The Bronsted acid catalyzed, enantioselective vinylogous Mannich reaction

Article abstract of DOI:10.1002/chem.200902537

The first catalytic, enantioselective vinylogous Mannich reaction of acyclic silyl dienolates is reported. A second-generation 2,2′-dihydroxy- 1,1′-binaphthyl (BINOL)-based phosphoric acid has been developed and further optimized as an enantioselective organocatalyst. Upon protonation of the imines, chiral contact ion pairs are generated in situ and attacked highly diastereoselectively by the nucleophile. γ-Substituted silyl dienolates that lead to more highly substituted Mannich products with a second stereogenic center in good diastereoselectivity have been employed in these reactions. The reaction path has been elucidated with NMR spectroscopy and mass spectrometry, which suggest that the protic reaction medium found to be optimal in these reactions serves to trap the cationic silicon species as silanol. A crystal structure of a phosphoric acid bound imine was obtained that provides insight into the binding mode and a rationale for the stereochemical course of the reaction.

Full text of DOI:10.1002/chem.200902537

DOI: 10.1002/chem.200902537
The Brønsted Acid Catalyzed, Enantioselective Vinylogous
Mannich Reaction
Marcel Sickert,[a] Falko Abels,[a] Matthias Lang,[a] Joachim Sieler,[b]
Claudia Birkemeyer,[c] and Christoph Schneider*[a]
Abstract: The first catalytic, enantiose-
Substituted silyl dienolates that lead to
more highly substituted Mannich prod-
ucts with a second stereogenic center
in good diastereoselectivity have been
employed in these reactions. The reac-
tion path has been elucidated with
NMR spectroscopy and mass spectrom-
lective vinylogous Mannich reaction of
acyclic silyl dienolates is reported. A
second-generation 2,2’-dihydroxy-1,1’-
binaphthyl (BINOL)-based phosphoric
acid has been developed and further
optimized as an enantioselective orga-
nocatalyst. Upon protonation of the
imines, chiral contact ion pairs are gen-
erated in situ and attacked highly dia-
stereoselectively by the nucleophile. g-
etry, which suggest that the protic reac-
tion medium found to be optimal in
these reactions serves to trap the cat-
ionic silicon species as silanol. A crystal
structure of a phosphoric acid bound
imine was obtained that provides in-
sight into the binding mode and a ra-
tionale for the stereochemical course
of the reaction.
Keywords: BINOL · enantioselec-
tivity · organocatalysis · Mannich
reaction · phosphoric acids
Introduction
g site, thus giving rise to g-substituted products in acid-cata-
lyzed Mukaiyama-type reactions predominantly.[2]
À
The asymmetric Mannich reaction is a fundamental C C
bond-forming process in organic chemistry; it furnishes val-
uable b-amino carbonyl systems.[1] The extension of the eno-
late component into a dienolate offers the opportunity for a
The highly functionalized vinylogous Mannich products
are valuable synthetic intermediates in organic synthesis and
have been frequently employed in natural product synthesis
in particular.[3] Despite the documented synthetic potential,
only very few catalytic, enantioselective processes had been
developed prior to our studies; these were limited to very
special substrate patterns. The first protocol was devised by
Martin et al. who employed a Ti–BINOL (BINOL=2,2’-di-
hydroxy-1,1’-binaphthyl) catalyst for the reaction of silyloxy
furans with imines and obtained amino-substituted g-bute-
nolides with good diastereoselectivity and up to 54% ee.[4]
Subsequently, Hoveyda and Snapper and co-workers devel-
oped a chiral silver catalyst with a dipeptide-based P,N
ligand for exactly the same reaction, thus giving rise to ex-
cellent diastereo- and enantioselectivities of up to 98% ee.[5]
Recently, Akiyama et al. documented a phosphoric acid cat-
alyzed vinylogous Mannich reaction of silyloxy furans and
imines that furnished the products with typically good dia-
stereocontrol and good to excellent enantiocontrol.[6] Shiba-
saki et al. reported a direct vinylogous Mannich reaction for
the asymmetric synthesis of g-butenolides by using a chiral
lanthanum–pybox (pybox=pyridine bisoxazoline) com-
plex.[7] A second substrate class that was employed with
great success in direct asymmetric vinylogous Mannich reac-
tions is 1,1-dicyanoalkenes, which were reacted with activat-
À
vinylogous Mannich reaction that generates a new C C
bond from the g site within the dienolate component and
leads to d-amino a,b-unsaturated carbonyl compounds. This
divergent regioselectivity is typically governed by the magni-
tude of the atomic orbital coefficients in the HOMO of the
dienolate. Whereas in lithium dienolates the size of this co-
efficient is larger at the a position, thereby leading to a-sub-
stituted products preferentially, silicon dienolates have a dif-
ferent electronic distribution and a larger coefficient at the
[a] Dipl.-Chem. M. Sickert, F. Abels, M. Lang, Prof. Dr. C. Schneider
Institut fꢀr Organische Chemie, Universitꢁt Leipzig
Johannisallee 29, 04103 Leipzig (Germany)
Fax : (+49)341-973-6599
E-mail: schneider@chemie.uni-leipzig.de
[b] Prof. Dr. J. Sieler
Institut fꢀr Anorganische Chemie, Universitꢁt Leipzig
Johannisallee 29, 04103 Leipzig (Germany)
[c] Dr. C. Birkemeyer
Institut fꢀr Analytische Chemie, Universitꢁt Leipzig
Linnestrasse 3, 04103 Leipzig (Germany)
2806
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Chem. Eur. J. 2010, 16, 2806 – 2818

FULL PAPER
ed imines catalyzed by a chiral thiourea Brønsted acid cata-
lyst that contained a basic amine moiety.[8] The products
were obtained with complete regio- as well as excellent dia-
stereo- and enantioselectivities. The same substrates were
later shown by Jørgensen et al. to also react under chiral
phase-transfer conditions with imines to yield products with
up to 95% ee.[9]
Results and Discussion
Initial studies: We first focused on the identification of the
most suitable alkoxy group within the silyl dienolate that
gave rise to the best enantioselectivity. Thus, we performed
reactions of 1a and various silyl dienolates 2 with 3a as cat-
alyst under otherwise identical reaction conditions (Table 1).
In 2008, we reported the first
catalytic, enantioselective, vi-
nylogous Mannich reaction of
Table 1. Optimization of the vinylogous Mannich reaction with different
alkoxy dienolates.[a]
an acyclic silyl dienolate 2b
with imines 1 that was catalyzed
by the chiral Brønsted acid
3a.[10a] A BINOL-based phos-
Entry
R
2
4
t [h][b]
Yield [%][c]
ee [%][d]
phoric acid of the same type
that Akiyama and Terada[11,12]
1
2
3
4
5
6
Me
Et
nPr
nBu
iPr
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
8
8
8
8
24
48
73
88
87
85
86
64
83
88
78
67
43
22
had introduced into the field of
asymmetric organocatalysis in-
dependently was employed
under carefully optimized reaction conditions and delivered
vinylogous Mannich products 4 in good yields, complete g-
regioselectivity, and ee values of up to 92% (Scheme 1).
tBu
[a] Reaction conditions: 1a (1 equiv), 2 (3 equiv), 3a (5 mol%), À308C,
0.16m in THF/tBuOH/2-Me-2-BuOH (1:1:1), H2O (1.0 equiv); TBS=tert-
butyldimethysilyl, PMP=p-methoxyphenyl. [b] Conversion >99%
(HPLC). [c] Isolated yield. [d] Determined through HPLC on chiral sta-
tionary phases.
It turned out that small alkoxy groups in silyl dienolate 2
gave higher enantioselectivities than larger alkoxy groups.
The highest selectivity of 88% ee was obtained with the
ethoxy group (Table 1, entry 2), whereas a tert-butyl ester
derived silyl dienolate furnished the vinylogous Mannich
product with only 22% ee (entry 6).
Scheme 1. Brønsted acid catalyzed vinylogous Mannich reaction of acy-
clic silyl dienolate 2b (E/Z 1:2.5).[10a]
Later we could extend this process successfully to reac-
tions of amide-based silyl dienolates.[10b] Subsequently, Car-
Secondly, we varied the N-aryl group that had been
shown to be the most suitable N-substituent for this reac-
tion. Generally, we found para-substituted aryl groups such
as the PMP group to give rise to the best selectivities
(Table 2). In contrast, ortho-substituted aryl groups such as
the ortho-hydroxyphenyl group that Akiyama et al. had
preferentially employed in their studies furnished a racemic
product under our reaction conditions.
retero and co-workers successfully developed
a chiral
copper catalyst that could be applied both to silyloxy furans
as well as acyclic silyl dienolates as nucleophiles in vinylo-
gous Mannich reactions.[13]
We have now further optimized this process with respect
to catalyst structure and scope. In particular, we have devel-
oped a superior second-generation Brønsted acid catalyst
that typically furnishes vinylogous Mannich products with
above 90% ee for most substrates investigated and with
>95% ee in select cases. Additionally, we have also found
g-substituted silyl dienolates to be suitable substrates for
this process, thus giving rise to products with two new chiral
centers in good diastereo- and enantiocontrol. Also, NMR
spectroscopic as well as mass spectrometric investigations
were performed to elucidate the reaction mechanism and in
particular the mode of regeneration of the chiral catalyst. Fi-
nally, we have obtained structural information on the imine-
bound catalyst that allows for a transition-state proposal of
this reaction.
Table 2. Optimization of the vinylogous Mannich reaction with different
imine protecting groups (PGs).[a]
Entry
PG
4
t [h][b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
p-Ph-O-Me
p-Ph-O-Et
p-Ph-O-Bn
p-Me-Ph
Ph
4b
4g
4h
4i
4j
4k
4l
8
6
48
17
12
1
88
92
86
91
83
88
88
86
88
89
0
o-HO-Ph
81
o-MeO-Ph[e]
36
20[e]
32
[a] Reaction conditions:
1 (1 equiv), 2b (E/Z=1:2.5, 3 equiv), 3a
(5 mol%), À308C, 0.16m in THF/tBuOH/2-Me-2-BuOH (1:1:1), H2O
(1.0 equiv). [b] Conversion >99% (HPLC). [c] Isolated yield. [d] Deter-
mined through HPLC on chiral stationary phases. [e] 20% conversion.
Chem. Eur. J. 2010, 16, 2806 – 2818
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www.chemeurj.org
2807

C. Schneider et al.
Table 3. Optimization of the vinylogous Mannich reaction with phospho-
Optimization of the process: In previous studies we had
identified the 3,3’-bismesityl-substituted BINOL-phosphoric
acid 3a as the optimal Brønsted acid for the vinylogous
Mannich reaction in a solvent system containing equal
amounts of tBuOH, 2-methyl-2-butanol, and THF with
1 equiv of water.[10a] The products were obtained in good
yields and a maximum of 92% ee. Some products, however,
were formed with significantly lower enantioselectivities;
these were synthetically not useful. In an attempt to further
increase the enantioselectivity of the reaction and possibly
develop a chiral Brønsted acid catalyst for a broader sub-
strate range, we investigated some more BINOL-based
phosphoric acids with different 3,3’-substituents. In particu-
lar, we systematically varied the size of the ortho and para
substituents within the 3,3’-aryl groups, as these positions
had been found earlier to be of prime importance for the
enantioselectivity of the reaction.[10a]
ric acids 3.[a]
Entry
Catalyst 3
t [h][b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3 f
3g
3h
3i
2.0
3.0
1.5
3.0
5.0
1.0
2.0
1.0
22
92
91
90
88
88
96
91
92
63
92
88
91
96 (98)[e]
93
95 (96)[e]
93
96 (97)[e]
88
[a] Reaction conditions: 1b (1 equiv), 2b (E/Z=1:2.5, 3 equiv),
3
(5 mol%), À308C, 0.16m in THF/tBuOH/2-Me-2-BuOH (1:1:1), H2O
(1.0 equiv). [b] Conversion >99% (HPLC). [c] Isolated yield. [d] Deter-
mined through HPLC on chiral stationary phases. [e] Enantioselectivity
at À508C.
Thus, a broad range of different phosphoric acids 3
(Scheme 2) that met these criteria were synthesized follow-
ing established procedures and tested in the vinylogous
unsubstituted furnished a highly selective catalyst 3g, which
gave rise to the product in 93% ee (Table 3, entry 7). More
importantly, catalyst 3h with a 2,4,6-triethyl substitution pat-
tern within the 3,3’-aryl groups furnished the vinylogous
Mannich product 5a in excellent yield and 96% ee in a very
short reaction time (entry 8). Finally, use of the TRIP cata-
lyst 3i developed by List and co-workers,[15] which was a
highly promising catalyst candidate for our reaction, too,
gave rise to the product in moderate yield and 88% ee
(entry 9).
With the three Brønsted acid catalysts 3d, 3 f, and 3h in
hand, which were identified as the most enantioselective
ones, we briefly attempted to further optimize the selectivity
of the reaction by lowering the reaction temperature.
Indeed, the enantioselectivity of the reaction could be slight-
ly improved by running the reaction at À508C, which
proved to be the lowest temperature at which the reaction
mixture was still liquid and could be stirred. All three cata-
lysts now exhibited synthetically very useful levels of selec-
tivity of 97–98% ee. Considering the exceptional ee and the
ease of preparation, we selected catalyst 3d as our standard
Brønsted acid catalyst to study the vinylogous Mannich re-
action further.
To further reduce the catalyst loading, we performed ex-
periments with 1–5 mol% of catalyst in a model reaction of
1b with 2b under otherwise identical reaction conditions.
As can be seen from Table 4, even with only 2 mol% of
phosphoric acid 3d vinylogous Mannich product 5a was ob-
tained in 90% yield and 97% ee after 48 h at À508C
(Table 4, entry 4). In some cases, precipitation of the imine
and/or the iminium salt occurred at this low temperature,
thereby resulting in quite long reaction times. Eventually,
we settled on a catalyst loading of 3 mol% in an attempt to
reduce the reaction time to an acceptable level and could
still isolate product 5a in 93% and 97% ee (entry 3).
As previously discovered, the reaction could be per-
formed in a three-component fashion, thereby obviating the
Scheme 2. Phosphoric acids 3a–i investigated in the vinylogous Mannich
reaction.
Mannich reaction of silyl dienolate 2b (E/Z=1:2.5)[14] and
imine 1b using our previously optimized reaction conditions
(Table 3). Catalyst 3b lacking only the para-methyl group
within the 3,3’-aryl groups still gave 88% ee in excellent
yield (Table 3, entry 2). Replacing this para-methyl group
with a phenyl group did not have a strong effect on the
enantioselectivity of the reaction (entry 3). However, plac-
ing a tBu group instead of a methyl group in the para posi-
tion significantly increased the selectivity to 96% ee while
maintaining a high yield of product 5a (entry 4). A further
increase of the steric size at this position did not correspond
to a higher selectivity, as exemplified by the adamantyl-sub-
stituted catalyst 3e (entry 5). Interestingly, the pentamethyl-
substituted catalyst 3 f furnished the product in excellent
yield and with almost the same selectivity as catalyst 3d
(entry 6).
With respect to the effect of the steric size of the ortho
substituents within the 3,3’-aryl groups, we had earlier dis-
covered that any catalyst lacking ortho substituents gave
very low selectivity.[10a] Increasing the size of the ortho sub-
stituent from methyl to ethyl and keeping the para position
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Vinylogous Mannich Reaction
FULL PAPER
Table 4. Optimization of catalyst loading.[a]
70% ee. With the new conditions, enantioselectivities in-
creased substantially and approached or even exceeded
90% ee for most substrates.
Thus, the best selectivities were obtained for benzalde-
hydes and para-substituted benzaldehydes with well above
90% ee (Table 5, entries 1–4). Yields and reaction times
varied depending on the reactivity and solubility of the in
situ formed imines. Use of meta- and ortho-substituted ben-
zaldehydes furnished Mannich products in excellent yields
and ee values in the high eighties or even 90% (entries 5–
10). Heteroaromatic aldimines were also good substrates for
this process; they furnished Mannich products with up to
92% ee (entries 11–14). Interestingly, in some cases, enantio-
selectivities increased dramatically compared with reactions
catalyzed with phosphoric acid 3a. Thus, 2-furyl aldehyde
now gave rise to 89% ee, whereas with 3a the selectivity
was just 74% ee (entry 12). Also, the 2-thiophene-substitut-
ed vinylogous Mannich product 5m was now obtained with
90% ee (entry 14). Aliphatic a-branched aldehydes could
also be employed as reaction partners in a three-component
reaction and delivered Mannich products 5n–p in good
yields and 80–87% ee, again typically exceeding the selectiv-
ities obtained with catalyst 3a (entries 15–17). Aliphatic un-
branched aldehydes, however, gave rise to vinylogous Man-
nich products with only moderate selectivities (e.g.,
entry 18).
Entry
Catalyst loading [mol%]
t [h][b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
5
4
3
2
1
14
16
24
48
288
95
93
93
90
90
98
97
97
97
97
[a] Reaction conditions:
1 (1 equiv), 2b (E/Z=1:2.5, 3 equiv), 3d
(5 mol%), À508C, 0.16m in THF/tBuOH/2-Me-2-BuOH (1:1:1), H2O
(1.0 equiv). [b] Conversion >99% (HPLC). [c] Isolated yield. [d] Deter-
mined through HPLC on chiral stationary phases.
need to synthesize the imine in a separate reaction. The
water formed in this condensation reaction did not harm the
reactions, as water was actually shown to accelerate the
turnover of the reaction (vide infra). Thus, all vinylogous
Mannich reactions reported herein were performed starting
from the respective aldehydes, para-anisidine, and silyl dien-
olate 2a (E/Z=1:2.5, 2 equiv) in a solvent mixture of equal
amounts of tBuOH, 2-methyl-2-butanol, and THF contain-
ing 1 equiv of water at À508C. By using these carefully opti-
mized reaction conditions, we set out to investigate the sub-
strate scope of the vinylogous Mannich reaction (Table 5).
Our previously established conditions had furnished prod-
ucts typically with 80% ee or slightly above and resulted in
90–92% ee only for select cases.[10a] Also, some heteroaro-
matic and aliphatic aldimines gave rise to only about
The absolute configuration of the vinylogous Mannich
products was established explicitly for 4a (83% ee) through
cleavage of the PMP group with subsequent tert-butoxycar-
bonyl (Boc) protection, which delivered the known ester 6
and was applied to all other products in analogy (Scheme 3;
[a]2D0 =À23.0 (c=0.4) for the S enantiomer; refs. [16]: [a]2D0 =
+27.4 (c=0.4) for the R enantiomer).[17]
Table 5. Scope of the three-component vinylogous Mannich reaction.[a]
Entry
R
Product
t [h][b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
Ph
4b
5a
5b
5c
5d
5e
5 f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
18
12
144
48
48
6.5
21
6
48
144
96
14
72
144
72
48
72
72
97
93
40
97
95
97
97
97
96
88
90
97
95
81
91
91
89
88
95
97
93
90
88
90
90
85
87
90
92
89
84
90
82
80
87
70
Scheme 3. Determination of absolute configuration.
p-Et-Ph
p-MeO-Ph
p-F-Ph
m-Me-Ph
m-Cl-Ph
o-Me-Ph
o-Br-Ph
o-NO2-Ph
2-naphthyl
3-furyl
g-Substituted dienolates: After the successful optimization
of the process, we investigated the use of g-substituted silyl
dienolates (E)-2g and (Z)-2g, respectively, as nucleophiles
in the reaction (Scheme 4). Here an additional stereochemi-
cal aspect had to be taken into account: the existence of
four double-bond stereoisomers of the substrate. Whereas
we had previously observed that the geometry of the double
bond directly attached to the acetal moiety had no effect on
the stereochemical outcome of the reaction (vide infra), it
was of interest to us to study the influence of the geometry
of the attached propenyl group.
9
10
11
12
13
14
15
16
17
18
2-furyl
3-thiophenyl
2-thiophenyl
tBu
iPr
cyclohexyl
n-heptyl
Accordingly, we submitted the stereoisomeric silyl dieno-
lates (3E)-2g and (3Z)-2g separately to our model reaction
with catalyst 3d (5 mol%). As can be seen from Scheme 4,
the 3E-configured silyl dienolate 2g delivered vinylogous
[a] Reaction conditions: aldehyde (1.1 equiv), p-anisidine (1.0 equiv), 2b
(E/Z=1:2.5, 2 equiv), 3d (3 mol%), À508C, 0.16m in THF/tBuOH/2-Me-
2-BuOH (1:1:1), H2O (1.0 equiv). [b] Conversion >99% (HPLC). [c] Iso-
lated yield. [d] Determined through HPLC on chiral stationary phases.
Chem. Eur. J. 2010, 16, 2806 – 2818
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2809

C. Schneider et al.
Table 6. Scope of the two-component vinylogous Mannich reaction.[a]
Entry
R
Product 7
Yield [%][b]
anti/syn[c]
ee [%][d]
1
2
3
4
5
6
7
8
9
Ph
7b
7a
7c
7d
7e
7 f
7g
7h
7i
75
97[e]
35
77
43
44
82
96
65
94:6
96
94
92
97
93
90
92
93
91
93
p-Et-Ph
p-Cl-Ph
m-Me-Ph
m-Cl-Ph
o-Me-Ph
o-I-Ph
3-pyridyl
3-furyl
2-furyl
88:12
88:12
91:9
94:6
88:12
91:9
90:10
74:26
88:12
10
7j
83
Scheme 4. Vinylogous Mannich reaction of substituted acyclic silyl dieno-
lates (3E)-2g and (3Z)-2g.
[a] Reaction conditions: 1 (1 equiv), (3E)-2g (1E/1Z=1:1.5, 3 equiv), 3d
(5 mol%), À308C, 0.16m in THF/tBuOH/2-Me-2-BuOH (1:1:1), H2O
(1.0 equiv). [b] Isolated yield. [c] Determined through HPLC and
1H NMR spectroscopy. [d] Determined through HPLC on chiral station-
ary phases. [e] Reaction complete after 2 d.
Mannich product anti-7 in 97% yield and with excellent
enantioselectivity of 94% ee and good diastereoselectivity of
88:12. On the other hand, 3Z-configured silyl dienolate 2g
did not give rise to a high-yielding reaction, even after pro-
longed reaction time, and furnished Mannich product syn-7
in only very moderate yield and low enantio- and diastereo-
selectivity.[18]
action. 2-Methyl-2-butanol was used as additional solvent to
keep the mixture liquid at the lowest possible reaction tem-
perature. On the other hand, THF had a beneficial effect on
the selectivity of the reaction.
Determination of the relative configuration of anti-7 was
accomplished through Stryker reduction and cyclization
under acidic conditions to afford lactam 8, the configuration
of which was unambiguously proven by J coupling constants
and NOESY measurements (Scheme 5).
To further elucidate the reaction pathway and in particu-
lar propose a model for the catalytic turnover, we followed
the reaction of imine 1k with silyl dienolate 2b in
[D10]nBuOH online by 1H NMR spectroscopy (Scheme 6,
Scheme 6. Online NMR spectroscopic investigation with imine 1k.
Scheme 5. Determination of the relative configuration of Mannich prod-
uct anti-7.
Figures 1 and 2). Over the course of the reaction, the
amount of imine and nucleophile decreased as the signals of
À
À
product 5k and tert-butyldimethysilyl (TBS) OH/TBS OD
À
Subsequently, we submitted a range of different aromatic
imines to the phosphoric acid (3d)-catalyzed vinylogous
Mannich reaction with silyl dienolate (3E)-2g and obtained
d-amino esters anti-7a–j in moderate to good yields, good
diastereoselectivities, as well as typically excellent enantiose-
lectivities above 90% ee (Table 6). We note that both aro-
matic as well as heteroaromatic aldimines proved to be
good substrates for this reaction.
and TBS O
G
À
TBS OH was presumably caused by adventitious water
present in the reaction mixture. In our standard reaction
mixture containing 1 equiv of water, TBS OH was formed
exclusively as byproduct of the reaction, as was identified by
NMR spectroscopy and comparison with
sample. This observation is consistent with the assumption
that the cationic silicon species generated upon nucleophilic
addition to the imine is trapped immediately by the solvent
À
a reference
À
Mechanistic investigations: In previous studies, we had
found a solvent system containing equal amounts of tBuOH,
2-methyl-2-butanol, and THF with 1 equiv of water to be
optimal for the Mukaiyama-type vinylogous Mannich reac-
tion of silyl dienolates.[10a] In particular, the alcohol compo-
nents were shown to be important for the rate of the reac-
tion with the small water content further accelerating the re-
mixture as TBS OH. In addition, this implies that the phos-
phate anion is readily protonated by the protic medium to
regenerate the active catalyst, which was additionally
proved by ESIMS (vide infra).
Another important conclusion that was drawn from the
online NMR spectroscopy experiment is related to the E/Z
ratio of silyl dienolate 2b, which we have always employed
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Chem. Eur. J. 2010, 16, 2806 – 2818

Vinylogous Mannich Reaction
FULL PAPER
ments in an attempt to slow down the reaction and detect
relevant reaction intermediates.[19,20]
A prominent complex with m/z 1024.5 was detected in
ethyl acetate; this represented the contact ion pair 10
(Figure 3). In addition, the protodesilylated counterion pair
with m/z 910.4 was also observed.
To further identify the observed peaks, ESIMS/MS experi-
ments were conducted (Figure 4). In the ion trap, the com-
plex m/z 1024.5 fragmented predominantly into the TBS-
protected catalyst (m/z 669) and vinylogous Mannich prod-
uct 4b (m/z 326). The assignment of the detected species
was further supported through high-resolution masses
(Table 7).
On the basis of the accumulated NMR spectroscopic and
MS data, we propose that complex m/z 1024.5 is formed as
the initial reaction product by nucleophilic addition of silyl
Figure 1. Online NMR spectrum (600 MHz, [D10]nBuOH) after 10 min at
À368C (23% conversion).
Figure 3. Part of the ESIMS spectrum of the reaction represented in
Scheme 6 after 2 h at RT.
Figure 2. Online NMR spectrum (600 MHz, [D10]nBuOH) after 80 min at
À368C (80% conversion).
as a 1:2.5 (E/Z) mixture. Over the course of the entire reac-
tion, this ratio remained virtually constant, thereby suggest-
ing that both isomers either reacted with very similar rates
and selectivities or isomerized readily under the reaction
conditions.
To further substantiate this mechanistic proposal and pos-
sibly detect reaction intermediates we decided to follow the
reaction by ESI mass spectrometry (Scheme 7). Because the
reaction was too rapid under the established conditions at
room temperature to follow by ESIMS, we employed an
aprotic solvent such as ethyl acetate for the ESIMS experi-
Scheme 7. Model reaction for ESIMS/MS.
Figure 4. ESIMS/MS spectrum of complex m/z 1024.5.
Chem. Eur. J. 2010, 16, 2806 – 2818
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2811

C. Schneider et al.
Table 7. High-resolution mass data of detected species.
Species[a]
Mass
(calcd)
Mass
(found)
Formula
Error
[ppm]
A
326.17507
699.30540
326.17518
699.30690
C20H24NO3
C44H47O4PSi
0.3
2.0
A
1024.47319 1024.47144
C64H71NO7PSi 1.7
C78H80N2O10P 2.0
[3a+24b+H]+ 1235.57291 1235.57001
dienolate 2b to imine 1a. This counterion pair 10 is subse-
quently hydrolyzed into vinylogous Mannich product 4b
À
and TBS OH with concomitant regeneration of Brønsted
acid catalyst 3a (Scheme 8). We cannot rule out, however,
Figure 5. Crystal structure of the imine (1a)–phosphoric acid (3d)
À
À
adduct. Both selected bond lengths P1 O1 and P1 O2 are 1.613(3) ꢃ.
À
Hence, these bonds can be considered to be P O single bonds. Bond
À
À
lengths between P1 O3 and P1 O4 are 1.476(3) and 1.464(4) ꢃ, respec-
tively.
À
À
À
fixed by a strong N H···O bond (N2 H 0.87 ꢃ, N2 O3
2.653(6) ꢃ, N2-H2-O3 160.28).
Figure 5 suggests that the right upper Re face of the imini-
um ion is effectively shielded by the 3-aryl group at C13 (X-
ray numbering). Hence the nucleophilic attack of silyl dien-
olate 2b is directed to the opposite Si face, which is consis-
tent with the predominant formation of the S enantiomer 4a
as discussed above. It also nicely supports the important
role that the para-tBu group within the 3-aryl group acts in
blocking the upper side even more efficiently and making
Brønsted acid 3d the more enantioselective catalyst.
Scheme 8. Proposed catalytic cycle.
that the silylated Brønsted acid catalyst TBS-3a is formed
first from counterion pair 10, as detected in the ESIMS/MS
experiment, which is subsequently hydrolyzed to generate
À
phosphoric acid 3a and TBS OH. In the aqueous reaction
medium, the lifetime of TBS-3a should, however, be very
short, if it exists at all.[21]
Crystal structure of an imine-bound phosphoric acid: To
shed some light on the way the chiral Brønsted acid binds to
the imine and possibly on the origin of asymmetric induc-
tion, we attempted a cocrystallization of phosphoric acid 3d
and benzaldimine 1a. Single crystals suitable for X-ray dif-
fraction analysis were eventually obtained by slow evapora-
tion of a solution of both components in CHCl3. The imini-
um phosphate crystallized as a dimer in a “crown ether” ar-
rangement in which the space group symmetry C2 is generat-
ed by a twofold rotation axis. For the sake of clarity,
Figure 5 only shows the monomer of this iminium phos-
phate. As there is no significant difference in the bond
Conclusion
We have established the first catalytic, enantioselective, vi-
nylogous Mannich reaction of acyclic silyl dienolates to fur-
nish valuable d-amino a,b-unsaturated esters 4 in excellent
yields and regioselectivity as well as typically good to very
good enantioselectivity of up to 97% ee. A second-genera-
tion chiral Brønsted acid catalyst 3d was developed that in-
creased the previously obtained enantioselectivities substan-
tially. The g-substituted silyl dienolate (3E)-2g furnished vi-
nylogous Mannich products with two new stereogenic cen-
ters that were established with good diastereo- and high
enantioselectivity. Mechanistic investigations including
NMR spectroscopy and mass spectrometry led to the con-
clusion that the protic reaction medium, which has been
found optimal for the reaction, serves to trap the cationic
silicon species as silanol and to regenerate the chiral Brønst-
À
À
lengths between P1 O3 (1.476(3) ꢃ) and P1 O4
(1.464(4) ꢃ), we conclude that the hydrogen atom is most
likely localized on the N2 atom. Thus, the adduct can be for-
mulated as a close-contact ion pair of the composition
[C44H45PO4]À
ACHTUNGTRENNUNG
[C14H13NO]+. Moreover, the iminium ion is
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Chem. Eur. J. 2010, 16, 2806 – 2818

Vinylogous Mannich Reaction
FULL PAPER
enantiomeric assay: Chiralcel OD-H, isocratic (hexane/2-propanol 95:5,
flow 0.5 mLminÀ1): l=250 nm; 76.19 (5R), 81.14 min (5S); elemental
analysis calcd (%) for C20H23NO3: C 73.82, H 7.12, N 4.30; found: C
73.64, H 7.05, N 4.29.
ed acid catalyst through protonation. A crystal structure of
the imine-bound chiral catalyst was obtained, which re-
vealed that one of the 3-aryl groups within the Brønsted
acid catalyst shields the Re face of the imine, thereby direct-
ing the incoming nucleophile to the opposite side.
Compound 5a: 12 h; yield 93%; 97% ee; Rf =0.40 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =+7.7 (c=0.7 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=7.27 (m, 2H; ArH), 7.17 (m, 2H; ArH), 6.94 (dt, J=15.5,
7.5 Hz, 1H; 3-CH), 6.71 (m, 2H; ArH), 6.49 (m, 2H; ArH), 5.94 (dt, J=
15.5, 1.5 Hz, 1H; 2-CH), 4.43 (dd, J=7.0, 6.0 Hz, 1H; N-CH), 4.19 (q,
J=7.0 Hz, 2H; O-CH2), 3.84 (s, 1H; NH), 3.70 (s, 3H; O-CH3), 2.72–2.60
(m, 4H; CH2, ArCH2), 1.30 (t, J=7.0 Hz, 3H; CH3), 1.24 ppm (t, J=
7.5 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3): d=166.2, 152.1, 145.0,
143.3, 141.2, 140.1, 128.3, 126.3, 124.1, 114.8, 114.8, 60.43, 57.58, 55.85,
41.37, 28.52, 15.52, 14.32 ppm; IR (film): n˜ =3391, 2963, 2932, 2831, 2066,
1905, 1715, 1694, 1618, 1512, 1441, 1367, 1311, 1238, 1179, 1160, 1114,
1095, 1039, 981, 819, 759, 713, 550, 520 cmÀ1; UV/Vis (CHCl3): lmax
(loge)=244 (4.297), 311 nm (3.722); HRMS (ESI): m/z: calcd for
C22H28NO3 [M+H]+: 354.2064; found: 354.2063; enantiomeric assay:
Chiralcel OD-H, isocratic (hexane/2-propanol 80:20, flow 1.0 mLminÀ1):
l=250 nm; 11.12 (5R), 13.90 min (5S).
Experimental Section
General: All vinylogous Mannich reactions were performed in flame-
dried glassware under an air atmosphere. Preparation of catalysts and nu-
cleophiles was performed in flame-dried glassware under an atmosphere
of dry nitrogen or argon. The following reaction solvents were distilled
from the indicated drying agents: dichloromethane (CaH2), tetrahydro-
furan (LiAlH4, triphenylmethane), diethyl ether (Na, benzophenone),
toluene (Na, benzophenone), N,N-dimethylformamide (Acros ACS
grade), acetonitrile (Acros ACS grade), and chloroform (Acros ACS
grade). Diethyl ether, petroleum ether, and ethyl acetate for chromatog-
raphy were of technical grade and distilled from KOH or CaCl2. All reac-
tions were monitored by thin-layer chromatography (TLC) on precoated
silica gel SIL G/UV254 plates (Machery, Nagel & Co.) or HPLC; spots
were visualized by treatment with a solution of vanillin (0.5 g), concen-
trated acetic acid (10 mL), and concentrated H2SO4 (5 mL) in methanol
(90 mL) or molybdophosphoric acid (5 g) in ethanol (250 mL). Flash
column chromatography was performed by using Merck silica gel 60 230–
400 mesh. 1H and 13C NMR spectra were recorded using VARIAN
Gemini 200 (200 MHz) and VARIAN Gemini 300 (300 MHz) spectrome-
ters, or a Bruker Avance DRX 400 (400 MHz) spectrometer in CDCl3 at
258C with TMS as internal standard. Online NMR spectroscopic investi-
gations were recorded using a Bruker DRX-600 (600 MHz). IR spectra
Compound 5b: 144 h; yield 40%; 93% ee; Rf =0.15 (ethyl acetate/petro-
leum ether 1:5); [a]2D2 =+15.6 (c=0.9 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=8.21 (m, 2H; ArH), 7.54 (m, 2H; ArH), 6.87 (dt, J=15.5,
7.5, 0.5 Hz, 1H; 3-CH), 6.68 (m, 2H; ArH), 6.47 (m, 2H; ArH), 5.90 (dt,
J=15.5, 0.5 Hz, 1H; 2-CH), 4.38 (t, J=7.0 Hz, 1H; 5-CH), 4.18 (q, J=
7.0 Hz, 2H; O-CH2), 3.79 (s, 3H; O-CH3), 3.69 (s, 3H; O-CH3), 2.70 (m,
2H; CH2), 1.28 ppm (t, J=7.0 Hz, 3H; CH3); 13C NMR (100 MHz,
CDCl3): d=165.8, 158.5, 151.9, 144.4, 140.6, 134.4, 127.0, 123.8, 114.6,
114.4, 113.8, 60.03, 56.88, 55.38, 54.91, 40.98, 14.36 ppm; IR (film): n˜ =
3401, 2994, 2933, 2833, 1717, 1654, 1611, 1511, 1463, 1441, 1368, 1302,
1245, 1178, 1110, 1095, 1039, 983, 819, 787, 761, 548 cmÀ1
; UV/Vis
(CHCl3): lmax (loge)=247 (4.439), 309 nm (3.888); HRMS (ESI): m/z:
calcd for C21H26NO4 [M+H]+: 356.1856; found: 356.1857; enantiomeric
assay: Chiralcel OD, isocratic (hexane/2-propanol 90:10, flow
0.5 mLminÀ1): l=250 nm; 27.17 (5R), 30.10 min (5S).
were obtained using
a FTIR spectrometer (Genesis ATI, Mattson/
Unicam). UV spectra were obtained using a Beckmann DU-650 spec-
trometer. Melting points are uncorrected. Optical rotations were mea-
sured using a Polarotronic polarometer (Schmidt & Haensch). HPLC
analyses were performed using a JASCO MD-2010 plus instrument with
a chiral stationary phase column (Chiralcel OD, ODH, OJ, ADH pur-
chased from Daicel Co., Ltd.). Mass spectra were measured at 70 eV
(EI) using a Finnigan MAT 95A spectrometer. High-resolution mass
spectra (HRMS; ESI/Na+) were measured using a Bruker Daltonics
APEX II FT-ICR spectrometer. ESIMS/MS were measured using a
Bruker Daltonics Esquire 3000+. The nucleophiles 2 were prepared ac-
cording to the literature.[14,18,22]
Compound 5c: 48 h; yield 97%; 90% ee; Rf =0.25 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =+39.6 (c=2.1 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.33–7.30 (m, 2H; ArH), 7.04–6.98 (m, 2H; ArH), 6.87 (dt,
J=15.5, 7.5 Hz, 1H; 3-CH), 6.68 (m, 2H; ArH), 6.44 (m, 2H; ArH), 5.90
(dt, J=15.5, 1.5 Hz, 1H; 2-CH), 4.41 (t, J=7.0 Hz, 1H; N-CH), 4.18 (q,
J=7.0 Hz, 2H; O-CH2), 3.69 (s, 3H; O-CH3), 2.65 (m, 2H; CH2),
1.28 ppm (t, J=7.0 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=
166.1, 162.0 (J
N
ACHTUNGTRENNUNG(C,F)=
3.0 Hz), 128.0 (d, J
G
ACHTUNGTRENNUNG
General procedure for three-component vinylogous Mannich reaction
114.8, 60.58, 57.45, 55.79, 41.31, 14.35 ppm; IR (film): n˜ =3389, 3060,
3027, 2981, 2933, 2832, 1713, 1653, 1618, 1511, 1452, 1384, 1237, 1160,
1095, 1038, 982, 820, 756, 702 cmÀ1; UV/Vis (CHCl3): lmax (loge)=243
(4.115), 309 nm (3.217); MS (ESI): m/z (%): 124 (100), 344 (80) [M+H]+;
enantiomeric assay: Chiralcel AD-H, isocratic (hexane/2-propanol 95:5,
flow 0.5 mLminÀ1): l=250 nm; 42.46 (5R), 44.88 min (5S); elemental
analysis calcd (%) for C20H22FNO3: C 69.95, H 6.46, N 4.08; found: C
69.82, H 6.45, N 4.12.
(Table 5): In an oven-dried 10 mL flask,
a solution of p-anisidine
(0.40 mmol, 1.00 equiv) and chiral phosphoric acid 3d (8.0 mg,
0.012 mmol, 0.03 equiv) in a freshly prepared solvent mixture (THF,
tBuOH, 2-Me-2-BuOH 1:1:1 and 1.0 equiv H2O; 2.50 mL) was stirred for
1 min at RT, after which the respective aldehyde (0.44 mmol, 1.10 equiv)
was added and the mixture was cooled to À508C. Subsequently dienolate
2b (185 mg, 0.80 mmol, 2.00 equiv, E/Z 1:2.5) was added in one portion.
The resulting mixture was stirred rapidly for the indicated times, where-
upon the solvent was removed in vacuo. The residue was purified by
silica gel chromatography (diethyl ether/petroleum ether 1:5) to afford
the vinylogous Mannich products. In all cases, the data are given for the
2E,5S isomer (except for 5q: 2E,5R).
Compound 5d: 48 h; yield 95%; 88% ee; Rf =0.25 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =+27.6 (c=1.3 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.16–7.14 (m, 3H; ArH), 7.06 (d, J=7.0 Hz, 1H; ArH), 6.93
(dt, J=15.5, 7.5 Hz, 1H; 3-CH), 6.70 (m, 2H; ArH), 6.48 (m, 2H; ArH),
5.93 (d, J=15.5 Hz, 1H; 2-CH), 4.40 (dd, J=7.0, 6.0 Hz, 1H; N-CH),
4.19 (q, J=7.0 Hz, 2H; O-CH2), 3.80 (s, 1H; NH), 3.68 (s, 3H; O-CH3),
2.73 (ddd, J=14.5, 7.5, 6.0 Hz, 1H; CHH), 2.73 (ddd, J=14.5, 7.5, 7.0 Hz,
1H; CHH), 2.34 (s, 3H; ArCH3), 1.27 ppm (t, J=7.0 Hz, 3H; CH3);
13C NMR (100 MHz, CDCl3): d=166.2, 152.2, 144.9, 142.9, 141.2, 138.4,
128.7, 128.2, 127.0, 124.1, 123.4, 114.9, 114.8, 60.47, 57.83, 55.79, 41.40,
21.65, 14.35 ppm; IR (film): n˜ =3391, 2982, 2932, 2831, 1715, 1653, 1607,
1590, 1513, 1463, 1442, 1367, 1242, 1178, 1119, 1095, 1039, 981, 819, 788,
Compound 4b: 18 h; yield 97%; 95% ee; Rf =0.40 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =+30.7 (c=2.0 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=7.34–7.10 (m, 5H; ArH), 6.90 (dt, J=15.5, 7.5 Hz, 1H; 3-
CH), 6.68 (m, 2H; ArH), 6.46 (m, 2H; ArH), 5.91 (dt, J=15.5, 0.5 Hz,
1H; 2-CH), 4.42 (dd, J=7.5, 6.0 Hz, 1H; N-CH), 4.18 (q, J=7.0 Hz, 2H;
O-CH2), 3.69 (s, 3H; O-CH3), 2.70 (m, 2H; CH2), 1.28 ppm (t, J=7.0 Hz,
3H; CH3); 13C NMR (75 MHz, CDCl3): d=166.2, 152.4, 144.3, 142.8,
140.9, 128.9, 127.5, 126.4, 124.3, 114.8, 114.7, 60.52, 57.87, 55.82, 41.42,
14.36 ppm; IR (film): n˜ =3389, 3060, 3027, 2981, 2933, 2832, 1713, 1653,
769, 704, 521, 446 cmÀ1
; UV/Vis (CHCl3): lmax (loge)=244 (4.132),
310 nm (3.631); MS (ESI): m/z (%): 340 (35) [M+H]+, 362 (100)
[M+Na]+; enantiomeric assay: Chiralcel OD-H, isocratic (hexane/2-
propanol 90:10, flow 0.5 mLminÀ1): l=250 nm; 34.32 (5R), 36.84 min
1618, 1511, 1452, 1384, 1237, 1160, 1095, 1038, 982, 820, 756, 702 cmÀ1
;
UV/Vis (CHCl3): lmax (loge)=245 (4.343), 308 nm (3.868); MS (ESI):
m/z (%): 348 (40) [M+Na]+, 651 (10) [2M+H]+, 673 (100) [2M+Na]+;
Chem. Eur. J. 2010, 16, 2806 – 2818
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2813

C. Schneider et al.
(5S); elemental analysis calcd (%) for C21H25NO3: C 74.31, H 7.42, N
4.13; found: C 74.12, H 7.29, N 4.20.
250 nm; 10.96 (5R), 13.49 min (5S); elemental analysis calcd (%) for
C20H22N2O5: C 64.85, H 5.99, N 7.56, O 21.60; found: C 64.45, H 5.86, N
7.48, O 21.20.
Compound 5e: 6.5 h; yield 97%; 90% ee; Rf =0.35 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =+24.8 (c=1.9 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.35 (s, 1H; ArH), 7.24–7.21 (m, 3H; ArH), 6.87 (dt, J=
15.5, 7.5 Hz, 1H; 3-CH), 6.69 (m, 2H; ArH), 6.45 (m, 2H; ArH), 5.91 (d,
J=15.5 Hz, 1H; 2-CH), 4.39 (dd, J=7.5, 5.5 Hz, 1H; N-CH), 4.18 (q, J=
7.0 Hz, 2H; O-CH2), 3.70 (s, 3H; O-CH3), 2.68 (m, 2H; CH2), 1.28 ppm
(t, J=7.0 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=166.1, 152.6,
145.3, 144.0, 140.6, 134.8, 130.2, 127.7, 126.6, 124.6, 124.6, 115.0, 114.9,
60.62, 57.51, 55.82, 41.32, 14.36 ppm; IR (film): n˜ =3389, 2982, 2934, 2832,
1712, 1654, 1619, 1511, 1464, 1368, 1312, 1239, 1191, 1094, 1076, 981, 878,
819, 787, 760, 697, 402 cmÀ1; UV/Vis (CHCl3): lmax (loge)=243 (4.027),
308 nm (3.556); HRMS (ESI): m/z: calcd for C40H44Cl2N2O6Na
[2M+Na]+: 741.2470; found: 741.2470; enantiomeric assay: Chiralcel
OD-H, isocratic (hexane/2-propanol 90:10, flow 1.0 mLminÀ1): l=
250 nm; 23.81 (5R), 26.66 min (5S).
Compound 5i: 144 h; yield 88%; 90% ee; Rf =0.25 (ethyl acetate/petro-
leum ether 1:5); [a]2D2 =+14.7 (c=0.4 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.84–7.81 (m, 4H; ArH), 7.49–7.43 (m, 3H; ArH), 6.95 (dt,
J=15.5, 7.0 Hz, 1H; 3-CH), 6.68 (m, 2H; ArH), 6.51 (m, 2H; ArH), 5.94
(d, J=15.5 Hz, 1H; 2-CH), 4.59 (dd, J=7.0, 5.5 Hz, 1H; N-CH), 4.17 (q,
J=7.0 Hz, 2H; O-CH2), 3.67 (s, 3H; O-CH3), 2.77 (m, 2H; CH2),
1.27 ppm (t, J=7.0 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=
166.1, 152.4, 144.6, 141.1, 140.5, 133.6, 133.0, 128.8, 128.0, 127.8, 126.3,
125.9, 125.2, 124.5, 124.4, 115.0, 114.9, 60.52, 58.09, 55.82, 41.43,
14.36 ppm; IR (film): n˜ =3399, 3058, 2983, 2933, 2831, 1717, 1654, 1601,
1512, 1463, 1441, 1368, 1309, 1238, 1178, 1126, 1095, 1040, 982, 893, 857,
818, 787, 761, 624, 521, 478 cmÀ1; UV/Vis (CHCl3): lmax (loge)=247
(4.141), 316 nm (3.416); MS (70 eV, EI): m/z (%): 262 (100), 375 (80)
[M]+; enantiomeric assay: Chiralcel OD-H, isocratic (hexane/2-propanol
80:20, flow 1.5 mLminÀ1): l=250 nm; 18.73 (5R), 24.99 min (5S); ele-
mental analysis calcd (%) for C24H25NO3: C 76.77, H 6.71; found: C
76.56, H 6.57.
Compound 5 f: 21 h; yield 97%; 90% ee; Rf =0.30 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =+42.4 (c=1.6 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.41–7.36 (m, 1H; ArH), 7.20–7.12 (m, 3H; ArH), 6.95 (dt,
J=15.5, 7.5 Hz, 1H; 3-CH), 6.68 (m, 2H; ArH), 6.40 (m, 2H; ArH), 5.93
(d, J=15.5 Hz, 1H; 2-CH), 4.62 (dd, J=9.0, 5.0 Hz, 1H; N-CH), 4.18 (q,
J=7.0 Hz, 2H; O-CH2), 3.68 (s, 3H; O-CH3), 2.62 (m, 2H; 4-CH2), 2.43
(s, 3H; ArCH3), 1.27 ppm (t, J=7.0 Hz, 3H; CH3); 13C NMR (100 MHz,
CDCl3): d=166.2, 152.2, 145.0, 141.2, 140.6, 134.8, 127.2, 126.8, 125.3,
124.3, 114.9, 114.6, 60.55, 55.83, 53.94, 39.75, 19.25, 14.28 ppm; IR (film):
n˜ =3393, 2928, 2854, 2832, 1712, 1651, 1620, 1512, 1462, 1384, 1368, 1237,
1162, 1111, 1092, 1040, 981, 819, 782, 756, 727, 627, 552, 482 cmÀ1; UV/
Vis (CHCl3): lmax (loge)=244 (4.060), 309 nm (3.541); MS (14 eV, EI):
m/z (%): 226 (100), 340 (80) [M]+; enantiomeric assay: Chiralcel OD-H,
isocratic (hexane/2-propanol 90:10, flow 1.0 mLminÀ1): l=250 nm; 14.76
(5R), 19.84 min (5S); elemental analysis calcd (%) for C21H25NO3: C
74.31, H 7.42, N 4.13; found: C 74.45, H 7.52, N 4.15.
Compound 5j: 96 h; yield 90%; 92% ee; Rf =0.30 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =+6.6 (c=1.1 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=7.29 (dd, J=1.5, 1.5 Hz, 1H; ArH), 7.28–7.23 (m, 1H; ArH),
6.84 (dt, J=15.5, 7.5 Hz, 1H; 3-CH), 6.68 (m, 2H; CH), 6.48 (m, 2H;
ArH), 6.26 (dd, J=1.5, 0.5 Hz, 1H; ArH), 5.82 (dt, J=15.5, 1.5 Hz, 1H;
2-CH), 4.39 (t, J=6.5 Hz, 1H; N-CH), 4.10 (q, J=7.0 Hz, 2H; O-CH2),
3.65 (s, 3H; O-CH3), 2.62 (m, 2H; CH2), 1.20 ppm (t, J=7.0 Hz, 3H;
CH3); 13C NMR (100 MHz, CDCl3): d=166.2, 152.6, 144.5, 143.6, 140.9,
139.7, 127.2, 124.4, 115.3, 114.9, 108.9, 60.53, 55.84, 50.21, 39.13,
14.38 ppm; IR (film): n˜ =3399, 2929, 2854, 2832, 1719, 1654, 1512, 1464,
1441, 1368, 1312, 1243, 1206, 1165, 1096, 1041, 984, 874, 786, 600 cmÀ1
;
UV/Vis (CHCl3): lmax (loge)=244 (4.275), 289 nm (3.751); HRMS (ESI):
m/z: calcd for C18H22NO4 [M+H]+: 316.1543; found: 316.1545; enantio-
meric assay: Chiralcel OD-H, isocratic (hexane/2-propanol 95:5, flow
0.5 mLminÀ1): l=250 nm; 62.00 (5R), 66.67 min (5S).
Compound 5g: 6 h; yield 97%; 85% ee; Rf =0.25 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =+179.8 (c=2.2 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=7.56 (dd, J=7.5, 1.5 Hz, 1H; ArH); 7.40 (dd, J=7.5, 1.5 Hz,
1H; ArH); 7.24 (td, J=7.5, 1.5 Hz, 1H; ArH), 7.11 (td, J=7.5, 1.5 Hz,
1H; ArH), 6.98 (ddd, J=15.5, 7.5, 6.5 Hz, 1H; CH), 6.68 (m, 2H; ArH),
6.38 (m, 2H; ArH), 5.91 (d, J=15.5 Hz, 1H; CH), 4.83 (dd, J=8.5,
4.0 Hz, 1H; N-CH), 4.19 (q, J=7.0 Hz, 2H; O-CH2), 3.90 (s, 1H; NH),
3.68 (s, 3H; O-CH3), 2.79 (dddd, J=15.0, 6.5, 4.0, 1.5 Hz, 1H; CHH),
2.50 (dddd, J=15.0, 8.5, 7.5, 1.0 Hz, 1H; CHH), 1.28 ppm (t, J=7.0 Hz,
3H; CH3); 13C NMR (100 MHz, CDCl3): d=166.2, 152.4, 144.8, 140.6,
132.8, 130.0, 128.6, 127.5, 124.5, 123.1, 114.9, 114.7, 60.57, 56.58, 55.58,
39.37, 14.37 ppm; IR (film): n˜ =3389, 2982, 2934, 2832, 1712, 1654, 1619,
1511, 1464, 1368, 1312, 1239, 1191, 1094, 1076, 981, 878, 819, 787, 760,
697, 402 cmÀ1; UV/Vis (CHCl3): lmax (loge)=243 (4.367), 309 nm (3.540);
MS (ESI): m/z (%): 404/406 (100) [M+H]+, 426/428 (20) [M+Na]+;
enantiomeric assay: Chiralcel AD-H, isocratic (hexane/2-propanol 80:20,
flow 0.5 mLminÀ1): l=250 nm; 13.70 min (5R), 15.67 min (5S); elemental
analysis calcd (%) for C20H22BrNO3: C 59.42, H 5.48, N 3.46; found: C
59.46, H 5.76, N 3.56.
Compound 5k: 14 h; yield 97%; 89% ee; Rf =0.40 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =À51.0 (c=0.5 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=7.32 (dd, J=2.0 Hz, J=1.0 Hz, 1H; ArH), 6.89 (dt, J=15.5,
7.5 Hz, 1H; 3-CH), 6.75 (m, 2H; ArH), 6.58 (m, 2H; ArH), 6.28 (dd, J=
3.5, 2.0 Hz, 1H; ArH), 6.16 (d, J=3.5 Hz, 1H; ArH), 5.89 (dt, J=15.5,
1.5 Hz, 1H; 2-CH), 4.57 (t, J=6.5 Hz, 1H; N-CH), 4.17 (q, J=7.0 Hz,
2H; O-CH2), 3.73 (s, 3H; O-CH3), 2.62 (td, J=6.5, 1.5 Hz, 2H; 4-CH2),
1.28 ppm (t, J=7.0 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=
166.3, 154.9, 152.9, 144.2, 141.9, 140.5, 124.4, 115.6, 114.9, 110.4, 106.8,
60.51, 55.81, 52.25, 37.48, 14.38 ppm; IR (film): n˜ =3373, 2982, 2935, 2832,
1715, 1656, 1620, 1513, 1441, 1368, 1238, 1164, 1119, 1095, 1070, 1039,
982, 914, 883, 739, 598, 522; UV/Vis (CHCl3): lmax (loge)=244 (4.162),
306 nm (3.470); HRMS (ESI): m/z: calcd for C36H43N2O8 [2M+H]+:
631.3014; found: 631.3018; enantiomeric assay: Chiralcel AD-H, isocratic
(hexane/2-propanol 80:20, flow 1.0 mLminÀ1): l=250 nm; 9.07 (5S),
14.81 min (5R).
Compound 5l: 72 h; yield 95%; 84% ee; Rf =0.30 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =À11.7 (c=0.9 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=7.29 (dd, J=5.0, 3.0 Hz, 1H; ArH), 7.17–7.12 (m, 1H; ArH),
7.03 (dd, J=5.0, 1.5 Hz, 1H; ArH), 6.90 (dt, J=15.5, 7.5 Hz, 1H; 3-CH),
6.72 (m, 2H; ArH), 6.52 (m, 2H; ArH), 5.90 (dt, J=15.5, 1.5 Hz, 1H; 2-
CH), 4.58 (t, J=6.0 Hz, 1H; N-CH), 4.18 (q, J=7.0 Hz, 2H; O-CH2),
3.72 (s, 3H; O-CH3), 3.70 (s, 1H; NH), 2.77 (ddd, J=7.5, 6.0, 1.5 Hz, 2H;
CH2), 1.28 ppm (t, J=7.0 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3): d=
166.2, 152.5, 144.6, 144.3, 141.1, 126.5, 126.0, 124.3, 121.2, 115.1, 114.9,
60.50, 55.84, 53.97, 40.07, 14.36 ppm; IR (film): n˜ =3384, 3102, 2981, 2933,
2831, 1814, 1713, 1652, 1618, 1510, 1441, 1367, 1237, 1177, 1117, 1094,
1036, 982, 892, 858, 820, 787, 692, 656, 521 cmÀ1; UV/Vis (CHCl3): lmax
(loge)=244 (4.384), 309 nm (3.728); HRMS (ESI): m/z: calcd for
C36H43N2O6S2 [2M+H]+: 663.2557; found: 663.2562; enantiomeric assay:
Chiralcel OD-H, isocratic (hexane/2-propanol 80:20, flow 0.5 mLminÀ1):
l=250 nm; 30.06 (5R), 33.63 min (5S).
Compound 5h: 48 h; yield 96%; 87% ee; Rf =0.20 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =+166.7 (c=1.3 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.95 (dd, J=8.0, 1.0 Hz, 1H; ArH), 7.69 (dd, J=8.0, 1.0 Hz,
1H; ArH), 7.55 (ddd, J=8.0, 7.0, 1.0 Hz, 1H; ArH), 7.40 (ddd, J=8.0,
7.0, 1.0 Hz, 1H; ArH), 6.95 (ddd, J=15.5, 8.0, 7.0 Hz, 1H; 3-CH), 6.65
(m, 2H; ArH), 6.37 (m, 2H; ArH), 5.96 (dt, J=15.5, 1.5 Hz, 1H; 2-CH),
5.14 (dd, J=8.5, 4.5 Hz, 1H; N-CH), 4.18 (q, J=7.0 Hz, 2H; O-CH2),
3.92 (s, 1H; NH), 3.68 (s, 3H; O-CH3), 2.88 (m, 1H; CHH), 2.58 (dddd,
J=15.0, 8.5, 8.0, 1.0 Hz, 1H; CHH), 1.29 ppm (t, J=7.0 Hz, 3H; CH3);
13C NMR (100 MHz, CDCl3): d=166.0, 152.7, 149.1, 143.8, 140.1, 138.6,
133.8, 128.4, 125.2, 124.9, 124.6, 114.9, 114.7, 60.64, 55.79, 53.29, 40.31,
14.37 ppm; IR (film): n˜ =3390, 2983, 2934, 2833, 1711, 1655, 1619, 1511,
1463, 1441, 1351, 1239, 1161, 1095, 1039, 982, 820, 760, 738, 690, 627 cmÀ1
;
UV/Vis (CHCl3): lmax (loge)=247 (4.422), 296 nm (3.967); MS (ESI): m/
z (%): 371 (100) [M+H]+, 393 (95) [M+Na]+; enantiomeric assay: Chir-
alcel AD-H, isocratic (hexane/2-propanol 80:20, flow 1.0 mLminÀ1): l=
2814
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 2806 – 2818

Vinylogous Mannich Reaction
FULL PAPER
Compound 5m: 144 h; yield 81%; 90% ee; Rf =0.25 (ethyl acetate/petro-
leum ether: 1:5); [a]D22 =+18.4 (c=1.0 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=7.19 (dd, J=5.0, 1.0 Hz, 1H; ArH), 6.97–6.87 (m, 3H; CH,
3-CH, ArH), 6.74 (m, 2H; ArH), 6.58 (m, 2H; ArH), 5.91 (d, J=
15.5 Hz, 1H; 2-CH), 4.74 (t, J=6.5 Hz, 1H; N-CH), 4.18 (q, J=7.0 Hz,
2H; O-CH2), 3.72 (s, 3H; O-CH3), 2.81 (t, J=6.5 Hz, 2H; CH2),
1.28 ppm (t, J=7.0 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=
166.1, 152.8, 147.8, 144.1, 140.7, 127.0, 124.6, 124.3, 124.0, 115.5, 114.9,
60.50, 55.77, 54.15, 41.09, 14.34 ppm; IR (film): n˜ =3379, 3104, 3066, 3031,
2982, 2934, 2903, 2831, 1712, 1653, 1617, 1592, 1513, 1483, 1441, 1408,
1368, 1239, 1176, 1116, 1094, 1038, 980, 851, 820, 794, 757, 704, 578,
521 cmÀ1; UV/Vis (CHCl3): lmax (loge)=244 (4.162), 306 nm (3.470);
HRMS (ESI): m/z: calcd for C18H22NO3S [M+H]+: 332.1315; found:
332.1316; enantiomeric assay: Chiralcel OD-H, isocratic (hexane/2-prop-
anol 90:10, flow 1.0 mLminÀ1): l=250 nm; 24.25 (5R), 27.20 min (5S).
CDCl3): d=6.97 (dt, J=15.5, 7.5 Hz, 1H; 3-CH), 6.79 (m, 2H; ArH),
6.55 (m, 2H; ArH), 5.86 (d, J=15.5 Hz, 1H; 2-CH), 4.19 (q, J=7.0 Hz,
2H; O-CH2), 3.76 (s, 3H; O-CH3), 3.65 (pent, J=6.5 Hz, 1H; N-CH),
3.22 (s, 1H; NH), 2.44 (m, 2H; CH2), 1.60–1.00 (m, 15H; (CH2)6, CH3),
0.88 ppm (t, J=6.5 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=
166.5, 152.2, 145.6, 141.5, 123.8, 115.2, 114.9, 60.41, 55.96, 53.34, 37.75,
34.75, 31.93, 29.71, 29.37, 26.22, 22.77, 14.41, 14.23 ppm; IR (film): n˜ =
3389, 2928, 2855, 1719, 1652, 1511, 1464, 1368, 1317, 1242, 1178, 1095,
1043, 983, 877, 819, 787, 762 cmÀ1; UV/Vis (CHCl3): lmax (loge)=244
(3.989), 310 nm (3.426); MS (ESI): m/z (%): 348 (80) [M+H]+, 360 (100)
[M+Na]+; enantiomeric assay: Chiralcel AD-H, isocratic (hexane/2-
propanol 98:2, flow 0.5 mLminÀ1): l=250 nm; 30.31 (5R), 32.96 min
(5S); elemental analysis calcd (%) for C21H33NO3: C 72.58, H 9.57, N
4.03; found: C 72.54, H 9.72, N 3.78.
General procedure for two-component vinylogous Mannich reaction
(Table 6): An oven-dried, 10 mL flask containing a solution of aldimine
(0.400 mmol, 1.00 equiv) and chiral phosphoric acid 3d (13.4 mg,
0.020 mmol, 0.05 equiv) in a freshly prepared solvent mixture (THF,
tBuOH, 2-Me-2-BuOH 1:1:1 and H2O (1.0 equiv); 2.50 mL) was cooled
to À308C. Subsequently dienolate (3E)-2g (290 mg, 1.20 mmol,
3.00 equiv) was added in one portion. The resulting mixture was stirred
rapidly at À308C for 72 h after which the solvent was removed in vacuo.
The residue was purified by silica gel chromatography (ethyl acetate/pe-
troleum ether 1:10) to afford vinylogous Mannich product in the indicat-
ed yield and ee values. In all cases, the data is given for the 2E,4S,5S
isomer.
Compound 5n: 72 h; yield 91%; 82% ee; Rf =0.50 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =+21.2 (c=0.4 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=6.95 (dt, J=15.5, 7.5 Hz, 1H; 3-CH), 6.72 (m, 2H; ArH),
6.52 (m, 2H; ArH), 5.80 (dt, J=15.5, 1.0 Hz, 1H; 2-CH), 4.12 (q, J=
7.0 Hz, 2H; O-CH2), 3.73 (s, 3H; O-CH3), 3.19 (s, 1H; NH), 3.15 (dd, J=
9.0, 4.0 Hz, 1H; N-CH), 2.58 (dddd, J=14.5, 7.5, 4.0, 1.0 Hz, 1H; CHH),
2.20 (dddd, J=14.5, 9.0, 7.5, 1.0 Hz, 1H; CHH), 1.20 (t, J=7.0 Hz, 3H;
CH3), 0.96 ppm (s, 9H; CACTHNUTRGNEUNG
(CH3)3); 13C NMR (75 MHz, CDCl3): d=166.4,
151.8, 147.6, 143.3, 122.8, 115.1, 114.5, 62.91, 60.22, 55.94, 36.20, 35.20,
27.08, 14.36 ppm; IR (film): n˜ =3395, 2956, 2831, 1713, 1650, 1618, 1511,
1440, 1367, 1234, 1159, 1095, 1042, 979, 817, 752, 522 cmÀ1; UV/Vis
(CHCl3): lmax (loge)=245 (3.995), 315 nm (3.411); HRMS (ESI): m/z:
calcd for C18H28NO3 [M+H]+: 306.2064; found: 306.2063; enantiomeric
assay: Chiralcel OD-H, isocratic (hexane/2-propanol 95:5, flow
0.5 mLminÀ1): l=250 nm; 20.69 (5R), 22.41 min (5S).
Compound anti-7a: 48 h; yield 97%; anti/syn: 88:12, anti: 94% ee; Rf =
0.40 (ethyl acetate/petroleum ether 1:5); [a]2D2 =À33.2 (c=0.7 in CH2Cl2);
1H NMR (400 MHz, CDCl3): d=7.26–7.23 (m, 2H; ArH), 7.14 (m, 2H;
ArH), 6.93 (dd, J=15.5, 7.5 Hz, 1H; CH), 6.71 (m, 2H; ArH), 6.49 (m,
2H; ArH), 5.93 (dd, J=15.5, 1.5 Hz, 1H; CH), 4.19 (q, J=7.0 Hz, 2H;
O-CH2), 4.13 (d, J=7.0 Hz, 1H; N-CH), 3.82 (s, 1H; NH), 3.67 (s, 3H;
O-CH3), 2.66–2.59 (m, 3H), 1.30 (t, J=7.0 Hz, 3H; CH3), 1.24 (t, J=
7.5 Hz, 3H; CH3), 1.04 ppm (d, J=6.5 Hz, 3H; CH3); 13C NMR
(100 MHz, CDCl3): d=166.4, 152.1, 150.7, 143.3, 141.5, 139.1, 128.1,
127.3, 122.4, 114.8, 114.8, 62.95, 60.53, 55.85, 40.08, 28.59, 17.17, 15.51,
14.39 ppm; IR (film): n˜ =3399, 2929, 1713, 1650, 1504, 1441, 1384, 1039,
Compound 5o: 48 h; yield 91%; 80% ee; Rf =0.50 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =+48.5 (c=0.4 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=6.96 (dt, J=15.5, 7.0 Hz, 1H; 3-CH), 6.75 (m, 2H; ArH),
6.52 (m, 2H; ArH), 5.84 (d, J=15.5 Hz, 1H; 2-CH), 4.17 (q, J=7.0 Hz,
2H; O-CH2), 3.74 (s, 3H; O-CH3), 3.28 (m, 2H; N-CH, NH), 2.44 (dddd,
J=14.5, 9.0, 7.0, 1.5 Hz, 1H; CHH), 2.34 (dddd, J=14.5, 7.0, 7.0, 1.5 Hz,
1H; CHH), 1.87 (m, 1H; CH), 1.27 (t, J=7.0 Hz, 3H; CH3), 1.27 (d, J=
7.0 Hz, 3H; CH3), 1.27 ppm (d, J=7.0 Hz, 3H; CH3); 13C NMR
(100 MHz, CDCl3): d=166.4, 151.0, 146.2, 141.9, 123.4, 115.1, 114.8,
60.30, 58.77, 55.89, 34.16, 30.78, 18.80, 18.43, 14.34 ppm; IR (film): n˜ =
3391, 2958, 2831, 1714, 1651, 1619, 1512, 1441, 1386, 1235, 1177, 1095,
1041, 981, 819, 755, 712, 586, 520 cmÀ1; UV/Vis (CHCl3): lmax (loge)=245
(4.028), 315 nm (3.464); MS (ESI): m/z (%): 292 (50) [M+H]+, 314 (100)
[M+Na]+; enantiomeric assay (determination after reduction with diiso-
butylaluminium hydride (DIBAL) to corresponding allyl alcohol): Chiral-
cel OD-H, isocratic (hexane/2-propanol 80:20, flow 1.0 mLminÀ1): l=
250 nm; 6.57 (5S), 7.72 min (5R); elemental analysis calcd (%) for
C17H25NO3: C 70.07, H 8.65, N 4.81; found: C 69.96, H 8.48, N 4.81.
876, 819, 767, 554 cmÀ1
; UV/Vis (CHCl3): lmax (loge)=246 (4.220),
310 nm (3.686); HRMS (ESI): m/z: calcd for C23H30NO3 [M+H]+:
368.2220; found: 368.2220; enantiomeric assay: Chiralcel OD, isocratic
(hexane/2-propanol 95:5, flow 0.5 mLminÀ1): l=250 nm; 19.73 (4S,5S),
23.48 min (4R,5R).
Compound anti-7b: Yield 75%; anti/syn: 94:6, anti: 96% ee; Rf =0.50
(ethyl acetate/petroleum ether 1:5); [a]2D2 =À6.5 (c=1.2 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.31–7.22 (m, 5H; ArH), 6.95 (dd, J=
16.0, 8.0 Hz, 1H; CH), 6.66 (m, 2H; ArH), 6.44 (m, 2H; ArH), 5.93 (dd,
J=16.0, 1.5 Hz, 1H; CH), 4.18 (q, J=7.0 Hz, 2H; O-CH2), 4.15 (d, J=
7.0 Hz, 1H; N-CH), 3.67 (s, 3H; O-CH3), 2.69 (m, 1H; CH), 1.30 (t, J=
7.0 Hz, 3H; CH3), 1.04 ppm (d, J=6.0 Hz, 3H; CH3); 13C NMR
(100 MHz, CDCl3): d=166.4, 152.2, 150.4, 141.9, 141.4, 128.6, 127.4,
127.3, 122.5, 114.8, 114.8, 63.25, 60.58, 55.85, 44.05, 17.17, 14.38 ppm; IR
(film): n˜ =3401, 2980, 2933, 2832, 1715, 1650, 1513, 1453, 1384, 1280,
1180, 1040, 985, 820, 788, 762, 702 cmÀ1; UV/Vis (CHCl3): lmax (loge)=
245 (4.229), 309 nm (3.656); HRMS (ESI): m/z: calcd for C21H26NO3
[M+H]+: 340.1907; found: 340.1907; enantiomeric assay: Chiralcel OD-
H, isocratic (hexane/2-propanol 95:5, flow 0.5 mLminÀ1): l=250 nm;
25.49 (4S,5S), 29.25 min (4R,5R).
Compound 5p: 72 h; yield 89%; 87% ee; Rf =0.50 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =+16.5 (c=0.6 in CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=6.96 (dt, J=15.5, 7.0 Hz, 1H; 3-CH), 6.75 (m, 2H; ArH),
6.52 (m, 2H; ArH), 5.84 (dt, J=15.5, 1.5 Hz, 1H; 2-CH), 4.17 (q, J=
7.0 Hz, 2H; O-CH2), 3.74 (s, 3H; O-CH3), 3.38 (s, 1H; NH), 3.26 (ddd,
J=9.0, 5.5, 5.5 Hz, 1H; N-CH), 2.44 (dddd, J=14.5, 9.0, 7.0, 1.5 Hz, 1H;
CHH), 2.34 (dddd, J=14.5, 7.0, 5.5, 1.5 Hz, 1H; CHH), 1.85–1.00 ppm
(m, 14H); 13C NMR (100 MHz, CDCl3): d=166.5, 151.9, 146.3, 142.0,
123.5, 115.2, 114.7, 60.35, 58.32, 55.93, 41.24, 34.41, 29.56, 29.19, 26.65,
26.44, 26.41, 14.41 ppm; IR (film): n˜ =3392, 2980, 2926, 2851, 1715, 1651,
1618, 1511, 1448, 1367, 1317, 1237, 1179, 1113, 1096, 1042, 978, 892, 818,
754, 520 cmÀ1; UV/Vis (CHCl3): lmax (loge)=246 (4.062), 313 nm (3.505);
MS (ESI): m/z (%): 332 (50) [M+H]+, 354 (100) [M+Na]+; enantiomeric
assay (determination after reduction with DIBAL to corresponding allyl
alcohol): Chiralcel OD-H, isocratic (hexane/2-propanol 80:20, flow
1.0 mLminÀ1): l=250 nm; 6.53 (5S), 7.65 min (5R); elemental analysis
calcd (%) for C20H29NO3: C 72.47, H 8.82, N 4.23; found: C 72.37, H
8.47, N 4.23.
Compound anti-7c: Yield 35%; anti/syn: 88:12, anti: 92% ee; Rf =0.40
(ethyl acetate/petroleum ether 1:5); [a]2D2 =À36.5 (c=0.2 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.30–7.25 (m, 4H; ArH), 6.89 (dd, J=
16.0, 8.0 Hz, 1H; CH), 6.66 (m, 2H; ArH), 6.41 (m, 2H; ArH), 5.93 (dd,
J=16.0, 1.5 Hz, 1H; CH), 4.21 (q, J=7.0 Hz, 2H; O-CH2), 4.14 (d, J=
7.0 Hz, 1H; N-CH), 3.67 (s, 3H; O-CH3), 2.64 (m, 1H; CH), 1.30 (t, J=
7.0 Hz, 3H; CH3), 1.04 ppm (d, J=7.0 Hz, 3H; CH-CH3); 13C NMR
(75 MHz, CDCl3): d=166.2, 152.3, 149.7, 141.1, 139.3, 133.2, 128.9, 128.7,
122.9, 115.5, 114.8, 62.99, 60.63, 55.80, 43.68, 16.97, 14.36 ppm; IR (film):
n˜ =3398, 2980, 2932, 2832, 1716, 1651, 1595, 1512, 1489, 1463, 1409, 1384,
1242, 1180, 1014, 1038, 1014, 982, 819, 761, 521 cmÀ1; UV/Vis (CHCl3):
Compound 5q: 72 h; yield 88%; 70% ee; Rf =0.50 (ethyl acetate/petrole-
um ether 1:5); [a]2D2 =+30.6 (c=0.4 in CH2Cl2); 1H NMR (300 MHz,
Chem. Eur. J. 2010, 16, 2806 – 2818
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2815

C. Schneider et al.
lmax (loge)=244 (3.995), 310 nm (3.402); HRMS (ESI): m/z: calcd for
C21H25ClNO3 [M+H]+: 374.1517; found: 374.1515; enantiomeric assay:
Chiralcel OD-H, isocratic (hexane/2-propanol 95:5, flow 0.5 mLminÀ1):
l=250 nm; 30.57 (4S,5S), 40.61 min (4R,5R).
Compound anti-7h: Yield 96%; anti/syn: 90:10, anti: 93% ee; Rf =0.20
(ethyl acetate/petroleum ether 1:2, 10% NEt3); [a]2D2 =À6.0 (c=1.3 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=8.60 (d, J=2.0 Hz, 1H; ArH),
8.50 (dd, J=5.0, 2.0 Hz, 1H; ArH); 7.66 (dt, J=8.0, 2.0 Hz, 1H; ArH),
7.21 (dd, J=8.0, 5.0 Hz, 1H; ArH), 6.90 (dd, J=15.5, 8.5 Hz, 1H; CH),
6.65 (m, 2H; ArH), 6.41 (m, 2H; ArH), 5.90 (dd, J=15.5, 1.5 Hz, 1H;
CH), 4.22–4.15 (m, 3H; N-CH, O-CH2), 3.93 (s, 1H; NH), 3.64 (s, 3H;
O-CH3), 2.67 (m, 1H; CH), 1.28 (t, J=7.0 Hz, 3H; CH3), 1.04 ppm (d,
J=6.5 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=166.1, 152.5,
149.4, 149.1, 148.8, 140.6, 137.3, 134.6, 123.6, 123.0, 114.9, 114.8, 60.91,
60.54, 55.68, 43.66, 16.94, 14.26 ppm; IR (film): n˜ =3369, 2927, 2854, 1716,
1651, 1590, 1577, 1512, 1463, 1426, 1383, 1243, 1180, 1095, 1038, 984, 787,
716 cmÀ1; UV/Vis (CHCl3): lmax (loge)=244 (4.262), 289 nm (3.755);
HRMS (ESI): m/z: calcd for C20H25N2O3 [M+H]+: 341.1860; found:
341.1858; enantiomeric assay: Chiralcel OJ, isocratic (hexane/2-propanol
90:10, flow 1.0 mLminÀ1): l=250 nm; 44.42 (4S,5S), 54.11 min (4R,5R).
Compound anti-7d: Yield 77%; anti/syn: 91:9, anti: 97% ee; Rf =0.50
(ethyl acetate/petroleum ether 1:5); [a]2D2 =À15.6 (c=2.7 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.24–7.04 (m, 4H; ArH), 6.99 (dd, J=
16.0, 8.0 Hz, 1H; CH), 6.68 (m, 2H; ArH), 6.48 (m, 2H; ArH), 5.93 (dd,
J=16.0, 1.5 Hz, 1H; CH), 4.22 (q, J=7.0 Hz, 2H; O-CH2), 4.13 (d, J=
6.5 Hz, 1H; N-CH), 3.67 (s, 3H; O-CH3), 2.66 (m, 1H; CH), 2.34 (s, 3H;
CH3), 1.31 (t, J=7.0 Hz, 3H; CH3), 1.04 ppm (d, J=6.5 Hz, 3H; CH3);
13C NMR (100 MHz, CDCl3): d=166.4, 152.1, 150.6, 141.8, 141.3, 137.9,
128.4, 128.3, 128.0, 124.5, 122.4, 115.9, 114.8, 66.31, 60.47, 55.75, 43.93,
21.61, 17.13, 14.33 ppm; IR (film): n˜ =3399, 2931, 2831, 1713, 1650, 1606,
1512, 1442, 1384, 1242, 1180, 1094, 1037, 985, 865, 819, 788, 766, 704 cmÀ1
;
UV/Vis (CHCl3): lmax (loge)=244 (4.107), 312 nm (3.552); HRMS (ESI):
m/z: calcd for C22H28NO3 [M+H]+: 354.2064; found: 354.2064; enantio-
meric assay: Chiralcel OJ, isocratic (hexane/2-propanol 95:5, flow
0.5 mLminÀ1): l=250 nm; 17.93 (4S,5S), 19.81 min (4R,5R).
Compound anti-7i: Yield 65%; anti/syn: 74:26, anti: 91% ee; Rf =0.40
(ethyl acetate/petroleum ether 1:5); [a]2D2 =À7.8 (c=1.8 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.37–7.35 (m, 1H; ArH), 7.33–7.29 (m,
1H; ArH), 6.95 (dd, J=16.0, 7.5 Hz, 1H; CH), 6.74 (m, 2H; ArH), 6.53
(m, 2H; ArH), 6.34–6.31 (m, 1H; ArH), 5.85 (dd, J=16.0, 1.0 Hz, 1H;
CH), 4.26 (d, J=6.5 Hz, 1H; N-CH), 4.23 (q, J=7.5 Hz, 2H; O-CH2),
3.71 (s, 3H; O-CH3), 2.71 (m, 1H; CH), 1.30 (t, J=7.5 Hz, 3H; CH3),
1.12 ppm (d, J=6.5 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=
166.5, 152.5, 150.4, 143.4, 141.4, 140.4, 126.2, 122.5, 115.2, 114.9, 109.3,
60.56, 55.87, 55.54, 42.20, 16.25, 14.39 ppm; IR (film): n˜ =3389, 3055,
2981, 2933, 2903, 2831, 1712, 1651, 1619, 1562, 1511, 1460, 1437, 1384,
Compound anti-7e: Yield 43%; anti/syn: 94:6, anti: 93% ee; Rf =0.40
(ethyl acetate/petroleum ether 1:5); [a]2D2 =À11.9 (c=1.2 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.33 (m, 1H; ArH), 7.22–7.17 (m, 3H;
ArH), 6.98 (dd, J=16.0, 8.0 Hz, 1H; CH), 6.67 (m, 2H; ArH), 6.41 (m,
2H; ArH), 5.93 (dd, J=16.0, 1.0 Hz, 1H; CH), 4.23 (q, J=7.0 Hz, 2H;
O-CH2), 4.11 (d, J=6.5 Hz, 1H; N-CH), 3.67 (s, 3H; O-CH3), 2.65 (m,
1H; CH), 1.30 (t, J=7.0 Hz, 3H; CH3), 1.07 ppm (d, J=6.5 Hz, 3H;
CH3); 13C NMR (100 MHz, CDCl3): d=166.2, 152.5, 149.7, 144.4, 141.0,
134.7, 129.9, 127.8, 127.4, 125.6, 122.9, 114.9, 114.9, 62.90, 60.66, 55.85,
43.94, 17.20, 14.38 ppm; IR (film): n˜ =3398, 2981, 2934, 2833, 1714, 1651,
1621, 1595, 1512, 1465, 1384, 1369, 1243, 1180, 1095, 1038, 984, 820, 787,
763, 698 cmÀ1; UV/Vis (CHCl3): lmax (loge)=243 (4.007), 308 nm (3.502);
HRMS (ESI): m/z: calcd for C21H25ClNO3 [M+H]+: 374.1517; found:
374.1518; enantiomeric assay: Chiralcel OD-H, isocratic (hexane/2-prop-
anol 95:5, flow 0.5 mLminÀ1): l=250 nm; 29.12 (4S,5S), 32.45 min
(4R,5R).
1363, 1310, 1239, 1179, 1128, 1094, 1073, 1038, 980, 911, 755, 662 cmÀ1
;
UV/Vis (CHCl3): lmax (loge)=244 (4.362); 311 nm (3.645); HRMS (ESI):
m/z: calcd for C19H24NO4 [M+H]+: 330.1700; found: 330.1699; enantio-
meric assay: Chiralcel OD-H, isocratic (hexane/2-propanol 95:5, flow
0.5 mLminÀ1): l=250 nm; 29.94 (4S,5S), 39.57 min (4R,5R).
Compound anti-7j: Yield 83%; anti/syn: 88:12, anti: 93% ee; Rf =0.40
(ethyl acetate/petroleum ether 1:5); [a]2D2 =À59.7 (c=2.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.36–7.34 (m, 1H; ArH), 6.95 (dd, J=
16.0, 7.5 Hz, 1H; CH), 6.74 (m, 2H; ArH), 6.53 (m, 2H; ArH), 6.30–6.27
(m, 1H; ArH), 6.18–6.15 (m, 1H; ArH), 5.92 (dd, J=16.0, 1.0 Hz, 1H;
CH), 4.34 (d, J=6.5 Hz, 1H; N-CH), 4.22 (q, J=7.5 Hz, 2H; O-CH2),
3.71 (s, 3H; O-CH3), 2.92 (m, 1H; CH), 1.30 (t, J=7.5 Hz, 3H; CH3),
1.12 ppm (d, J=6.5 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=
166.5, 154.5, 152.6, 150.3, 141.8, 141.4, 122.5, 115.4, 114.9, 110.3, 107.7,
60.53, 57.50, 55.83, 41.33, 16.38, 14.37 ppm; IR (film): n˜ =3373, 2979,
2935, 2905, 2833, 1711, 1652, 1619, 1513, 1464, 1369, 1242, 1182, 1097,
1037, 984, 923, 883, 867, 737, 599, 520 cmÀ1; UV/Vis (CHCl3): lmax
(loge)=245 (4.180), 306 nm (3.665); HRMS (ESI): m/z: calcd for
C19H24NO4 [M+H]+: 330.1700; found: 330.1700; enantiomeric assay:
Chiralcel AD-H, isocratic (hexane/2-propanol 95:5, flow 0.5 mLminÀ1):
l=250 nm; 24.16 (4R,5R), 25.55 min (4S,5S).
Compound anti-7 f: Yield 44%; anti/syn: 88:12, anti: 90% ee; Rf =0.45
(ethyl acetate/petroleum ether 1:5); [a]2D2 =À11.0 (c=0.8 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.34–7.12 (m, 4H; ArH), 6.99 (dd, J=
16.0, 7.5 Hz, 1H; CH), 6.68 (m, 2H; ArH), 6.38 (m, 2H; ArH), 5.94 (dd,
J=16.0, 1.0 Hz, 1H; CH), 4.47 (d, J=6.5 Hz, 1H; N-CH), 4.21 (q, J=
7.0 Hz, 2H; O-CH2), 3.79 (s, 3H; O-CH3), 2.73 (m, 1H; CH), 2.47 (s,
3H; CH3), 1.31 (t, J=7.0 Hz, 3H; CH3), 1.14 ppm (d, J=6.5 Hz, 3H;
CH3); 13C NMR (100 MHz, CDCl3): d=166.3, 152.1, 150.1, 141.5, 140.0,
135.2, 130.8, 127.0, 126.6, 126.3, 122.6, 114.8, 114.6, 60.48, 58.91, 55.75,
43.08, 19.62, 16.84, 14.33 ppm; IR (film): n˜ =3398, 2978, 2831, 1713, 1650,
1620, 1513, 1462, 1384, 1368, 1241, 1181, 1037, 983, 867, 818, 790, 761,
730, 647, 556, 521, 462 cmÀ1; UV/Vis (CHCl3): lmax (loge)=244 (4.072),
299 nm (3.454); HRMS (ESI): m/z: calcd for C22H28NO3 [M+H]+:
354.2064; found: 354.2062; enantiomeric assay: Chiralcel AD-H, isocratic
(hexane/2-propanol 95:5, flow 0.25 mLminÀ1): l=250 nm; 36.42 (4R,5R),
38.87 min (4S,5S).
Determination of the relative configuration of 7 through conversion into
(5S,6S)-8: A solution of (BDP)CuH solution (BDP=1,2-bis(diphenyl-
phosphino)benzene; 0.60 mL, 1m in toluene, preparing following proce-
dure)[23] was added dropwise to an oven-dried 2 mL test tube that con-
tained a solution of (2E,4S,5S)-7 (110 mg, 0.30 mmol, anti/syn 3.5:1, anti:
91% ee) and tBuOH (88 mL, 3 equiv) in dry, degassed toluene (1 mL) at
RT. The solution was stirred for 24 h at RT and the solvent was removed
in vacuo. A mixture of MeOH/HCl (2n)/THF (7 mL, 5:1:1) was added to
the residue and heated to reflux for 48 h. The solution was extracted two
times with ethyl acetate (10 mL) and the combined organic phases were
washed with 1n HCl (10 mL), dried over MgSO4, filtered, and the sol-
vent was removed in vacuo. The residue was purified by short silica gel
chromatography (ethyl acetate/petroleum ether 1:5 to ethyl acetate) to
afford the (5,6)-trans-piperidin-2-one in 57% yield (55 mg, 91% ee) and
(5,6)-cis-piperidin-2-one in 11% yield (11 mg). Rf =0.15 (ethyl acetate/
petroleum ether 1:1); [a]2D2 =À117.2 (c=0.7 in CH2Cl2); 1H NMR
(300 MHz, CDCl3): d=7.07 (m, 4H; ArH), 6.90 (m, 2H; ArH), 6.70 (m,
2H; ArH), 4.39 (d, J=6.5 Hz, 1H; CH), 3.70 (s, 3H; O-CH3), 2.69 (t, J=
7.0 Hz, CH2), 2.59 (t, J=7.0 Hz, 2H; Ar-CH2), 2.13 (m, 1H; CH), 1.99
(m, 1H; CHH), 1.64 (ddt, J=14.0, 7.0, 7.0 Hz, 1H; CHH), 1.24 (t, J=
Compound anti-7g: Yield 82%; anti/syn: 91:9, anti: 92% ee; Rf =0.40
(ethyl acetate/petroleum ether 1:5); [a]2D2 =+82.0 (c=0.8 in CH2Cl2);
1H NMR (400 MHz, CDCl3): d=7.87 (d, J=8.0 Hz, 1H; ArH), 7.26–7.22
(m, 2H; ArH), 6.97–6.91 (m, 3H; ArH, CH), 6.68 (m, 2H; ArH), 6.36
(m, 2H; ArH), 5.90 (dd, J=16.0, 1.0 Hz, 1H; CH), 4.56 (d, J=6.5 Hz,
1H; N-CH), 4.21 (q, J=7.0 Hz, 2H; O-CH2), 3.93 (d, J=6.5 Hz, NH),
3.67 (s, 3H; O-CH3), 2.83 (m, 1H; CH), 1.31 (t, J=7.0 Hz, 3H; CH3),
1.14 ppm (d, J=7.0 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=
166.2, 152.2, 148.7, 143.2, 140.8, 139.9, 129.3, 128.7, 128.5, 123.1, 114.9,
114.8, 100.1, 65.58, 60.53, 55.75, 42.10, 16.88, 14.34 ppm; IR (film): n˜ =
3398, 2980, 2932, 2832, 1716, 1651, 1595, 1512, 1489, 1463, 1409, 1384,
1242, 1180, 1014, 1038, 1014, 982, 819, 761, 521 cmÀ1; UV/Vis (CHCl3):
lmax (loge)=244 (4.086), 299 nm (3.574); HRMS (ESI): m/z: calcd for
C21H25INO3 [M+H]+: 466.0874; found: 466.0871; enantiomeric assay:
Chiralcel OD-H, isocratic (hexane/2-propanol 95:5, flow 0.5 mLminÀ1):
l=250 nm; 21.13 (4S,5S), 25.08 min (4R,5R).
2816
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 2806 – 2818

Vinylogous Mannich Reaction
FULL PAPER
7.5 Hz, 3H; Ar-CH2), 1.14 ppm (d, J=7.0 Hz, 3H; CH3), 13C NMR
(75 MHz, CDCl3): d=171.0, 158.0, 143.5, 138.6, 135.3, 128.8, 127.9, 127.4,
114.2, 72.42, 55.37, 36.44, 30.86, 28.48, 25.76, 18.54, 15.42 ppm; IR (film):
n˜ =3434, 2961, 2931, 2873, 1722, 1654, 1607, 1510, 1498, 1456, 1440, 1405,
1384, 1337, 1283, 1243, 1215, 1172, 1148, 1037, 938, 827, 798, 770,
541 cmÀ1; UV/Vis (CHCl3): lmax (loge)=242 (3.842), 268 nm (3.490);
HRMS (ESI): m/z: calcd for C21H26NO3 [M+H]+: 324.1958; found:
368.1958.
n˜ =3054, 2962, 2927, 2851, 1607, 1453, 1401, 1376, 1249, 1041, 749 cmÀ1
;
UV/Vis (CHCl3): lmax (loge)=232 nm (4.463); MS (ESI): m/z (%): 635
(10) [M+H]+, 657 (100) [M+Na]+; elemental analysis calcd (%) for
C46H50O2: C 87.02, H 7.94; found: C 87.15, H 8.07.
3,3’-(4-tert-Butyl-2,6-dimethylphenyl)-2,2’-dihydroxy-1,1’-binaphthyl (13):
A precooled solution (08C) of BBr3 (1.5 mL, 15.8 mmol, 5.0 equiv) was
added dropwise to an oven-dried, 250 mL flask containing a solution of
12 (2.05 g, 2.84 mmol, 1.0 equiv) in dry CH2Cl2 (100 mL) at 08C under a
nitrogen atmosphere. The solution was stirred for 2 h at 08C and 48 h at
RT, after which H2O (100 mL) was added carefully at 08C. The resulting
mixture was stirred for 10 min and extracted three times with CH2Cl2
(100 mL). The combined organic phases were dried over MgSO4, filtered,
and the solvent was removed in vacuo. The residue was purified by short
silica gel chromatography (CH2Cl2/petroleum ether 1:4) to afford the title
compound in 99% (1.93 g) yield as white foam. Rf =0.40 (CH2Cl2/petro-
leum ether 1:2); [a]2D2 =+26.0 (c=0.5 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.91 (d, J=8.0 Hz, 2H), 7.82 (s, 2H), 7.39 (ddd, J=8.0, 6.5,
1.5 Hz, 2H), 7.32 (ddd, J=8.0, 6.5, 1.5 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H),
7.21 (s, 4H), 5.01 (s, 2H; OH), 2.19 (s, 6H; CH3), 2.11 (s, 6H; CH3),
Determination of the absolute configuration of vinylogous Mannich
products through conversion into (1S,3E)-6: [CeACHTNURTGENNUG(NO3)6ACHTUGNTERN(NUGN NH4)2] (CAN;
822 mg, 1.5 mmol, 5 equiv) in H2O (6 mL) was added to a solution of
(2E,5S)-4a (93 mg, 0.30 mmol, 1.0 equiv, 83% ee) in CH3CN (7.5 mL) at
08C. The solution was stirred for 4 h at 08C. Boc2O (785 mg, 3.6 mmol,
12 equiv) was added and the solution was stirred for another 18 h at RT.
Saturated NaHCO3 solution (5 mL/0.1 mmol) was added to the mixture
and extracted three times with ethyl acetate (10 mL), and the combined
organic phases were washed with saturated NaCl solution (10 mL), dried
over MgSO4, filtered, and the solvent was removed in vacuo to afford the
title compound in 63% yield (83% ee). Rf =0.55 (ethyl acetate/petroleum
ether 1:5); [a]2D2 =À23.0 (c=0.4 in CH2Cl2), ref. [16]: for (R) (>99% ee):
[a]2D2 =+27.4 (c=0.4 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.40–
7.23 (m, 5H; ArH), 6.84 (dt, J=15.5, 7.0 Hz, 1H; CH), 5.86 (d, J=
15.5 Hz, 1H; CH), 4.82 (m, 2H; NH, N-CH), 3.70 (s, 3H; O-CH3), 2.69
1.37 ppm (s, 18H; CACTHNUTRGNEUNG
(CH3)3); 13C NMR (100 MHz, CDCl3): d=151.0,
150.1, 136.9, 136.8, 133.6, 132.9, 130.7, 129.7, 129.5, 128.4, 126.9, 124.9,
124.8, 124.7, 123.9, 113.2, 34.57, 31.53, 21.06, 20.98 ppm; IR (KBr): n˜ =
3524, 3498, 3391, 3055, 2962, 2885, 1622, 1604, 1571, 1495, 1482, 1437,
1379, 1361, 1313, 1278, 1261, 1246, 1195, 1179, 1145, 1115, 1061, 1024,
992, 973, 930, 907, 868, 852, 820, 786, 749 cmÀ1; UV/Vis (CHCl3): lmax
(loge)=234 (4.051), 244 (4.667), 291 (3.991), 333 nm (3.956); MS (ESI):
m/z (%): 605 (100) [MÀH]À; elemental analysis calcd (%) for C44H46O2:
C 87.09, H 7.64; found: C 87.07, H 7.83.
(m, 2H; CH2), 1.41 ppm (s, 9H; CACHTNUGRTNEUNG
(CH3)3); 13C NMR (100 MHz, CDCl3):
d=166.6, 155.1, 144.4, 141.1, 128.9, 127.7, 126.4, 123.9, 79.97, 53.89, 51.64,
39.50, 28.45 ppm; IR (film): n˜ =3385, 3063, 3035, 2963, 2928, 2852, 1720,
1680, 1517, 1458, 1439, 1390, 1366, 1315, 1294, 1267, 1222, 1172, 1020,
980, 758, 702, 676, 562, 524 cmÀ1; UV/Vis (CHCl3): lmax (loge)=238
(3.367), 241 (3.366), 295 nm (2.597); HRMS (ESI): m/z: calcd for
C18H28NO3 [M+H]+: 306.2064; found: 306.2063.
Phosphoric acid (R)-3d: POCl3 (1.37 g, 820 mL, 8.91 mmol, 3.0 equiv)
was added carefully to an ice-cooled stirred solution of 13 (1.80 g,
2.97 mmol, 1.0 equiv) in dry pyridine (20 mL), and the reaction mixture
was stirred for 18 h at RT. The reaction mixture was cooled to 08C, and
H2O (2.0 mL, 0.1 mol) was added carefully and the mixture was stirred
for another 24 h at RT. The mixture was treated with 1n HCl (20 mL)
and the mixture was stirred for 5 h and extracted two times with Et2O
(50 mL). The combined organic phases were washed five times with 1n
HCl (25 mL), dried over MgSO4, filtered, and the solvent was removed
in vacuo to afford the title compound in 91% (1.89 g) yield as gray
powder. Rf =0.05 (CH2Cl2); [a]2D2 =À87.7 (c=1.0 in CH2Cl2); 1H NMR
(300 MHz, CDCl3): d=9.92 (s, 1H; POOH), 7.91 (d, J=8.0 Hz, 2H),
7.80 (s, 2H), 7.50 (dd, J=8.0, 7.5 Hz, 2H), 7.38–7.32 (m, 4H), 6.96 (s,
Preparation of phosphoric acid 3d
4-tert-Butyl-2,6-dimethylphenylboronic acid (11): nBuLi (32.0 mL,
79.7 mmol, 2.5m in hexane, 1.5 equiv) was slowly added to a cooled
(À788C), stirred solution of 5-tert-butyl-2-bromo-1,3-dimethylbenzene
(12.8 g, 53.1 mmol, 1.0 equiv)[24] in dry THF (500 mL), and the reaction
mixture was allowed to stir for 2 h at À788C. Trimethoxyborate
(18.1 mL, 159 mmol, 3.0 equiv) was added dropwise within 10 min. The
reaction mixture was stirred for another 2 h at À788C and at RT over-
night. The colorless solution was treated with 1n HCl (180 mL) and the
mixture was stirred for 5 h and extracted three times with CH2Cl2
(200 mL). The combined organic phases were washed with 1n HCl, dried
over MgSO4, filtered, and the solvent was removed in vacuo. The residue
was treated with petroleum ether at À308C to crystallize the title com-
4H), 2.19 (s, 6H; CH3), 2.03 (s, 6H; CH3), 0.96 ppm (s, 18H; C
13C NMR (75 MHz, CDCl3): d=150.2, 145.1 (d, J
(P,C)=6.5 Hz), 136.3,
136.2, 133.2 (d, J(P,C)=3.5 Hz), 132.9, 132.1, 132.0, 131.8, 128.3, 127.3,
126.4, 125.8, 124.9, 124.0, 122.4 (d, J(P,C)=3.0 Hz), 34.08, 31.11, 21.50,
ACHTUNGTRENNUNG(CH3)3);
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
pound in 51% (5.61 g) yield as
CDCl3): d=7.03 (s, 2H; ArH), 4.44 (s, 2H; B(OH)2), 2.39 (s, 6H; CH3);
1.30 ppm (s, 9H;
(CH3)3); 13C NMR (100 MHz, CDCl3): d=152.9,
a
white solid. 1H NMR (400 MHz,
AHCTUNGTRENNUNG
21.04 ppm; 31P NMR (81 MHz, CDCl3): d=7.18 ppm; IR (KBr): n˜ =3433,
3062, 2962, 2865, 1608, 1574, 1497, 1407, 1377, 1377, 1264, 1243, 1190,
1022, 969, 906, 864, 749 cmÀ1; UV/Vis (CH3CN): lmax (loge)=222 (4.998),
294 (4.667), 291 (4.003), 333 nm (4.079); HRMS (ESI): m/z: calcd for
C44H44O4P [MÀH]À: 667.2983; found: 667.2974.
CACHTUNGTRENNUNG
142.2, 139.6, 124.4, 34.61, 31.32, 23.41 ppm; IR (KBr): n˜ =3328, 2962,
2864, 1726, 1607, 1434, 1359, 1342, 1297, 862 cmÀ1; UV/Vis (CHCl3): lmax
(loge)=235 nm (3.352); HRMS (ESI): m/z: calcd for C24H37B2O4
[2MÀH]À: 411.2883; found: 411.2888.
3,3’-(4-tert-Butyl-2,6-dimethylphenyl)-2,2’-dimethoxy-1,1’-binaphthyl (12):
An oven-dried, 250 mL flask was filled stepwise with 3,3’-bisiodo-2,2’-di-
methoxy-1,1’-binaphthyl[25] (2.50 g, 4.43 mmol, 1.0 equiv), boronic acid 11
(3.65 g, 17.7 mmol, 4.0 equiv), BaOH2·8H2O (5.59 g, 17.7 mmol,
X-ray crystallography: Obtained data were collected using
a STOE
IPDS1 diffractometer (MoKa radiation). The program SIR2004[26] was
used for solving the structure and SHELX-97[27] for the refinement. Crys-
ACTHNUTRGNEUNG
tal data for the adduct [C44H45PO4]À[C14H13NO]+·CHCl3: monoclinic; C2
(no. 5); a=22.287(2), b=15.9325(9), c=16.336(1) ꢃ; b=92.19(1)8; V=
5796.6(7) ꢃ3; Z=4; T=213 K; m=0.231 mmÀ1 1calcd =1.145 gcmÀ3
;
;
4.0 equiv), and [PdACHTUNGTRENNUNG(PPh3)4] (512 mg, 0.44 mmol, 0.1 equiv) under an
argon atmosphere. An argon-degassed solution of DME/H2O (5:1,
60 mL) was added to the solids and heated to reflux for 48 h, after which
1n HCl (100 mL) was added and extracted three times with CH2Cl2
(50 mL). The combined organic phases were dried over MgSO4, filtered,
and the solvent was removed in vacuo. The residue was purified by short
silica gel chromatography (CH2Cl2/petroleum ether 1:6) to afford the title
compound in 93% (2.64 g) yield as white foam. Rf =0.30 (CH2Cl2/petro-
leum ether 1:5); [a]2D2 =+31.5 (c=0.5 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.88 (d, J=8.0 Hz, 2H), 7.75 (s, 2H), 7.40–7.30 (m, 6H), 6.99
(s, 4H), 3.10 (s, 6H; OCH3), 2.24 (s, 6H; CH3), 2.19 (s, 6H; CH3),
2qmax =50.08; 16532 reflections measured; 8763 unique (Rint =0.0355);
R1 =0.0538 (4836 reflections with (I>2s(I))); wR2 =0.1410 (all data); ab-
solute structure parameter 0.00(9); GOF=0.796; 622 parameters and 8
constraints. CCDC-744893 contains the supplementary crystallographic
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.
1.38 ppm (s, 18H; CACHTUNGTRENNUNG
(CH3)3); 13C NMR (100 MHz, CDCl3): d=154.7,
150.2, 136.0, 136.0, 135.6, 134.6, 133.9, 130.9, 130.7, 127.9, 126.1, 125.9,
125.5, 124.7, 124.5, 124.4, 60.08, 34.49, 31.62, 21.38, 21.22 ppm; IR (KBr):
Chem. Eur. J. 2010, 16, 2806 – 2818
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2817

C. Schneider et al.
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Acknowledgements
We are grateful to the Deutsche Forschungsgemeinschaft for generous fi-
nancial support of this work (SPP 1179 “Organokatalyse,” Schn 441/7-1)
and to Wacker AG for the donation of chemicals. We would also like to
thank Dr. L. Hennig (University of Leipzig) for the NMR spectroscopic
measurements.
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ˇ
ˇ
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Received: September 15, 2009
Published online: January 22, 2010
2818
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ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 2806 – 2818