 6C; Car), 129.85 (t; Car), 131.05 (t, 6Car; C-trityl), 132.40 (t; Car),
134.07 (q; Car), 134.48 (q, 2C; Car), 139.25 (q, 2C; Car), 145.53 (q; 4C;
C
ar +3C-trityl), 157.69 (q; Car, COH), 168.48 ppm (t; CH=N); IR (KBr):
n˜ =3536 (vw), 3057 (vw), 3029 (vw), 2961 (w), 2867 (vw), 1950 (vw), 1810
(vw), 1620 (w), 1598 (vw), 1581 (vw), 1493 (w), 1445 (w), 1411 (vw), 1393
(vw), 1364 (vw), 1266 (vw), 1189 (vw), 1073 (vw), 1029 (vw), 1013 (vw),
980 (vw), 916 (vw), 871 (vw), 806 (vw), 749 (w), 725 (vw), 700 (w), 659
(vw), 629 (vw), 614 (vw), 509 cmÀ1 (vw); EIMS (70 eV): m/z (%): 647
(100) [M+], 420 (6), 256 (38); HR-EIMS: calcd for C48H41NO: 647.3188;
found: 647.3184; elemental analysis calcd (%) for C48H41NO: C 88.99, H
6.38, N 2.16; found: C 88.74, H 6.71, N 1.81.
Synthesis of 6r: Compound 6r was synthesized according to general pro-
cedure
0.44 mmol) and 2,6-diphenylamine (211 mg, 0.86 mmol). After 1 d heat-
ing at reflux temperature, the raw material was purified by flash chroma-
tography (n-hexane/ethyl acetate 20:1). Yield: 163 mg (80%); yellow
solid; m.p. 118–1198C; Rf =0.66 (n-hexane/ethyl acetate 40:1); 1H NMR
Synthesis and characterization of ligands rac-11r and 12n–q
Synthesis of rac-11r: Compound 11r was synthesized according to gener-
al procedure C with rac-9 (100 mg, 0.40 mmol) and 2,6-diphenylamine
(194 mg, 0.79 mmol). After 1 d heating at reflux temperature, the raw
material was purified by flash chromatography (n-hexane). Yield: 106 mg
(55%); yellow oil; Rf =0.42 (n-hexane/ethyl acetate; 5:1); 1H NMR
(400 MHz, CDCl3): d=2.28 (ddd, J=6.1, 10.3, 13.0 Hz, 1H; CH2), 2.40–
2.58 (m, 2H; CH2), 2.71–2.98 (m, 4H; CH2), 3.33 (ddd, J=3.7, 9.7,
13.1 Hz, 1H; CH2), 5.27 (dd, J=1.83, 7.9 Hz, 1H; Har), 5.95 (d, J=
7.6 Hz, 1H; Har), 6.12 (dd, J=1.9, 7.9 Hz, 1H; Har), 6.25 (dd, J=1.9,
(400 MHz, CDCl3): d=1.11 (s, 9H; CACHTNUTRGENNGU(CH3)3), 1.29 (s, 9H; CACHTUNGTRENN(UNG CH3)3), 6.48
(d, J=2.4 Hz, 1H; Har), 7.14–7.18 (m, 2H; Har), 7.22–7.28 (m, 6H; Har),
7.33–7.35 (m, 6H; Har), 7.84 (s, 1H; CH=N), 12.84 ppm (s, 1H; COH);
13C NMR (100 MHz, CDCl3): d=29.30 (p, 3C; C
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG(CH3)3), 33.98 (q; CACHTUNGTRENNUNG(CH3)3), 34.98 (q; CACTHUGNTRENNNGU
11550
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11539 – 11556

Enantioselective Conjugate Addition Reactions
FULL PAPER
7.9 Hz, 1H; Har), 6.33 (d, J=7.8 Hz, 1H; Har), 6.34–6.40 (m, 1H; Har),
7.19–7.27 (m, 2H; Har), 7.32–7.47 (m, 11H; Har), 7.78 ppm (d, J=1.4 Hz,
1H; CH=N); 13C NMR (100 MHz, CDCl3): d=28.94 (s; CH2), 31.05 (s;
CH2), 33.07 (s; CH2), 34.17 (s; CH2), 118.69 (q; Car), 126.38 (t, 2C; Car),
126.65 (q; Car), 126.84 (t; Car), 127.77 (t, 4C; Car), 128.92 (t, 4C; Car),
129.03 (t; Car), 129.58 (t, 2C; Car), 130.82 (t; Car), 131.04 (t; Car), 132.09
(t; Car), 133.27 (t; Car), 134.66 (q, 2C; Car), 136.38 (q; Car), 137.84 (t; Car),
138.89 (q, 2C; Car), 139.08 (q; Car), 142.53 (q; Car), 144.63 (q; Car), 160.14
(q; Car, COH), 164.51 ppm (t; Car, CH=N); EIMS (70 eV): m/z (%): 479
(76) [M+], 375 (100); HR-EIMS: calcd for C35H29NO: 479.2249; found:
479.2253.
6.41–6.49 (m, 3H; Har), 6.58 (dd, J=1.8, 7.8 Hz, 1H; Har), 6.98 (dd, J=
1.8, 7.8 Hz, 1H; Har), 13.25 ppm (s, 1H; COH); 13C NMR (100 MHz,
CDCl3): d=20.03 (p; CH3C=N), 30.37 (s; CH2), 33.91 (s; CH2), 35.29 (s;
CH2), 36.82 (s; CH2), 47.43 (p; 2C; NACHTUNGTRNE(UGN CH3)2), 122.31 (q; Car), 126.63 (t;
Car), 127.00 (t; Car), 128.54 (q; Car), 129.14 (t; Car), 131.64 (t; Car), 132.85
(t; Car), 135.15 (t; Car), 137.65 (q; Car), 139.88 (q; Car), 140.71 (q; Car),
157.71 (q; Car, COH), 167.15 ppm (q; C=N); IR (KBr): n˜ =3007 (vw),
2954 (w), 2931 (w), 2850 (w), 2819 (vw), 2773 (vw), 1873 (vw), 1593 (vw),
1571 (w), 1499 (vw), 1426 (w), 1360 (vw), 1298 (vw), 1243 (vw), 1205
(vw), 1149 (vw), 1117 (vw), 1098 (vw), 1021 (vw), 999 (vw), 967 (w), 934
(vw), 880 (vw), 844 (w), 797 (w), 717 (w), 695 (vw), 668 (vw), 612 (vw),
590 (vw), 541 (vw), 516 (vw), 477 (vw), 440 cmÀ1 (vw); EIMS (70 eV):
m/z (%): 308 (100) [M+], 204 (26), 161 (34); HR-EIMS: calcd for
C20H24N2O: 308.1889; found: 308.1885.
Synthesis of rac-12n: Compound 12n was synthesized according to gen-
eral procedure C with rac-10 (100 mg, 0.38 mmol) and aniline (103 mL,
105 mg, 1.13 mmol). After 6 d heating at reflux temperature, the raw ma-
terial was purified by flash chromatography (n-pentane/diethyl ether
20:1). Yield: 89 mg (68%); yellow solid; m.p. 136–1408C; Rf =0.46 (n-
hexane/ethyl acetate 5:1); 1H NMR (400 MHz, CDCl3): d=2.26 (s, 3H;
CH3), 2.54–2.62 (m, 1H; CH2), 2.68–2.75 (m, 1H; CH2), 2.89–3.06 (m,
1H; CH2), 3.00–3.06 (m, 1H; CH2), 3.12–3.24 (m, 2H; CH2), 3.40–3.54
(m, 2H; CH2), 6.32 (d, J=7.6 Hz, 1H; Har), 6.46–6.55 (m, 3H; Har), 6.63
(dd, J=1.8, 7.9 Hz, 1H; Har), 6.96–7.02 (m, 3H; Har), 7.18–7.24 (m, 1H;
Har), 7.41–7.46 (m, 2H; Har), 14.50 ppm (s, 1H; COH); 13C NMR
(100 MHz, CDCl3): d=22.67 (p; CH3), 30.40 (s; CH2), 33.88 (s; CH2),
35.60 (s; CH2), 37.43 (s; CH2), 121.11 (t; 2Car), 122.61 (q; Car), 126.06 (t;
2Car), 126.54 (t; Car), 127.33 (t; Car), 129.14 (q; Car), 129.88 (t; Car), 131.47
(t; Car), 133.01 (t; Car), 136.30 (t; Car), 137.64 (q; Car), 139.95 (q; Car),
141.19 (q; Car), 144.30 (q; Car), 147.92 (q; Car), 160.36 (q; Car, COH),
171.75 ppm (q; C=N); IR (KBr): n˜ =3033 (vw), 2928 (w), 2851 (vw), 1871
(vw), 1737 (vw), 1576 (w), 1498 (vw), 1436 (w), 1367 (vw), 1304 (vw),
1207 (vw), 1168 (vw), 1154 (vw), 1113 (vw), 1070 (vw), 1025 (vw), 981
(vw), 933 (vw), 903 (vw), 880 (vw), 864 (vw), 830 (vw), 804 (vw), 790
(vw), 764 (vw), 717 (vw), 698 (vw), 669 (vw), 615 (vw), 587 (vw), 562
(vw), 517 (vw), 440 (vw), 411 cmÀ1 (vw); EIMS (70 eV): m/z (%): 341
(68) [M+], 236 (100); HR-EIMS (C24H23NO): calcd: 341.1779; found:
341.1777.
Synthesis of rac-12q: Compound 12q was synthesized according to gen-
eral procedure C with rac-10 (100 mg, 0.38 mmol) and cyclohexylamine
(113 mg, 1.13 mmol). After 3 d heating at reflux temperature, the raw
material was purified by flash chromatography (n-hexane/ethyl acetate
20:1). Yield: 100 mg (75%); orange solid; m.p. 162–1638C; Rf =0.53 (n-
hexane/ethyl acetate 5:1); 1H NMR (400 MHz, CDCl3): d=1.36–1.74 (m,
6H; H-c-hexyl), 1.84–2.00 (m, 4H; H-c-hexyl), 2.31 (s, 3H; CH3), 2.45–
2.61 (m, 2H; CH2), 2.79–2.89 (m, 1H; CH2), 2.93–3.02 (m, 1H; CH2),
3.06–3.19 (m, 2H; CH2), 3.36–3.43 (m, 2H; CH2), 3.56–3.67 (m, 1H;
NCH), 6.15 (d, J=7.5 Hz, 1H; Har), 6.30 (dd, J=1.9, 7.7 Hz, 1H; Har),
6.40 (d, J=7.5 Hz, 1H; Har), 6.44–6.46 (dd, J=1.9, 7.9 Hz, 1H; Har),
6.58–6.61 (dd, J=1.8, 7.9 Hz, 1H; Har), 6.96–7.00 (dd, J=1.8, 7.7 Hz, 1H;
Har), 16.32 ppm (s, 1H; COH); 13C NMR (100 MHz, CDCl3): d=19.21
(p; CH3), 24.45 (s; C-c-hexyl), 24.53 (s; C-c-hexyl), 25.58 (s; C-c-hexyl),
30.46 (s; CH2), 33.19 (s; C-c-hexyl), 33.83 (s; C-c-hexyl), 33.87 (s; CH2),
35.43 (s; CH2), 37.54 (s; CH2), 56.22 (t; NCH), 121.50 (q; Car), 125.09 (t;
Car), 127.03 (t; Car), 129.59 (t; Car), 129.99 (q; Car), 131.18 (t; Car), 132.78
(t; Car), 135.90 (t; Car), 137.53 (q; Car), 139.99 (q; Car), 140.60 (q; Car),
165.06 (q; Car, COH), 168.59 ppm (q; C=N); IR (KBr): n˜ =3640 (vw),
3008 (w), 2929 (m), 2847 (m), 2665 (w), 1881 (w), 1594 (m), 1499 (w),
1439 (m), 1361 (w), 1346 (w), 1299 (w), 1232 (w), 1167 (w), 1115 (w),
1078 (w), 997 (w), 949 (w), 932 (w), 879 (w), 794 (w), 766 (w), 717 (w),
687 (w), 669 (w), 615 (w), 590 (w), 565 (vw), 537 (w), 515 (w), 465 cmÀ1
(vw); EIMS (70 eV): m/z (%): 347 (93) [M+], 243 (100), 160 (29); HR-
EIMS: calcd for C24H29NO: 347.2249; found: 347.2247.
Synthesis of rac-12o: Compound 12o was synthesized according to gen-
eral procedure C with rac-10 (100 mg, 0.38 mmol) and tert-butylaniline
(179 mL, 168 mg, 1.13 mmol). After 6 d heating at reflux temperature, the
raw material was purified by flash chromatography (n-pentane/diethyl
ether 20:1). Yield: 85 mg (56%); yellow solid; m.p. 113–1168C; Rf =0.51
(n-hexane/ethyl acetate 5:1); 1H NMR (400 MHz, CDCl3): d=1.34 (s,
Synthesis of (Sp)-12q: Yield: 60 mg (75%); [a]2D0 =À698.0 (c=0.88 g/
100 mL in CHCl3); the remaining spectroscopic data are the same as for
ligand rac-6e.
9H; CACHTUNGTRENNUNG(CH3)3), 2.29 (s, 3H; CH3), 2.54–2.61 (m, 1H; CH2), 2.66–2.75 (m,
Synthesis and characterization of [2.2]paracyclophane ligands
1H; CH2), 2.86–3.06 (m, 2H; CH2), 3.11–3.26 (m, 2H; CH2), 3.41–3.57
(m, 2H; CH2), 6.31 (d, J=7.6 Hz, 1H; Har), 6.46–6.52 (m, 3H; Har), 6.63
(dd, J=1.8, 7.9 Hz, 1H; Har), 6.91–6.95 (m, 2H; Har), 6.98 (dd, J=1.8,
7.9 Hz, 1H; Har), 7.43–7.47 (m, 2H; Har), 14.77 ppm (s, 1H; COH);
13C NMR (100 MHz, CDCl3): d=22.67 (p; CH3), 30.40 (s; CH2), 31.47 (p,
Synthesis of 12j: Compound 12j was synthesized according to general
procedure C with rac-10 (154 mg, 0.58 mmol) and enantiopure (R)-1-cy-
clopropylethylamine (167 mg, 1.73 mmol). After 11 d heating (1158C
bath temperature), the raw material was purified by flash chromatogra-
phy (n-hexane/ethyl acetate 40:1). The combined yield of both fractions
was 49%.
3C; CACHTUNGTRENNUNG(CH3)3), 33.87 (s; CH2), 34.50 (q; CAHCUTNGTRENN(GUN CH3)3), 35.59 (s; CH2), 37.48
(s; CH2), 120.99 (t; 2Car), 122.55 (q; Car), 124.83 (t; Car), 126.66 (t; Car),
127.37 (t; Car), 129.15 (q; Car), 129.26 (t; 2Car), 129.88 (t; Car), 131.56 (t;
Car), 133.01 (t; Car), 136.46 (t; Car), 137.66 (q; Car), 139.99 (q; Car), 141.26
(q; Car), 147.29 (q; Car), 160.10 (q; Car, COH), 171.75 ppm (q; C=N); IR
(KBr): n˜ =3009 (w), 2962 (m), 2929 (m), 1888 (vw), 1742 (w), 1577 (m),
1501 (w), 1435 (m), 1364 (w), 1323 (w), 1302 (w), 1267 (w), 1214 (w),
1179 (w), 1114 (w), 1016 (w), 996 (vw), 932 (w), 857 (w), 806 (w), 766
(w), 717 (w), 673 (vw), 655 (vw), 621 (vw), 577 (w), 554 (vw), 513 (w),
460 (vw), 439 (vw), 408 cmÀ1 (vw); EIMS (70 eV): m/z (%): 397 (77) [M+],
293 (100), 278 (28), 248 (18); HR-EIMS: calcd for C28H31NO: 397.2406;
found: 397.2403.
Isomer (Sp,R)-12j: Yield: 47 mg (24%); orange oil; 1H NMR (400 MHz,
CDCl3): d=0.18–0.28 (m, 2H; CH2CH2), 0.50–0.60 (m, 2H; CH2CH2),
1.15–1.24 (m, 1H; CH2CH2CH), 1.45 (d, J=6.4 Hz, 3H; CH3CH), 2.25 (s,
3H; CH3CN), 2.46–2.59 (m, 2H; CH2), 2.81–2.90 (m, 1H; CH2), 2.94–
3.02 (m, 1H; CH2), 3.06–3.18 (m, 2H; CH2), 3.24 (dq, J=0.8, 6.4 Hz, 1H;
NCH), 3.34–3.45 (m, 2H; CH2), 6.14 (d, J=7.5 Hz, 1H; Har), 6.33 (dd,
J=1.9, 7.8 Hz, 1H; Har), 6.41 (d, J=7.5 Hz, 1H; Har), 6.46 (dd, J=1.9,
7.9 Hz, 1H), 6.60 (dd, J=1.8, 7.9 Hz, 1H; Har), 6.99 (dd, J=1.8, 7.8 Hz,
1H; Har), 15.94 ppm (s, 1H; COH); 13C NMR (100 MHz, CDCl3): d=
2.57 (s; C-c-prop), 3.18 (s; C-c-prop), 17.95 (t; C-c-prop), 19.44 (p;
CH3CN), 21.56 (CH3CHN), 30.41 (s; CH2), 33.88 (s; CH2), 35.45 (s;
CH2), 37.46 (s; CH2), 57.39 (t; NCH), 121.89 (q; Car), 125.39 (t; Car),
127.09 (t; Car), 129.63 (t; Car), 129.67 (q; Car), 131.29 (t; Car), 132.78 (t;
Car), 135.88 (t; Car), 137.55 (q; Car), 140.00 (q; Car), 140.57 (q; Car), 163.66
(q; Car, COH), 168.69 ppm (q; C=N); EIMS: m/z: (%): 333 [M+] (42),
229 (60), 104 (100); HR-EIMS: calcd for C23H27NO: 333.2093; found:
333.2094.
Synthesis of rac-12p: Compound 12p was synthesized according to gen-
eral procedure C with rac-10 (100 mg, 0.38 mmol) and N,N-dimethylhy-
drazine (asym., 87.0 mL, 69.0 mg, 1.13 mmol). After 5 d heating at reflux
temperature, the raw material was purified by flash chromatography (n-
hexane/ethyl acetate 20:1). Yield: 41 mg (35%); yellow solid; m.p. 99–
1018C; Rf =0.26 (n-hexane/ethyl acetate 20:1); 1H NMR (400 MHz,
CDCl3): d=2.37 (s, 3H; CH3C=N), 2.51–2.59 (m, 2H; CH2), 2.74 (s, 6H;
1
N
A
Isomer (Rp,R)-12j: Yield: 48 mg (25%); orange oil; H NMR (400 MHz,
CDCl3): d=0.31–0.44 (m, 2H; CH2CH2), 0.61–0.72 (m, 2H; CH2CH2),
Chem. Eur. J. 2008, 14, 11539 – 11556
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11551

S. Brꢀse et al.
1.18–1.29 (m, 1H; CH2CH2CH), 1.37 (d, J=6.4 Hz, 3H; CH3CH), 2.25 (s,
3H; CH3CN), 2.47–2.63 (m, 2H; CH2), 2.83–2.90 (m, 1H; CH2), 2.96–
3.03 (m, 1H; CH2), 3.08–3.19 (m, 2H; CH2), 3.23 (dq, J=0.8, J=6.4 Hz
1H; NCH), 3.35–3.44 (m, 2H; CH2), 6.18 (d, J=7.5 Hz, 1H; Har), 6.41
(d, J=7.5 Hz, 1H; Har), 6.44–6.47 (m, 2H; Har), 6.60 (dd, J=1.8, 7.9 Hz,
1H; Har), 7.00 (dd, J=1.8, 7.8 Hz, 1H; Har), 16.07 ppm (brs, 1H; COH);
13C NMR (100 MHz, CDCl3): d=1.71 (s; C-c-prop), 2.33 (s; C-c-prop),
17.66 (p; CH3CN), 18.80 (t; C-c-prop), 20.34 (CH3CHN), 29.60 (s; CH2),
33.05 (s; CH2), 34.57 (s; CH2), 36.63 (s; CH2), 56.61 (t; NCH), 121.00 (q;
Car), 124.51 (t; Car), 126.29 (t; Car), 128.89 (q; Car), 128.96 (t; Car), 130.42
(t; Car), 131.95 (t; Car), 135.05 (t; Car), 136.71 (q; Car), 139.09 (q; Car),
139.74 (q; Car), 163.05 (q; Car, COH), 167.61 ppm (q; C=N); EIMS
(70 eV): m/z (%): 333 [M+] (40), 229 (57), 104 (100); HR-EIMS: calcd
for C23H27NO: 333.2093; found: 333.2096.
Synthesis of 12l: Compound 12l was synthesized according to general
procedure C with rac-10 (152 mg, 0.57 mmol) and enantiopure (S)-1-(3-
bromophenyl)ethylamine (343 mg, 2.67 mmol). After 2 d heating at
reflux temperature, the raw material was purified by flash chromatogra-
phy (n-hexane/ethyl acetate 40:1). The combined yield of both fractions
was 60%.
Isomer (Rp,S)-12l: Yield: 76 mg (30%); orange oil; [a]2D0 =+502.4 (c=
1
3.44 g/100 mL in CHCl3); Rf =0.34 (n-hexane/ethyl acetate 5:1); H NMR
(400 MHz, CDCl3): d=1.72 (d, J=6.6 Hz, 3H; CH3CHN), 2.27 (s, 3H;
CH3CN), 2.50–2.57 (m, 1H; CH2), 2.59–2.67 (m, 1H; CH2), 2.85–2.94 (m,
1H; CH2), 2.97–3.05 (m, 1H; CH2), 3.08–3.22 (m, 2H; CH2), 3.34–3.46
(m, 2H; CH2), 4.83 (q, J=6.6 Hz, 1H; NCH), 6.21 (d, J=7.5 Hz, 1H;
Har), 6.41–6.44 (m, 2H; Har), 6.49 (dd, J=1.8, 7.8 Hz, 1H; Har), 6.62 (dd,
J=1.8, 7.8 Hz, 1H; Har), 7.04 (dd, J=1.8, 7.8 Hz, 1H; Har), 7.21 (t, J=
7.8 Hz, 1H; Har), 7.29–7.31 (m, 1H; Har), 7.36–7.40 (m, 1H; Har),
7.48 ppm (t, J=1.7 Hz, 1H; Har); 13C NMR (100 MHz, CDCl3): d=20.65
(p; CH3CN), 25.31 (p; CH3CHN), 30.47 (s; CH2), 33.90 (s; CH2), 35.49
(s; CH2), 37.36 (s; CH2), 54.56 (t; NCH), 122.34 (q; Car, C-Br), 122.76 (q;
Car), 124.87 (t; Car), 125.91 (t; Car), 127.18 (t; Car), 129.47 (q; Car), 129.54
(t; Car), 129.64 (t; Car), 130.37 (t; Car), 130.63 (t; Car), 131.54 (t; Car),
132.82 (t; Car), 136.29 (t; Car), 137.62 (q; Car), 140.06 (q; Car), 140.86 (q;
Car), 146.17 (q; Car), 162.57 (q; Car, COH), 170.86 ppm (q; C=N); IR
(KBr): n˜ =3008 (w), 2966 (w), 2926 (m), 2851 (w), 1883 (vw), 1736 (vw),
1590 (m), 1500 (w), 1475 (w), 1419 (m), 1360 (w), 1340 (vw), 1321 (w),
1297 (w), 1234 (w), 1199 (vw), 1155 (vw), 1131 (vw), 1110 (vw), 1092
(vw), 1071 (w), 995 (vw), 979 (vw), 934 (vw), 878 (w), 785 (w), 717 (w),
696 (w), 671 (w), 619 (vw), 587 (vw), 567 (vw), 509 (vw), 442 cmÀ1 (vw);
EIMS (70 eV): m/z (%): 449/447 (32/32) [M+], 345/343 (23/23), 266 (88),
161 (100), 104 (77); HR-EIMS: calcd for C26H26NOBr: 447.1198; found:
447.1201.
Synthesis of 12k: Compound 12k was synthesized according to general
procedure C with rac-10 (151 mg, 0.57 mmol) and enantiopure (S)-1-(3-
chlorophenyl)ethylamine (265 mg, 2.00 mmol). After 2 d heating at reflux
temperature, the raw material was purified by flash chromatography (n-
hexane/ethyl acetate 40:1). The combined yield of both fractions was
66%.
Isomer (Rp,S)-12k: Yield: 71 mg (31%); orange oil; [a]2D0 =+560.2 (c=
1
0.47 g/100 mL in CHCl3); Rf =0.33 (n-hexane/ethyl acetate 5:1); H NMR
(400 MHz, CDCl3): d=1.64 (d, J=6.6 Hz, 3H; CH3CHN), 2.19 (s, 3H;
CH3CN), 2.41–2.58 (m, 2H; CH2), 2.78–2.85 (m, 1H; CH2), 2.88–2.97 (m,
1H; CH2), 3.03–3.13 (m, 2H; CH2), 3.26–3.36 (m, 2H; CH2), 4.76 (q, J=
6.6 Hz, 1H; NCH), 6.13 (d, J=7.5 Hz, 1H; Har), 6.35 (d, J=7.5 Hz, 1H;
Har), 6.33–6.42 (m, 2H; Har), 6.54 (dd, J=1.8, 7.8 Hz, 1H; Har), 6.96 (dd,
J=1.8, 7.8 Hz, 1H; Har), 7.13–7.25 ppm (m, 4H; Har); 13C NMR
(100 MHz, CDCl3): d=19.59 (p; CH3CN), 24.25 (p; CH3CHN), 29.41 (s;
CH2), 32.84 (s; CH2), 34.43 (s; CH2), 36.29 (s; CH2), 56.84 (t; NCH),
121.30 (q; Car), 123.36 (t; Car), 124.85 (t; Car), 125.57 (t; Car), 126.12 (t;
Car), 126.37 (t; Car), 128.40 (q; Car), 128.57 (t; Car), 129.24 (t; Car), 130.48
(t; Car), 131.77 (t; Car), 133.47 (q; Car), 135.20 (t; Car), 136.56 (q; Car),
139.01 (q; Car), 139.79 (q; Car), 144.84 (q; Car), 161.43 (q; Car, COH),
169.78 ppm (q; C=N); IR (KBr): n˜ =3009 (w), 2927 (m), 2851 (w), 1595
(m), 1500 (w), 1417 (m), 1359 (w), 1340 (w), 1321 (w), 1298 (mw), 1233
(m), 1200 (w), 1155 (w), 1110 (w), 1081 (w), 1016 (vw), 993 (vw), 978
(vw), 936 (vw), 879 (w), 788 (w), 718 (w), 696 (w), 672 (vw), 621 (w), 588
(w), 568 (w), 509 cmÀ1 (w); EIMS (70 eV): m/z (%): 403 (69) [M+], 299
(52), 266 (100), 162 (86), 104 (72); HR-EIMS: calcd for C23H26NOCl:
403.1703; found: 403.1701.
Isomer (Sp,S)-12l: Yield: 76 mg (30%); orange oil; [a]2D0 =À113.8 (c=
1
3.19 g/100 mL in CHCl3); Rf =0.25 (n-hexane/ethyl acetate 5:1); H NMR
(400 MHz, CDCl3): d=1.64 (d, J=6.6 Hz, 3H; CH3CHN), 2.25 (s, 3H;
CH3CN), 2.40–2.47 (m, 1H; CH2), 2.49–2.57 (m, 1H; CH2), 2.82–2.90 (m,
1H; CH2), 2.95–3.07 (m, 2H; CH2), 3.15–3.25 (m, 2H; CH2), 3.39–3.46
(m, 1H; CH2), 4.83 (q, J=6.6 Hz, 1H; NCH), 6.14 (dd, J=1.8, 7.8 Hz,
1H; Har), 6.20 (d, J=7.5 Hz, 1H; Har), 6.43 (d, J=7.5 Hz, 1H; Har), 6.47
(dd, J=1.8, 7.9 Hz, 1H; Har), 6.58 (dd, J=1.8, 7.9 Hz, 1H; Har), 7.02 (dd,
J=1.8, 7.8 Hz, 1H; Har), 7.31 (t, J=7.8 Hz, 1H; Har), 7.44–7.47 (m, 2H;
Har), 7.70 ppm (t, J=1.8 Hz, 1H; Har); 13C NMR (100 MHz, CDCl3): d=
20.54 (p; CH3CN), 24.95 (p; CH3CHN), 30.52 (s; CH2), 33.89 (s; CH2),
35.41 (s; CH2), 37.15 (s; CH2), 57.65 (t; NCH), 122.43 (q; Car, C-Br),
122.88 (q; Car), 125.05 (t; Car), 125.93 (t; Car), 127.09 (t; Car), 129.30 (q;
Car), 129.68 (t; Car), 130.04 (t; Car), 130.38 (t; Car), 130.48 (t; Car), 131.62
(t; Car), 132.71 (t; Car), 136.44 (t; Car), 137.63 (q; Car), 139.96 (q; Car),
140.93 (q; Car), 146.93 (q; Car), 162.29 (q; Car, COH), 170.59 ppm (q; C=
N); EIMS (70 eV): m/z (%): 449/447 (91/90) [M+], 345/343 (58/59), 266
(29), 160 (100), 104 (86); HR-EIMS: calcd for C26H26NOBr: 447.1198;
found: 447.1195; elemental analysis calcd (%) for C26H26NOBr: C 69.64,
H 5.84, N 3.12; found: C 69.97, H 5.99, N 2.77.
Isomer (Sp,S)-12k: Yield: 81 mg (35%); orange solid; [a]2D0 =À197.0 (c=
1
0.51 g/100 mL in CHCl3); Rf =0.25 (n-hexane/ethyl acetate 5:1); H NMR
(400 MHz, CDCl3): d=1.65 (d, J=6.6 Hz, 3H; CH3CHN), 2.26 (s, 3Hp;
CH3CN), 2.40–2.47 (m, 1H; CH2), 2.51–2.58 (m, 1H; CH2), 2.83–2.91 (m,
1H; CH2), 2.94–3.08 (m, 2H; CH2), 3.15–3.28 (m, 2H; CH2), 3.43 (ddd,
J=2.6, 2.6, 12.8 Hz, 1H; CH2), 4.84 (q, J=6.6 Hz, 1H; NCH), 6.13 (dd,
J=1.8, 7.8 Hz, 1H; Har), 6.21 (d, J=7.5 Hz, 1H; Har), 6.43 (d, J=7.5 Hz,
1H; Har), 6.48 (dd, J=1.8, 7.9 Hz, 1H; Har), 6.58 (dd, J=1.8, 7.9 Hz, 1H;
Har), 7.02 (dd, J=1.8, 7.8 Hz, 1H; Har), 7.30 (dt, J=1.7, 7.8 Hz, 1H; Har),
7.38 (t, J=7.7 Hz, 1H; Har), 7.42 (dt, J=1.7, 7.7 Hz, 1H; Har), 7.53 ppm
(t, J=1.7 Hz, 1H; Har); 13C NMR (100 MHz, CDCl3): d=20.54 (p;
CH3CN), 24.94 (p; CH3CHN), 30.52 (s; CH2), 33.89 (s; CH2), 35.41 (s;
CH2), 37.15 (s; CH2), 57.75 (t; NCH), 122.47 (q; Car), 124.59 (t; Car),
125.93 (t; Car), 126.77 (t; Car), 127.07 (t; Car), 127.45 (t; Car), 129.27 (q;
Car), 130.04 (t; Car), 130.19 (t; Car), 131.62 (t; Car), 132.72 (t; Car), 134.66
(q; Car), 136.41 (t; Car), 137.64 (q; Car), 139.967 (q; Car), 140.92 (q; Car),
146.69 (q; Car), 162.19 (q; Car, COH), 170.54 ppm (q; C=N); IR (KBr):
n˜ =3070 (w), 3010 (w), 2965 (w), 2927 (w), 2848 (w), 1959 (vw), 1871
(vw), 1740 (vw), 1580 (w), 1500 (w), 1471 (w), 1427 (w), 1375 (w), 1316
(vw), 1297 (w), 1242 (w), 1199 (vw), 1161 (vw), 1135 (vw), 1080 (w), 1033
(vw), 998 (vw), 983 (vw), 933 (vw), 879 (w), 838 (vw), 797 (w), 763 (vw),
717 (w), 705 (w), 666 (vw), 622 (vw), 586 (vw), 552 (vw), 532 (vw), 509
(w), 449 (vw), 422 (vw), 408 cmÀ1 (vw); EIMS (70 eV): m/z (%): 403
(100) [M+], 299 (42), 160 (51); HR-EIMS: calcd for C23H26NOCl:
403.1703; found: 403.1705; elemental analysis calcd (%) for C23H26NOCl:
C 77.31, H 6.49, N 3.47; found: C 77.33, H 6.49, N 3.16.
Synthesis of 12e: Compound 12e was synthesized according to general
procedure C with rac-10 (100 mg, 0.38 mmol) and enantiopure (S)-1-ami-
notetraline (166 mg, 1.13 mmol). After 3 d heating at reflux temperature,
the raw material was purified by flash chromatography (n-hexane/ethyl
acetate 20:1). The combined yield of both fractions was 74%.
Isomer (Rp,S)-12e: Yield: 54 mg (36%); orange oil; [a]2D0 =+119.1 (c=
0.54 g/100 mL CHCl3); Rf =0.50 (n-hexane/ethyl acetate 5:1); 1H NMR
(400 MHz, CDCl3): d=1.93–2.11 (m, 2H; CH2CH2CH2), 2.16–2.27 (m,
2H; CH2CH2CH2), 2.47 (s, 3H; CH3CN), 2.46–2.53 (m, 1H; CH2), 2.56–
2.65 (m, 1H; CH2), 2.89–3.18 (m, 6H; 2CH2, CH2CH2CH2), 3.32–3.38 (m,
1H; CH2), 3.42–3.48 (m, 1H; CH2), 4.96 (dd, J=4.6, 7.4 Hz, 1H; NCH),
6.25 (d, J=7.6 Hz, 1H; Har), 6.39–6.41 (m, 1H; Har), 6.43 (d, J=7.6 Hz,
1H; Har), 6.45–6.47 (m, 1H; Har), 6.60–6.63 (m, 1H; Har), 6.93–6.95 (m,
1H; Har), 7.02 (d, J=7.55 Hz, 1H; Har), 7.12–7.22 (m, 3H; Har),
15.37 ppm (brs, 1H; COH); 13C NMR (100 MHz, CDCl3): d=19.98 (p;
CH3CN), 20.80 (s; CH2CH2CH2), 29.42 (s; CH2CH2CH2), 30.39 (s; CH2),
31.58 (s; CH2CH2CH2), 33.83 (s; CH2), 35.51 (s; CH2), 37.47 (s; CH2),
56.91 (t; NCH), 122.58 (q; Car), 125.87 (t; Car), 126.41 (t; Car), 127.11 (t;
11552
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Chem. Eur. J. 2008, 14, 11539 – 11556

Enantioselective Conjugate Addition Reactions
FULL PAPER
Car), 127.17 (t; Car), 127.82 (t; Car), 129.25 (t; Car), 129.42 (q; Car), 129.56
(t; Car), 131.42 (t; Car), 132.84 (t; Car), 135.91 (t; Car), 136.68 (q; Car),
137.16 (q; Car), 137.55 (q; Car), 140.02 (q; Car), 140.65 (q; Car), 162.01 (q;
Car, COH), 169.97 ppm (q; C=N); IR (KBr): n˜ =3301 (vw), 3019 (vw),
2932 (vw), 2859 (vw), 2285 (vw), 1660 (vw), 1585 (vw), 1500 (vw), 1433
(vw), 1361 (vw), 1299 (vw), 1263 (vw), 1234 (vw), 1157 (vw), 1111 (vw),
1021 (vw), 800 (vw), 746 (vw), 719 (vw), 672 (vw), 619 (vw), 588 (vw),
569 (vw), 510 (vw), 439 (vw), 414 cmÀ1 (vw); EIMS (70 eV): m/z (%):
395 (45) [M+], 266 (83), 161 (100), 131 (80), 104 (80), 91 (46); HR-
EIMS: calcd for C28H29NO: 395.2249; found: 395.2252.
Isomer (Sp,S)-12e: Yield: 53 mg (35%); yellow/orange oil; [a]2D0 =À557.3
(c=0.44 g/100 mL CHCl3); Rf =0.43 (n-hexane/ethyl acetate 5:1);
1H NMR (400 MHz, CDCl3): d=1.84–1.98 (m, 2H; CH2CH2CH2), 2.05–
2.17 (m, 2H; CH2CH2CH2), 2.48 (s, 3H; CH3CN), 2.44–2.53 (m, 1H;
CH2), 2.68–2.77 (m, 1H; CH2), 2.84–3.17 (m, 6H; 2CH2, CH2CH2CH2),
3.32–3.38 (m, 1H; CH2), 3.41–3.48 (m, 1H; CH2), 4.91–4.95 (m, 1H;
NCH), 6.21 (d, J=7.5 Hz, 1H; Har), 6.28 (dd, J=1.8, 7.8 Hz, 1H; Har),
6.41 (d, J=7.5 Hz, 1H; Har), 6.46 (dd, J=1.8, 7.8 Hz, 1H; Har), 6.61 (dd,
J=1.8, 7.8 Hz, 1H; Har), 6.77 (dd, J=1.8, 7.8 Hz, 1H; Har), 7.20–7.30 (m,
4H; Har), 15.69 ppm (brs, 1H; COH); 13C NMR (100 MHz, CDCl3): d=
20.08 (p; CH3CN), 20.43 (s; CH2CH2CH2), 29.32 (s; CH2CH2CH2), 31.45
(s; CH2CH2CH2), 30.62 (s; CH2), 33.82 (s; CH2), 35.61 (s; CH2), 37.41 (s;
CH2), 56.61 (t; NCH), 122.22 (q; Car), 125.64 (t; Car), 126.03 (t; Car),
127.25 (t; Car), 127.33 (t; Car), 127.96 (t; Car), 129.55 (q, t; 2Car), 130.34
(t; Car), 131.48 (t; Car), 132.66 (t; Car), 136.30 (t; Car), 137.11 (q; Car),
137.17 (q; Car), 137.54 (q; Car), 140.01 (q; Car), 140.81 (q; Car), 163.10 (q;
Car, COH), 169.28 ppm (q; C=N); IR (KBr): n˜ =3431 (vw), 3014 (vw),
2927 (w), 2844 (vw), 1586 (w), 1488 (vw), 1438 (w), 1353 (vw), 1295 (vw),
1238 (vw), 1159 (vw), 1124 (vw), 1069 (vw), 1006 (vw), 930 (vw), 878
(vw), 806 (vw), 754 (w), 718 (vw), 682 (vw), 589 (vw), 541 (vw), 516 (vw),
453 cmÀ1 (vw); EIMS (70 eV): m/z (%): 395 (51) [M+], 266 (28), 161
(52), 131 (100); HR-EIMS: calcd for C28H29NO: 395.2249; found:
395.2246; elemental analysis calcd (%) for C28H29NO: C 85.02, H 7.39, N
3.54; found: C 84.62, H 7.40, N 3.20.
2H; CH2), 3.00–3.08 (m, 1H; CH2), 3.12–3.27 (m, 2H; CH2), 3.43–3.51
(m, 1H; CH2), 5.61 (q, J=6.6 Hz, 1H; NCH), 6.15–6.17 (m, 2H; Har),
6.42 (d, J=7.5 Hz, 1H; Har), 6.5 (dd, J=1.8, 7.8 Hz, 1H; Har), 6.58 (dd,
J=1.8, 7.8 Hz, 1H; Har), 7.09 (dd, J=1.8, 7.8 Hz, 1H; Har), 7.50–7.67 (m,
3H; Har), 7.84–7.89 (m, 2H; Har), 7.95 (dd, J=1.0, 8.1 Hz, 1H; Har), 8.28
(d, J=8.5 Hz, 1H; Har), 16.17 ppm (brs, 1H; COH); 13C NMR
(100 MHz, CDCl3): d=20.68 (p; CH3CN), 24.46 (p; CH3CHN), 30.51 (s;
CH2), 33.97 (s; CH2), 35.42 (s; CH2), 37.15 (s; CH2), 54.56 (t; NCH),
122.26 (q; Car), 122.87 (t; Car), 124.01 (t; Car), 125.59 (t; Car), 125.77 (t;
Car), 125.79 (t; Car), 126.34 (t; Car), 127.21 (t; Car), 127.86 (t; Car), 129.33
(t; Car), 129.47 (q; Car), 130.21 (q; Car), 130.57 (t; Car), 131.65 (t; Car),
132.58 (t; Car), 134.14 (q; Car), 136.57 (t; Car), 137.74 (q; Car), 140.09 (q;
Car), 140.65 (q; Car), 141.09 (q; Car), 163.73 (q; Car, COH), 170.90 ppm (q;
C=N); IR (KBr): n˜ =2963 (w), 2926 (w), 2855 (w), 1663 (vw), 1582 (vw),
1508 (vw), 1436 (vw), 1360 (vw), 1261 (w), 1095 (w), 1024 (w), 863 (vw),
801 (w), 718 (vw), 668 (vw), 617 (vw), 589 (vw), 510 (vw), 485 (vw), 440
(vw), 406 cmÀ1 (vw); EIMS (70 eV): m/z (%): 419 (100) [M+], 315 (27),
155 (92); HR-EIMS: calcd for C30H29NO: 419.2249; found: 419.2251.
Synthesis of 12h: Compound 12h was synthesized according to general
procedure C with rac-10 (100 mg, 0.38 mmol) and enantiopure (S)-1-(2-
naphthyl-)ethylamine (194 mg, 1.13 mmol). After 3 d heating at reflux
temperature, the raw material was purified by flash chromatography (n-
hexane/ethyl acetate 20:1). The combined yield of both fractions was
78%.
Isomer (Rp,S)-12h: Yield: 59 mg (37%); orange oil; [a]2D0 =+601.7 (c=
1.96 g/100 mL CHCl3); Rf =0.43 (n-hexane/ethyl acetate 5:1); 1H NMR
(400 MHz, CDCl3): d=1.83 (d, J=6.6 Hz, 3H; CH3CHN), 2.30 (s, 3H;
CH3CN), 2.50–2.58 (m, 1H; CH2), 2.61–2.71 (m, 1H; CH2), 2.85–2.93 (m,
1H; CH2), 2.97–3.06 (m, 1H; CH2), 3.08–3.25 (m, 2H; CH2), 3.37–3.49
(m, 2H; CH2), 5.05 (q, J=6.6 Hz, 1H; NCH), 6.19 (d, J=7.5 Hz, 1H;
Har), 6.43 (d, J=7.5 Hz, 1H; Har), 6.44–6.51 (m, 2H; Har), 6.63 (dd, J=
1.8, 7.8 Hz, 1H; Har), 7.08 (dd, J=1.8, 7.8 Hz, 1H; Har), 7.41–7.49 (m,
2H; Har), 7.52 (dd, J=1.8, 8.5 Hz, 1H; Har), 7.73 (d, J=1.2 Hz, 1H; Har),
7.80–7.84 (m, 2H; Har), 7.85 (d, J=8.5 Hz, 1H; Har), 15.97 ppm (brs, 1H;
COH); 13C NMR (100 MHz, CDCl3): d=20.53 (p; CH3CN), 25.36 (p;
CH3CHN), 30.50 (s; CH2), 33.91 (s; CH2), 35.49 (s; CH2), 37.41 (s; CH2),
58.29 (t; NCH), 122.15 (q; Car), 124.54 (t; Car), 124.74 (t; Car), 125.63 (t;
Car), 125.83 (t; Car), 126.23 (t; Car), 127.20 (t; Car), 127.67 (t; Car), 127.88
(t; Car), 128.84 (t; Car), 129.67 (q; Car), 129.71 (t; Car), 131.46 (t; Car),
132.67 (q; Car), 132.79 (t; Car), 133.42 (q; Car), 136.22 (t; Car), 137.64 (q;
Car), 140.09 (q; Car), 140.86 (q; Car), 141.08 (q; Car), 163.60 (q; Car, COH),
170.67 ppm (q; C=N); IR (KBr): n˜ =3650 (vw), 3292 (vw), 3053 (w), 2927
(w), 2852 (w), 1892 (vw), 1617 (w), 1508 (w), 1438 (w), 1363 (vw), 1300
(vw), 1234 (vw), 1176 (vw), 1156 (vw), 1128 (vw), 1111 (vw), 1085 (vw),
1018 (vw), 978 (vw), 950 (vw), 894 (vw), 858 (vw), 820 (vw), 748 (vw),
718 (vw), 699 (vw), 669 (vw), 621 (vw), 589 (vw), 569 (vw), 510 (vw),
479 cmÀ1 (w); EIMS (70 eV): m/z (%): 419 (49) [M+], 315 (16), 155
(100); HR-EIMS: calcd for C30H29NO: 419.2249; found: 419.2247.
Synthesis of 12g: Compound 12g was synthesized according to general
procedure C with rac-10 (100 mg, 0.38 mmol) and enantiopure 1-(S)-1-(1-
naphthyl)ethylamine (194 mg, 1.13 mmol). After 3 d heating at reflux
temperature, the raw material was purified by flash chromatography (n-
hexane/ethyl acetate 20:1). The combined yield of both fractions was
97%.
Isomer (Rp,S)-12g: Yield: 81 mg (51%); orange oil; [a]2D0 =+589.2 (c=
0.30 g/100 mL CHCl3); Rf =0.46 (n-hexane/ethyl acetate 5:1); 1H NMR
(400 MHz, CDCl3): d=1.91 (d, J=6.6 Hz, 3H; CH3CHN), 2.20 (s, 3H;
CH3CN), 2.52–2.59 (m, 1H; CH2), 2.64–2.72 (m, 1H; CH2), 2.84–2.94 (m,
1H; CH2), 3.00–3.07 (m, 1H; CH2), 3.11–3.26 (m, 2H; CH2), 3.35–3.51
(m, 2H; CH2), 5.67 (q, J=6.6 Hz, 1H; NCH), 6.19 (d, J=7.5 Hz, 1H;
Har), 6.50 (d, J=7.5 Hz, 1H; Har), 6.46–6.53 (m, 2H; Har), 6.65 (dd, J=
1.8, 7.8 Hz, 1H; Har), 7.10 (dd, J=1.8, 7.8 Hz, 1H; Har), 7.39–7.43 (m,
1H; Har), 7.47–7.49 (m, 1H; Har), 7.50–7.54 (m, 1H; Har), 7.58–7.61 (m,
1H; Har), 7.74 (d, J=8.1 Hz, 1H; Har), 7.90 (dd, J=1.2, 8.1 Hz, 1H; Har),
8.14 (d, J=8.4 Hz, 1H; Har), 16.38 ppm (brs, 1H; COH); 13C NMR
(100 MHz, CDCl3): d=20.68 (p; CH3CN), 24.86 (p; CH3CHN), 30.54 (s;
CH2), 33.94 (s; CH2), 35.51 (s; CH2), 37.51 (s; CH2), 53.99 (t; NCH),
121.91 (q; Car), 122.32 (t; Car), 123.44 (t; Car), 125.48 (t; Car), 125.64 (t;
Car), 126.10 (t; Car), 126.33 (t; Car), 127.22 (t; Car), 127.65 (t; Car), 129.27
(t; Car), 129.79 (t; Car), 129.98 (q; Car), 130.26 (q; Car), 131.41 (t; Car),
132.81 (t; Car), 133.87 (q; Car), 136.36 (t; Car), 137.66 (q; Car), 139.74 (q;
Car), 140.11 (q; Car), 141.02 (q; Car), 164.80 (q; Car, COH), 171.27 ppm (q,
C=N); IR (KBr): n˜ =2925 (m), 2854 (m), 1885, 1733 (vw), 1679 (vw),
1583 (vw), 1509 (w), 1455 (vw), 1375 (w), 1298 (w), 1259 (w), 1235 (w),
1173 (w), 1094 (vw), 1023 (vw), 933 (vw), 879 (vw), 800 (vw), 777 (w),
718 (w), 668 (vw), 645 (vw), 616 (vw), 588 (vw), 513 (vw), 447 (vw),
411 cmÀ1 (vw); EIMS (70 eV): m/z (%): 419 (34) [M+], 315 (10), 155
(100); HR-EIMS: calcd for C30H29NO: 419.2249; found:419.2246.
Synthesis of 12 f: Compound 12 f was synthesized according to general
procedure C with rac-10 (100 mg, 0.38 mmol) and enantiopure 1-(S)-
trans-(S)-2-phenylmethoxycyclohexylamine (232 mg, 1.13 mmol). After
3 d heating at reflux temperature, the raw material was purified by flash
chromatography (n-hexane/ethyl acetate 20:1). The combined yield of
both fractions was 86%.
Isomer (Rp,S,S)-12 f: Yield: 77 mg (45%); orange solid; [a]2D0 =+590.4
(c=0.83 g/100 mL CHCl3); m.p. 90–948C; Rf =0.43 (n-hexane/ethyl ace-
tate 5:1); 1H NMR (400 MHz, CDCl3): d=1.37–1.50 (m, 3H; c-hexyl),
1.68–1.93 (m, 3H; c-hexyl), 1.95–2.08 (m, 1H; c-hexyl), 2.13–2.25 (m,
1H; c-hexyl), 2.35 (s, 3H; CH3CN), 2.45–2.63 (m, 2H; CH2), 2.81–2.9 (m,
1H; CH2), 2.95–3.03 (m, 1H; CH2), 3.06–3.20 (m, 2H; CH2), 3.33–3.47
(m, 2H; CH2), 3.47–3.57 (m, 1H; c-hexyl), 3.65–3.75 (m, 1H; c-hexyl),
4.43 (d, J=11.3 Hz, 1H; OCHaHbPh), 4.52 (d, J=11.3 Hz, 1H;
OCHaHbPh), 6.19 (d, J=7.5 Hz, 1H; Har), 6.33 (dd, J=1.8, 7.7 Hz, 1H;
Har), 6.42 (d, J=7.5 Hz, 1H; Har), 6.47 (dd, J=1.8, 7.9 Hz, 1H; Har), 6.61
(dd, J=1.8, 7.9 Hz, 1H; Har), 6.98 (dd, J=1.8, 7.7 Hz, 1H; Har), 7.14–7.24
(m, 5H; Har), 16.00 ppm (brs, 1H; COH); 13C NMR (100 MHz, CDCl3):
d=20.21 (p; CH3CN), 24.09 (s; 2CH2), 30.50 (s; CH2), 30.55 (s; CH2),
32.53 (s; CH2), 33.91 (s; CH2), 35.42 (s; CH2), 37.43 (s; CH2), 61.70 (t;
Isomer (Sp,S)-12g: Yield: 74 mg (46%); orange oil; [a]2D0 =À10.8 (c=
0.40 g/100 mL CHCl3); Rf =0.39 (n-hexane/ethyl acetate 5:1); 1H NMR
(400 MHz, CDCl3): d=1.85 (d, J=6.6 Hz, 3H; CH3CHN), 2.23 (s, 3H;
CH3CN), 2.35–2.43 (m, 1H; CH2), 2.52–2.59 (m, 1H; CH2), 2.77–2.94 (m,
Chem. Eur. J. 2008, 14, 11539 – 11556
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11553

S. Brꢀse et al.
NCH), 71.96 (s; OCH2Ph), 81.91 (t; CHOCH2Ph), 122.22 (q; Car), 125.34
(q; Car), 127.04 (t; Car), 127.34 (t; Car, OCH2Ph), 127.85 (t; 2Car,
OCH2Ph), 128.21 (t; 2Car, OCH2Ph), 129.50 (q; Car), 129.57 (t; Car),
131.34 (t; Car), 132.78 (t; Car), 135.90 (t; Car), 137.64 (q; Car, OCH2Ph),
138.55 (q; Car), 139.99 (q; Car), 140.72 (q; Car), 163.54 (q; Car, COH),
170.76 ppm (q; C=N); IR (KBr): n˜ =3011 (w), 2929 (m), 2856 (m), 1598
(w), 1499 (w), 1439 (w), 1358 (w), 1301 (w), 1233 (w), 1157 (w), 1102 (w),
1075 (w), 1027 (w), 991 (w), 927 (w), 881 (w), 863 (w), 802 (w), 745 (w),
719 (w), 700 (w), 669 (w), 623 (w), 590 (w), 551 (vw), 520 (w), 474 cmÀ1
(vw); EIMS (70 eV): m/z (%): 453 (37) [M+], 349 (20), 258 (28), 91 (75),
43 (100); HR-EIMS: calcd for C31H35NO2: 453.2668; found: 453.2664.
50.99 (t; PhCHCH3), 53.19 (t; c-hexyl-CHCH3), 125.98 (t; Car), 126.79 (q;
Car), 127.13 (t; Car), 127.95 (q; Car), 129.46 (t; Car), 132.73 (t; Car), 133.96
(t; Car), 134.49 (t; Car), 136.97 (q; Car), 138.39 (q; Car), 140.55 (q; Car),
155.91 ppm (q; Car, C-OH); IR (KBr): n˜ =3319 (vw), 2982 (w), 2929 (w),
2850 (w), 1884 (vw), 1596 (w), 1566 (w), 1498 (vw), 1445 (w), 1401 (w),
1337 (vw), 1284 (vw), 1261 (w), 1211 (vw), 1173 (vw), 1150 (vw), 1121
(vw), 1066 (w), 1020 (vw), 1004 (vw), 981 (vw), 957 (vw), 938 (vw), 890
(vw), 863 (vw), 797 (w), 754 (vw), 717 (vw), 690 (vw), 655 (vw), 596 (vw),
572 (vw), 513 (vw), 462 (vw), 432 cmÀ1 (vw); EIMS (70 eV): m/z (%):
377 (11) [M+], 145 (9), 104 (9), 58 (38), 43 (100); HR-EIMS: calcd for
C26H35NO: 377.2719; found: 377.2721.
Isomer (Sp,S,S)-12 f: Yield: 71 mg (41%); orange solid; [a]2D0 =À358.0
(c=0.50 g/100 mL CHCl3); m.p. 1588C; Rf =0.35 (n-hexane/ethyl acetate
5:1); 1H NMR (400 MHz, CDCl3): d=1.30–1.5 (m, 3H; c-hexyl), 1.56–
1.70 (m, 1H; c-hexyl), 1.74–1.92 (m, 3H; c-hexyl), 2.29 (s, 3H; CH3CN),
2.31–2.39 (m, 2H; H-c-hexyl, CHaHb), 2.44–2.53(m, 1H; CH2), 2.71–2.85
(m, 2H; CH2), 2.95–3.03 (m, 1H; CH2), 3.10–3.21 (m, 2H; CH2), 3.34–
3.44 (m, 1H; CH2), 3.60–3.70 (m, 2H; NCH, CHOCH2Ph), 4.61 (d, J=
11.5 Hz, 1H; OCHaHbPh), 4.81 (d, J=11.5 Hz, 1H; OCHaHbPh), 6.10
(d, J=7.5 Hz, 1H; Har), 6.30 (dd, J=1.8, 7.7 Hz, 1H; Har), 6.36 (d, J=
7.5 Hz, 1H; Har), 6.46 (dd, J=1.8, 7.9 Hz, 1H; Har), 6.56 (dd, J=1.8,
7.9 Hz, 1H; Har), 6.98 (dd, J=1.8, 7.7 Hz, 1H; Har), 7.25–7.29 (m, 1H;
OCH2Ph), 7.31–7.35 (m, 2H; OCH2Ph), 7.38–7.41 (m, 2H; OCH2Ph),
16.06 ppm (brs, 1H; COH); 13C NMR (100 MHz, CDCl3): d=20.40 (p;
CH3CN), 24.08 (s; CH2), 24.17 (s; CH2), 30.21 (s; CH2), 30.51 (s; CH2),
32.05 (s; CH2), 33.96 (s; CH2), 34.99 (s; CH2), 37.17 (s; CH2), 61.62 (t;
NCH), 71.11 (s; OCH2Ph), 81.89 (t; CHOCH2Ph), 122.26 (q; Car), 125.11
(t; Car), 127.19 (t; Car), 127.48 (t; 2Car, OCH2Ph), 127.45 (t; Car,
OCH2Ph), 128.38 (t; 2Car, OCH2Ph), 129.29 (q; Car), 130.51 (t; Car),
131.62 (t; Car), 132.33 (t; Car), 136.26 (t; Car), 138.06 (q; Car, OCH2Ph),
138.93 (q; Car), 139.94 (q; Car), 141.16 (q; Car), 163.95 (q; Car, COH),
170.60 ppm (q; C=N); IR (KBr): n˜ =3030 (w), 3008 (w), 2936 (m), 2859
(w), 1600 (w), 1498 (w), 1439 (w), 1363 (w), 1344 (w), 1293 (w), 1237 (w),
1210 (w), 1157 (w), 1134 (vw), 1112 (w), 1073 (m), 1022 (w), 991 (vw),
928 (w), 879 (w), 844 (w), 801 (w), 748 (w), 717 (w), 700 (w), 669 (w), 620
(vw), 590 (vw), 566 (w), 536 (vw), 515 (vw), 453 cmÀ1 (vw); EIMS
(70 eV): m/z (%): 453 (24) [M+], 349 (14), 258 (25), 91 (100), 43 (57);
HR-EIMS: calcd for C31H35NO2: 453.2668; found: 453.2664; elemental
analysis calcd (%) for C31H35NO2: C 82.08, H 7.78, N 3.09; found: C
82.39, H 8.04, N 2.95.
Synthesis of (Sp,S,R)-16m: Compound (Sp,S,R)-16m was prepared and
purified according to the procedure for (Rp,S,S)-16m from (Sp,S)-12m
(153 mg, 0.53 mmol), NaBH4 (57.0 mg, 1.51 mg), and concentrated acetic
acid (87.0 mL, 91.0 mg, 1.51 mmol). Yield: 134 mg (67%, >99% de);
white crystals; [a]2D0 =À76.7 (c=0.55 g/100 mL acetone); m.p. 150–1548C;
Rf =0.50 (n-hexane/ethyl acetate 5:1+2.5% Et3N); 1H NMR (400 MHz,
CDCl3): d=1.16 (d, J=6.7 Hz, 3H; c-hexyl-CHCH3), 1.20 (d, J=6.6 Hz,
3H; PhCHCH3), 1.15–1.29 (m, 3H; H-c-hexyl), 1.31–1.44 (m, 2H; H-c-
hexyl), 1.64–1.98 (m, 6H; H-c-hexyl), 2.57 (ddd, J=5.5, 10.5, 13.0 Hz,
1H; CH2), 2.74–2.83 (m, 1H; CH2), 2.87–2.96 (m, 2H; CH2), 3.04 (ddd,
J=2.7, 10.4, 13.0 Hz, 1H; CH2), 3.11–3.27 (m, 3H; CH2, c-hexylCHCH3),
3.42 (ddd, J=2.9, 10.0, 12.9 Hz, 1H; CH2), 4.10 (q, J=6.6 Hz, 1H;
PhCHCH3), 6.08 (d, J=7.6 Hz, 1H, Har), 6.30 (d, J=7.6 Hz, 1H; Har),
6.44 (dd, J=1.8, 7.9 Hz, 1H; Har), 6.51 (dd, J=1.8, 7.8 Hz, 1H, Har), 6.64
(dd, J=1.8, 7.8 Hz, 1H; Har), 6.90 ppm (dd, J=1.8, 7.9 Hz, 1H; Har);
13C NMR (100 MHz, CDCl3): d=17.10 (p; c-hexyl-CHCH3), 22.84 (p;
PhCHCH3), 26.43 (s; C-c-hexyl), 26.73 (s; C-c-hexyl), 26.75 (s; C-c-
hexyl), 27.10 (s; C-c-hexyl), 30.09 (s; C-c-hexyl), 30.23 (s; CH2), 32.85 (s;
CH2), 34.10 (s; CH2), 34.85 (s; CH2), 41.22 (t; C-c-hexyl), 52.66 (t;
PhCHCH3), 54.78 (t; c-hexyl-CHCH3), 125.79 (t; Car), 126.39 (q; Car),
127.61 (t; Car), 127.90 (q; Car), 129.65 (t; Car), 132.71 (t; Car), 133.96 (t;
Car), 134.08 (t; Car), 137.04 (q; Car), 138.31 (q; Car), 140.60 (q; Car),
156.16 ppm (q; Car, C-OH); IR (KBr): n˜ =3321 (m), 2926 (s), 2855 (s),
1857 (w), 1598 (m), 1567 (m), 1498 (m), 1459 (s), 1438 (s), 1376 (m), 1325
(m), 1283 (m), 1252 (m), 1211 (m), 1167 (m), 1120 (m), 1103 (m), 1073
(m), 1058 (m), 1016 (m), 973 (m), 938 (m), 891 (m), 868 (m), 838 (w), 787
(m), 770 (m), 716 (m), 686 (w), 657 (m), 632 (vw), 589 (m), 562 (w), 516
(m), 477 (vw), 459 (vw), 417 cmÀ1 (w); EIMS (70 eV): m/z (%): 377 (81)
[M+], 145 (46), 104 (100); HR-EIMS: calcd for C26H35NO: 377.2719;
found: 377.2720.
Synthesis and characterization of ligands 16: Ligands 16i were synthe-
sized according to a literature procedure.[31]
Synthesis of (Rp,S,S)-16m: Compound (Rp,S)-12m (300 mg, 0.80 mmol)
was dissolved in a mixture of methanol (60 mL)/CH2Cl2 (30 mL) and
treated at room temperature with NaBH4 (112 mg, 2.96 mmol). Concen-
trated acetic acid (171 mL, 2.96 mmol) was then added dropwise to the
yellow reaction mixture, which became immediately colorless. Stirring
was maintained for 5 h at room temperature and the reaction was then
quenched by the addition of water. This mixture was made basic by the
addition of sodium carbonate and was then extracted with methylene
chloride. The combined organic layers were dried over MgSO4 and the
solvent was removed completely under reduced pressure. The obtained
raw material was purified by flash chromatography (n-pentane/diethyl
ether 10:1+2.5% Et3N). Yield: 220 mg (73%, >99% de); yellow crys-
tals; [a]2D0 =+107.3 (c=0.60 g/100 mL acetone); m.p. 104–1078C; Rf =
0.29 (CH2Cl2); 1H NMR (400 MHz, CDCl3): d=1.09 (d, J=6.5 Hz, 3H;
c-hexyl-CHCH3), 1.23 (d, J=6.5 Hz; PhCHCH3), 1.10–1.41 (m, 5H; H-c-
hexyl), 1.44–1.55 (m, 1H; H-c-hexyl), 1.74–1.77 (m, 2H; H-c-hexyl),
1.85–1.96 (m, 3H; H-c-hexyl), 2.57 (ddd, J=5.8, 13.0, 16.1 Hz, 1H; CH2),
2.71–2.91 (m, 3H; CH2), 3.06 (ddd, J=2.7, 10.4, 13.0 Hz, 1H; CH2), 3.11–
3.30 (m, 3H; CH2), 3.45 (ddd, J=2.71, 9.8, 12.8 Hz, 1H; CH2), 4.16 (q,
J=6.5 Hz, 1H; PhCHCH3), 6.13 (d, J=7.7 Hz, 1H; Har), 6.33 (d, J=
7.7 Hz, 1H; Har), 6.35 (dd, J=1.8, 7.9 Hz, 1H; Har), 6.50 (dd, J=1.8,
7.8 Hz, 1H; Har), 6.63 (dd, J=1.8, 7.8 Hz, 1H; Har), 6.86 ppm (dd, J=1.8,
7.9 Hz, 1H; Har); 13C NMR (100 MHz, CDCl3): d=16.04 (p; c-hexyl-
CHCH3), 20.29 (p; PhCHCH3), 26.53 (s; C-c-hexyl), 26.62 (s; C-c-hexyl),
26.70 (s; C-c-hexyl), 29.03 (s; C-c-hexyl), 29.39 (s; C-c-hexyl), 30.28 (s;
CH2), 33.10 (s; CH2), 34.00 (s; CH2), 34.88 (s; CH2), 43.91 (t; C-c-hexyl),
Acknowledgements
We thank the Fonds der Chemischen Industrie (Kekulꢅ stipend S. A.),
Dr. K. Ditrich for a generous gifts of chiral amines, and Prof. S. Mecking
for a sample of 2,6-diphenylaniline. We acknowledge the scientific input
of Dr. S. Hçfener and Dr. T. Muller.
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Chem. Eur. J. 2008, 14, 11539 – 11556

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Received: August 12, 2008
Published online: November 6, 2008
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