Homo- and heterogeneous organocatalysis: Enantioselective Mannich addition of ketones to endocyclic carbon-nitrogen double bonds

Article abstract of DOI:10.1016/j.tet.2010.10.079

The proline-catalyzed Mannich addition of ketones to chalkogenazines is reported. Yields and enantioselectivities of the corresponding products were good to excellent, using different types of organocatalysts. Furthermore the immobilization of hydroxyproline into a readily synthesized polystyrene- copolymer was accomplished. The catalytic performance of this heterogeneous catalyst was successfully demonstrated in the discussed Mannich reaction. Copyright

Full text of DOI:10.1016/j.tet.2010.10.079

Tetrahedron 67 (2011) 546e553
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Tetrahedron
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Homo- and heterogeneous organocatalysis: enantioselective Mannich addition
of ketones to endocyclic carbonenitrogen double bonds
*
€
Knut Schulz, Lars Ratjen, Jurgen Martens
€
€
Institut fur Reine und Angewandte Chemie, Carl von Ossietzky Universitat Oldenburg, P.O. Box 2503, 26111 Oldenburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The proline-catalyzed Mannich addition of ketones to chalkogenazines is reported. Yields and enantiose-
lectivities of the corresponding products were good to excellent, using different types of organocatalysts.
Furthermore the immobilization of hydroxyproline into a readily synthesized polystyrene-copolymer was
accomplished. The catalytic performance of this heterogeneous catalyst was successfully demonstrated in
the discussed Mannich reaction.
Received 7 September 2010
Received in revised form 25 October 2010
Accepted 26 October 2010
Available online 12 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Mannich addition
Chalkogenazines
Proline
Heterogeneous catalysis
Styrene copolymerisation
1. Introduction
structures bear an internal C,N-double bond, they are likewise
potential electrophiles for organocatalytic Mannich additions.
Over the last ten years the field of asymmetric organocatalysis
rapidly emerged, becoming a key area in modern organic synthetic
chemistry.1 Among the most powerful organocatalysts proline and
its derivatives were identified already in the early 1970s, however
the real breakthrough followed around the millennium break.2
Since then organocatalysis, and enamine catalysis in particular,
underwent an impressive progression, mainly focusing on the de-
velopment of new organocatalytic reactions, more active catalysts
and new accessible products.3
Within the reactions known to be catalyzed under metal-free
conditions, the Mannich reaction plays a key role, giving easy access
to nitrogen containing compounds. After the very first organo-
catalytic Mannich reaction of imines and ketones was reported in
the year 2000,4 various catalytic systems have been developed,
giving rise to different Mannich products.5 However the focus has
mainly been set on imines with exocyclic reactive C,N-double
bonds. Organocatalytic reports utilizing cyclic imines are to the best
of our knowledge only scarce.6
Scheme 1. Thiazines and oxazines.
Furthermore the development of heterogeneous catalysts for
organic syntheses is an important task.9 The easy immobilization of
organocatalytically active molecules into heterogeneous systems
can provide various possibilities for the connection and comparison
of homogeneous and heterogeneous catalysis.10 Due to the high
versatility of proline as a rather general organocatalyst, even ap-
plications in synthesis machines can be imagined.11
This work is supposed to deal with both, the homo- and het-
erogeneously catalyzed Mannich addition of ketones to
chalkogenazines.
Within the species of cyclic imines, the readily available chal-
kogenazines (Scheme 1) play an important role.7 These subunits
occur in an array of different biologically active compounds and are
ideally suited for further chemical manipulations.8 Since these
2. Results and discussion
The class of chalkogenazines was chosen as a new motif of pre-
formed imine substrates for the indirect Mannich addition with
carbonyl compounds like ketones. This so far unknown trans-
formation initially was carried out with 2,2-dimethyl-2H-benzo
[1,4]thiazine 1 as acceptor in acetone as solvent and donor with
* Corresponding author. Tel.: þ49 441 798 3837; fax: þ49 441 798 3757; e-mail
address: juergen.martens@univ-oldenburg.de (J. Martens).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.079

K. Schulz et al. / Tetrahedron 67 (2011) 546e553
547
Table 2
30 mol % of (S)-proline as the catalyst. The desired product 2a was
Reaction of compound 1a with acetone using different catalysts (50 mol %)
obtained in 61% yield with an excellent er of 99:1. With this first
result in hand a solvent screening using different polar solvent
systems was carried out (see Table 1).
Entry
1
Catalyst
Yielda (%)
erb
85
99:1
Table 1
Screening of the reaction conditions for the Mannich reaction of the benzothiazine 1
and acetone
2
3
92
55
98.5:1.5
Entry
Solvent
Time
Temperature [ꢀC]
Yielda (%)
erb
98.5:1.5
1
2
3
4
5
6
7
8
9
Acetone
DMF
Acetonitrile
DMSO
DMSO/water
DMSO/water
DMSO/water
DMSO/water
DMSO/water
1 day
1 day
1 day
7 days
1 day
7 days
24 h
20
20
20
20
20
20
0
61
56
80
83
85
99
40
98
89
99:1
99:1
99:1
99:1
99:1
99:1
>99.5:0.5
99:1
98.5:1.5
24 h
24 h
40
60
4
5
32
97.5:2.5
a
Isolated yield.
b
er was determined by chiral HPLC with Daicel Chiralpak AS.
The solvent system tested for the Mannich reaction of a cyclic
dihydro- -carboline by Ohsawa et al., DMSO with water as co-
b
d
d
solvent, furnished remarkable results for the present reaction of
benzothiazine 1 with acetone as well.12 The corresponding ami-
noketone 2a was obtained in 85% yield and an excellent er of 99:1
after 1 day at room temperature (Table 1, entry 5). Among the
solvents investigated, namely acetone, DMSO, DMF and MeCN the
results in DMSO were superior. The yield of the reaction was in-
creased by longer reaction time, after 7 days almost quantitative
amounts of product were isolated (Table 1, entry 6). However, the
enantioselectivity was not significantly solvent-dependent. The
following investigation of the temperature-dependance was car-
ried out in DMSO/water. In the tested temperature range between
6
9
63.5:36.5c
a
Isolated yields.
b
c
er was determined by chiral HPLC with Daicel Chiralpak AS.
Opposite enantiomer detected.
0
ꢀC and 60 ꢀC (Table 1, entries 7e9) the reactivity was influenced
decreased reactivity, further introduction of complexity had dra-
matic influence. Utilization of thiaproline 3d, first reported as ligand
in copper-catalyzed allylicoxidations andan efficientorganocatalyst
for domino reactions, exhibited further decreased reactivity.15 The
appearance of double gem-substitution, like in catalyst 3e, gave no
activity at all. Bicyclic catalyst 3f, a building block in the synthesis of
the angiotensin-converting enzyme-(ACE)-inhibitor Ramipril,
proved to be active, but showed only slight enantioselectivity,
however leading to the other enantiomer, presumably due to its
inverted configuration on the carboxylic acid moiety.16 From this
catalyst screening, proline was suggested as the catalyst of choice for
further investigation of the reported transformation.
considerably, whereas the er only dropped slightly. This underlined
the generally high enantioselective character of Mannich trans-
formations, in particular involving thiazine 1 as an electrophile. The
product 2a was demonstrated being (R)-configured using X-ray
analysis of a single crystal (see Scheme 2).13
The scope of the reaction was investigated involving differently
bulky 2-ketones and other acceptors (Table 3). The reactions took
place exclusively at the methyl group of the 2-ketones (products
2aef), presumably because the corresponding methyleenamine
intermediate formed between ketone and catalyst is more reactive
and susceptible. The other isomer was not isolated in any case.
Remarkably reactions involving cyclohexanone as donor could not
be accomplished. This suggests, that the gem-substitution in the
thiazine-moiety exhibits a high steric demand, prohibiting re-
actions with enamine-intermediates exceeding the size of a methyl
group. Furthermore it was observed, that the increase of size on the
second substituent on the ketone led to dramatically decreased
yields. The change of gem-dimethyl substitution on the thiazine to
the corresponding spiro-substituent was tolerated (products 2g,h),
but led to diminished reactivity, strengthening the aforementioned
observation. Oxazine derivatives reacted as well, following the
Scheme 2. X-ray structure of product 2a.
After having these initial promising results, the influence of
different amino acid based catalysts was investigated (see Table 2).
In this study unbranched, small, cyclic amino acids proved to be
very effective.
Proline 3a and its four-membered analogue, the naturally avail-
able non-proteinogenic (S)-azetidine-2-carboxylic acid 3b provided
the product in high yields and excellent enantioselectivities.14
Changes on the pyrrolidine framework influenced the catalytic
performance considerably. Whereas hydroxyproline 3conlyshowed

548
K. Schulz et al. / Tetrahedron 67 (2011) 546e553
Table 3
gem-substituted chalkogenazines are sterically demanding re-
actants. Since proline-catalyzed Mannich reactions usually follow
an enamine intermediate, a highly congested transition state with
strongly convergent interactions of the gem-substituents and the
active enamine-intermediate seems likely. Especially the low re-
activity of 2-ketones with bigger substituents support this obser-
vation (see Scheme 3).
Reaction scope incorporating different ketones and chalkogenazines
Entry
1
Product
Yielda
99
erb
99:1
2
3
52
32
99:1
98.5:1.5
4
5
16
5
98:2
Scheme 3. Steric congestion between the enamine intermediate and the substrate.
The positive results from this homogeneous organocatalytic
transformation led to the decision to use it as a model reaction for
investigations on heterogeneous organocatalysis. The field of het-
erogeneous catalysis is in terms of ecology and sustainability ex-
tremely important. Heterogeneous catalysts have a high potential
of reusability and can therefore support ‘Green Chemistry’.17
Within heterogeneous catalysis the metal-free catalysis plays
a relatively new role, wherein most developments were conducted
in recent years.18 The transfer of the described homogeneous
method was envisaged by immobilization of (S)-proline in a heter-
ogenous, macroporous carrier phase.19
dc
6
10
dc
As polymeric host system polystyrene was selected, involving
crosslinking units and porogenic agents to obtain macroporous
polymeric templates (see Scheme 4). Therefore the catalytically ac-
tive molecule, in this case a (S)-proline-scaffold had to be inserted in
this heterogeneous system. For that purpose, the natural product
(2S,4R)-4-hydroxyproline showed the most convenient structure, as
thehydroxyl functionisaneasilymodifyablegroup, asalreadyshown
previously. In order to insert the chosen (2S,4R)-4-hydroxyproline 4
in a polymer, the Boc-protected monomer, bearing a polymerizable
styrene-sidechain, was synthesized in two steps via protection with
Boc2O, leading to 5, followed by a classical Williamson etherification
with 4-vinyl-benzylchloride, furnishing compound 6.
For the heterogenisation purpose the bulk polymerisation
method was chosen.20 In this technique the monomer is dissolved in
the main monomer styrene and a specific amount of divinylbenzene
as crosslinking agent. A macrostructure can be disposed by the ad-
dition of porogenic solvents, in this case toluene and 1-dodecanol,
which cause the formation of a three-dimensional structure and
provide channels inside of the polymer. These macroporous channel
structures are a necessary condition for a successful performance in
the polymer, they can be visualized with microspcopic techniques
(see Scheme 4). They ideally have to enable an unhindered transport
of educts and products through the heterogeneous catalyst. To give
a form to the polymeric mixture, a shape, in the current work easily
prepared pipet-moulds, were used. The start of the polymerisation
process using bulk polymerisation is initiated by the addition of
a small and defined amount of a radical starter, here AIBN (see
7
8
9
61
43
99.5:0.5
97.5:2.5
69
16
99.5:0.5
99.5:0.5
10
a
Isolated yield after 7 days.
b
c
er was determined by chiral HPLC with Daicel Chiralpak AS.
Determination of er not possible.
trends regarding the size of the ketone substrates, however with
decreased activity (products 2i,j).
The observation, that the corresponding products showed ex-
cellent enantiomeric purities in all cases indicates, that the bicyclic

K. Schulz et al. / Tetrahedron 67 (2011) 546e553
549
with similarly high enantioselectivities, impure. For the products
obtained from the solvents acetone/water, MeCN/water and neat
acetone no further purification steps were necessary.
Table 4
Mannich-reaction catalysed with 8 in different solvents
Entry
Solvent
Time (h)
Yield (%)
era
93:7
90:10
88.5:11.5
93:7
1
2
3
4
5
Acetone
DMSO
DMF
96
96
96
96
66
86
91b
62b
47
MeCN
Acetonec
83
85:15
a
Detected by chiral HPLC (Chiralpak AS column).
b
c
Yield uncorrected (impurity shown by 1H NMR and HPLC).
Used as neat solvent without addition of water.
To proof the reusability of the heterogeneous catalyst, another
important goal in terms of ‘Green chemistry’, the identical polymer
was used in 10 successive reaction cycles. After 10 cycles 2a was still
obtained with an er of 85:15. However, to allow a higher level of
comparisonwith the homogeneously catalyzed reaction system, the
catalyst 8 was tested with varying substrates as well (see Table 5).
However the tendencies in reactivity of the keto-components
proved to be similar, and could be therefore considered as support
for the mechanistic discussion.
Table 5
Mannich-reaction catalysed with 8 using different donors and acceptors
Entry
Product
Yielda (%)
erb
Scheme 4. Preparation of the catalytically active polymer and visualization.
1
2
3
4
5
2a
2c
2d
2f
2i
86
93
95
20
62
93:7
polymerisation monitoring Scheme 4). The deprotection of the Boc-
group on the proline-moiety was conducted inside of the polymer-
ized macromolecular catalyst template 7, involving trifluoroacetic
acid in dichloromethane and successive treatment with triethyl-
amine in methanol, liberating heterogeneous catalyst 8. The clean-
ing of the monolithic column formed solids from porogenic solvents
and deprotective agents was performed by Soxhlet-extraction with
THF. Cutting the monoliths into discs resulted in bench-stable
templatesas catalytic additives for theMannichreaction(see picture
in Scheme 4). The analytic of the obtained polymer was conducted
via IR-spectroscopy and qualitative elemental analysis (see
Experimental section).
The most important property was the reactivity in the two
component Mannich reaction between chalkogenazines and ke-
tones. Therefore a specific amount of the polymer was added to an
otherwise identically prepared reaction mixture. The reaction con-
ditions were chosen with water as a main part of the sole solvent.
Circumventing column chromatography was a major goal in the
heterogeneous catalysis part of this work, mainly to reach a high
level of ‘Green Chemistry’ and applicability in a sense of mixing,
filtering and evaporating.21 Indeed the reaction was catalyzed suc-
cessfully in different organic solvents after 66e96 h (see Table 4).
The organic solvents werein all cases mixed with an equal amountof
water. The best results were achieved in acetone and water. In the
cases of organic solvents which provided superior results for the
homogeneouslycatalyzed reaction, such as DMSO and DMF, the mix,
filter and evaporate strategy failed. The products were, however
90:10
81.5:18.5
ec
91:9
a
Isolated yields.
b
c
er was determined by chiral HPLC with Daicel Chiralpak AS.
Determination of er not possible.
Obviously the yields for conversions of ketones with chalkoge-
nazines are equal or even higher than those obtained from homo-
geneously catalyzed reactions. This may be due to the easy reaction
handling and the loss-less workup. However the enantiomeric
excesses are in all cases lower. The reasoning for this phenomenon
can be found in the fact, that in the polymer the catalysts lie in gaps
in the connecting channels. This topological property may prohibit
the reaction to occur from the preferred sites at some of the cata-
lytically active sites.
However, the results achieved by the polymerically supported
proline in the three component Mannich reaction were auspicious.
The high versatility of this catalyst is underlined by the easy way of
preparing this reactive catalyst template, as well as by the
straightforward application during the catalysis.
3. Conclusion
In summary the first example of an organocatalytic synthesis of
3-ketosubstituted chalkogenazines, potential building blocks for

550
K. Schulz et al. / Tetrahedron 67 (2011) 546e553
biologically active compounds was achieved. The organocatalysts
involved, proline and analogues, delivered the corresponding
products in good yields and enantiomeric ratios.
4.3. General procedure homogenous phase (GP A)
To a solution of corresponding chalkogenazine in a mixture of
DMSO and water were given 20 mol % (S)-proline and the de-
scribed ketone and stirred for 7 days at room temperature. The
reaction mixture was quenched with methylene chloride. The
organic phase was washed with a saturated sodium hydro-
gencarbonate solution and water. The solution was dried over
magnesium sulfate. The solvent was removed in vacuum. The
crude product was purified by flash-column chromatography
(methylene chloride). The enantiomeric excess was determined
by chiral HPLC.
A transfer of the reaction strategy from homogeneously cata-
lyzed Mannich reactions to heterogeneous polystyrene-supported
catalysis was accomplished. The results of the homogeneously
catalyzed reaction were supported. The interesting facilities of
polymer-supported catalysts using polystyrene templates were
shown. The macroporous properties of the polymeric templates
could be visualized via atomic force microscopy. Further in-
vestigations on the reported Mannich reaction and additional ap-
plications of the heterogeneous catalysts are future tasks.
4. Experimental section
4.1. General information
4.4. General procedure heterogenous phase
The corresponding chalkogenazine 1 was dissolved in the par-
ticular solvent. Then the amount of heterogeneous catalyst 9, which
by calculation contained 30 mol % of the catalyst in respect to the
thiazine was added. Subsequently the mixture was stirred for the
given reaction time. The reaction workup could be performed ei-
ther following the GP A procedure or by simple filtration and
evaporation in high vacuum. In both ways, the product was
obtained in equally high purities. The obtained yields can be found
in Table 3.
Synthetic procedures, performed under argon atmosphere
were performed on a vacuum line using standard Schlenck tech-
niques. All reagents and solvents were commercial grade and
were purified prior to use when necessary. Preparative column
chromatography was carried out using Grace SiO2 (0.035e
0.070 mm, type KG 60). TLC was performed on Merck SiO2 F254
plates on aluminium sheets. 1H and 13C NMR spectra were recor-
ded with Bruker Avance DRX 500 and Avance DPX 300 spec-
trometers. Assignments of the signals in the 13C NMR spectrum
were supported by measurements applying DEPT and COSY
techniques. EIMS, CIMS and HRMS spectra were obtained with
a Finnigan MAT 95 spectrometer. IR spectra were recorded with
a Bruker Tensor 27 spectrometer equipped with a ‘GoldenGate’
diamond-ATR unit. The enantiomeric excess was determined by
chiral HPLC (column: Chiralpak AS). Microscopy experiments
were obtained with a Nanoscope IIIA Controller with Dimension
3100, BioScope and Enviroscope by Veeco.
4.4.1. (R)-1-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]thiazine-3-yl)-
propan-2-one (2a). Following GP A the corresponding benzothia-
zine (0.226 mmol, 40 mg), DMSO (3.2 mL), water (0.3 mL),
(S)-proline (0.068 mmol, 7.8 mg) and acetone (0.8 mL) were used.
The product was isolated as nearly colourless crystals, mp 57 ꢀC.
TLC: Rf¼0.73 (solvent: methylene chloride). The enantiomeric ex-
cess was determined by chiral HPLC [column: Chiralpak AS, solvent:
EtOH/n-hexane (1:9), flow: 1.0 mL minꢁ1; tR¼5.0 min (major en-
antiomer), tR¼13.1 min (minor enantiomer)]. IR: ¼3409, 3049,
n
2991, 2897, 1708, 1587, 1485, 743 cmꢁ1. 1H NMR (500 MHz, CDCl3)
d
¼6.95 (d, 3JH,H¼7.8 Hz,1H, HAr), 6.89 (dd, 3JH,H¼7.6, 7.6 Hz,1H, HAr),
3
4.2. Syntheses of chalkogenazines
6.62 (dd, JH,H¼7.5, 7.5 Hz, 1H, HAr), 6.48 (d, 3JH,H¼8.0 Hz, 1H, HAr),
3
4.68 (br s, 1H, NH), 3.61 (m, JH,H¼9.3 Hz, 1H, NCH), 2.78 (dd,
3
2
The preparations and analytic properties for the 2,2-dimethyl-2H-
1,4-benzothiazine (starting material for 2aef) and the 2,2-dimethyl-
2H-1,4-benzoxazine (starting material for 2i,j) were described in the
literature by our lab before.7
2JH,H¼17.9 Hz, JH,H¼2.9 Hz, 1H, CH2), 2.72 (dd, JH,H¼17.9 Hz,
3JH,H¼9.3 Hz, 1H, CH2), 2.14 (s, 1H, COCH3), 1.41 (s, 1H, CH3), 1.30 (s,
1H, CH3) ppm. 13C NMR (125 MHz, CDCl3)
d¼208.5, 139.0, 127.5,
125.5, 117.8, 115.3, 115.0, 54.9, 46.2, 41.9, 30.8, 29.7, 25.8 ppm. MS
(CI, iso-butane): m/z(%)¼236.1 (100) [MH]þ. HRMS (CI, iso-butane):
calcd for [C13H18NOS]þ 236.1109; found 236.1109.
4.2.1. Spiro[benzo[b][1,4]thiazine-2,10-cyclohexane] (starting mate-
rial for 2g,h). To a suspension of NaH (60% in oil, 50 mmol, 2.0 g) in
dry THF (20 mL) was added aminothiophenol (48 mmol, 6.00 g)
dissolvedin20mLdry THFat0ꢀCundervigorousstirring. Tomaintain
the mixture miscible, 50 mL dry THF were added additionally and the
resulting reaction mixture was stirred for 2 h at room temperature.
Afterthistime1-bromocyclohexanecarbaldehyde(50.5mmol,9.65g)
dissolved in 15 mL dry THF were added dropwise to the foamy re-
action mixture and stirred overnight at room temperature. Sub-
4.4.2. (R)-1-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]thiazine-3-yl)
butan-2-one (2b). Following GP A the corresponding benzothia-
zine (0.564 mmol, 100 mg), DMSO (6 mL), water (0.5 mL), (S)-
proline (0.169 mmol, 20.0 mg) and butan-2-one (1.22 g) were
used. The product was isolated as colourless oil (77 mg,
0.293 mmol, 52%). TLC: Rf¼0.76 (solvent: methylene chloride). The
enantiomeric excess was determined by chiral HPLC [column:
sequently 4 A-molecular sieves were added to the reaction mixture
Chiralpak AS, solvent: EtOH/n-hexane (1:9), flow: 1.0 mL minꢁ1
;
ꢀ
and stirring is continued for another 2 h. The mixture was filtered
through a pad of Celite and the solvent removed in vacuo. Column
chromatography (solvent: MTBE/hexanes 1:1 with an Rf¼0.63)
afforded the product as an off-white solid (6.20 g, 29.00 mmol, 57%),
tR¼4.2 min (major enantiomer), tR¼6.9 min (minor enantiomer)]
ee: 98%. IR:
n
¼3399, 2974, 2934, 1705, 1590, 1481, 742 cmꢁ1
.
1H
NMR (500 MHz, CDCl3)
d
¼6.95 (dd, 3JH,H¼7.5 Hz, 4JH,H¼1.1 Hz, 1H,
o-CHArS), 6.89 (ddd, 3JH,H¼7.5 Hz, 3JH,H¼7.9 Hz, 4JH,H¼1.1 Hz, 1H, p-
3
mp 100e102 ꢀC. IR:
n
¼2939, 2924, 2854, 1616, 1446, 1073, 769 cmꢁ1
.
CHArS), 6.62 (dd, JH,H¼7.5, 7.5 Hz, 1H, p-CHArN), 6.49 (d,
1H NMR (500 MHz, CDCl3):
d
¼1.50e1.80 [m, 10H, 5CH2], 7.11 [dd, 1H,
3JH,H¼7.9 Hz, 1H, o-CHArN), 3.64 (dd, JH,H¼9.4 Hz, JH,H¼2.9 Hz,
3
3
CHAr 3J¼7.9, 7.9 Hz], 7.18 [dd, 1H, CHAr 3J¼7.9, 7.9 Hz], 7.24 [d,1H, CHAr,
1H, CHCH2), 2.75 (dd, 2JH,H¼17.6 Hz, 3JH,H¼2.9 Hz, 1H, CH2CO), 2.69
3J¼7.9 Hz], 7.39 [d, 1H, CHAr, 3J¼7.9 Hz], 7.58 [s, 1H, N]CH] ppm. 13
C
(dd, JH,H¼17.6 Hz, JH,H¼9.4 Hz, 1H, CH2CO), 2.33e2.49 (m, 2H,
2
3
3
NMR (125 MHz, CDCl3):
d
¼21.0, 25.5, 33.1, 42.1, 122.9, 126.2, 127.2,
CH2CH3), 1.41 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.04 (dd, JH,H¼7.3,
127.6, 127.7, 141.7, 160.7 ppm. MS (CI, iso-butane): m/z(%)¼218.0 (100)
[MH]þ. HRMS (CI, iso-butane): calcd for [C13H16NS]þ: 218.1004; found
218.1004.
7.3 Hz, 3H, CH2CH3) ppm. 13C NMR (125 MHz, CDCl3)
d
¼211.25,
138.88, 127.47, 125.47, 117.88, 115.42, 115.25, 55.06, 44.84, 41.99,
36.76, 29.63, 25.75, 7.63 ppm. MS (CI, iso-butane): m/z(%)¼250.1

K. Schulz et al. / Tetrahedron 67 (2011) 546e553
551
(100) [MH]þ. HRMS (EI): calcd for [C14H19NOS] 249.1187; found
249.1187.
(CH3)2), 1.42 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.07 (d, 3JH,H¼7.0 Hz, 3H,
3
CH(CH3)2), 1.02 (d, JH,H¼7.0 Hz, 3H, CH(CH3)2) ppm. 13C NMR
(125 MHz, CDCl3)
d
¼214.73, 139.00, 127.43, 125.45, 117.78, 115.32,
4.4.3. (R)-1-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]thiazine-3-yl)
pentan-2-one (2c). Following GP A the corresponding benzothia-
zine (0.282 mmol, 50 mg), DMSO (3.2 mL), water (0.3 mL), (S)-
proline (0.056 mmol, 6.5 mg) and pentan-2-one (0.8 mL) were
used. The product was isolated as colourless oil (23.4 mg,
0.089 mmol, 32%). TLC: Rf¼0.80 (solvent: methylene chloride). The
enantiomeric excess was determined by chiral HPLC [column:
Chiralpak AS, solvent: iso-propanol/n-hexane (3:97), flow:
1.0 mL minꢁ1; tR¼5.9 min (major enantiomer), tR¼13.6 min (minor
115.16, 55.05, 43.03, 42.18, 41.61, 29.80, 29.68, 25.83, 18.07 ppm. MS
(CI, iso-butane): m/z(%)¼264.1 (40) [MH]þ. HRMS (EI): calcd for
[C15H22NOS] 264.1421; found 264.1421.
4.4.6. (R)-2-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]thiazine-3-yl)-
1-phenyl-ethanone (2f). Following GP
A
the corresponding
benzothiazine (0.282 mmol, 50 mg), DMSO (3.2 mL), water
(0.3 mL), (S)-proline (0.056 mmol, 6.5 mg) and acetophenone
(0.8 mL) were used. The excess of acetophenone was removed by
distillation before performing the purification by chromatography.
The product was isolated as colourless oil (8.4 mg, 0.028 mmol,
10%). TLC: Rf¼0.81 (solvent: methylene chloride). The enantiomeric
enantiomer)] ee 98%. IR:
1306, 744, 631 cmꢁ1
n
¼3400, 2962, 2931, 1705, 1592, 1483,
.
1H NMR (500 MHz, CDCl3)
d
¼6.94 (d,
3JH,H¼7.6 Hz, 1H, o-CHArS), 6.89 (dd, 3JH,H¼7.5 Hz, 3JH,H¼7.8 Hz, 1H,
p-CHArS), 6.61 (dd, 3JH,H¼7.5 Hz, 3JH,H¼7.6 Hz, 1H, p-CHArN), 6.47 (d,
excess could not be determined. IR:
n
¼3402, 2962, 2918,1678,1593,
3
3
3JH,H¼7.8 Hz, JH,H¼7.8 Hz, 1H, o-CHArN), 3.62 (dd, JH,H¼9.3 Hz,
1483, 1306, 744, 632 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d
¼7.92e7.89
3JH,H¼3.1 Hz, 1H, NCH), 2.74 (dd, JH,H¼17.6 Hz, JH,H¼3.1 Hz, 1H,
NCHCH2CO), 2.68 (dd, 2JH,H¼17.6 Hz, 3JH,H¼9.3 Hz, 1H, NCHCH2CO),
2.29e2.44 (m, 2H, CH2CH2CH3), 1.63e1.52 (m, 2H, CH2CH3), 1.41 (s,
(m, 1H, p-CHPh), 7.60e7.40 (m, 4H, oþm-CHPh), 6.96 (dd,
2
3
3JH,H¼7.8 Hz, 4JH,H¼1.3 Hz, 1H, o-CHArS), 6.86 (ddd, 3JH,H¼8.1, 7.7 Hz,
4JH,H¼1.3 Hz, 1H, p-CHS), 6.60 (ddd, JH,H¼7.7, 7.8 Hz, JH,H¼1.1 Hz,
1H, p-CN), 6.45 (dd, 3JH,H¼8.1, 1.0 Hz, 1H, o-C N), 4.78 (br s, 1H, NH),
3.82 (dd, 3JH,H¼3.7, 8.3 Hz, 1H, CH), 3.32e3.23 (m, 2H, CH2), 1.48 (s,
3H, CH3), 1.38 (s, 3H, CH3) ppm. 13C NMR (125 MHz, CDCl3):
3
4
3
3H, CH3), 1.30 (s, 3H, CH3), 0.89 (dd, JH,H¼7.4, 7.4 Hz, 3H,
CH2CH3) ppm. 13C NMR (125 MHz, CDCl3)
d
¼210.93, 139.03, 127.45,
125.46, 117.77, 115.30, 115.13, 55.01, 45.56, 45.25, 41.99, 29.65, 25.76,
17.15, 13.62 ppm. MS (CI, iso-butane): m/z(%)¼264.2 (100) [MH]þ.
HRMS (CI, iso-butane): calcd for [C15H22NOS]þ 264.1422; found
264.1422.
d
¼199.61, 139.05, 136.78, 133.43, 128.62, 128.08, 127.52, 125.51,
117.70, 115.36, 114.93, 55.29, 42.26, 41.59, 29.92, 26.02 ppm. MS (CI,
iso-butane): m/z(%)¼298.3 (100) [MH]þ. HRMS (CI, iso-butane):
calcd for [C18H20NOS]þ 298.1264; found 298.1264.
4.4.4. (R)-1-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]thiazine-3-yl)-
4-methylpentan-2-one (2d). Following GP A the corresponding
benzothiazine (0.282 mmol, 50 mg), DMSO (3.2 mL), water
(0.3 mL), (S)-proline (0.056 mmol, 6.5 mg) and 4-methylpentan-2-
one (0.8 mL) were used. The product was isolated as colourless oil
(12.4 mg, 0.045 mmol, 16%). TLC: Rf¼0.82 (solvent: methylene
chloride). The enantiomeric excess was determined by chiral HPLC
[column: Chiralpak AS, solvent: iso-propanol/n-hexane (1:99),
flow: 1.0 mL minꢁ1; tR¼5.6 min (major enantiomer), tR¼10.2 min
4.4.7. (R)-1-(3,4-Dihydrospiro[benzo[b][1,4]thiazine-2,10-cyclo-
hexan]-3-yl)propan-2-one (2g). Following GP A the corresponding
spiro-thiazine (0.37 mmol, 80 mg), DMSO (3.0 mL), water (0.3 mL),
(S)-proline (0.11 mmol, 13.0 mg) and acetone (0.9 mL) were used.
The reaction was performed for 3 days at 0 ꢀC before purification by
column chromatography. The product was isolated as colourless oil
(61.6 mg, 0.22 mmol, 61%). TLC: Rf¼0.73 (solvent: methylene
chloride). The enantiomeric excess was determined by chiral HPLC
[column: Chiralpak AS, solvent: iso-propanol/n-hexane (10:90),
flow: 1.0 mL minꢁ1; tR¼6.0 min (major enantiomer), tR¼10.5 min
(minor enantiomer)] ee: 96%. IR:
n
¼3400, 2958, 2870, 1704, 1591,
¼6.94
1482, 1366, 1305, 743, 630 cmꢁ1. 1H NMR (500 MHz, CDCl3)
d
3
4
3
(dd, JH,H¼7.7 Hz, JH,H¼1.3 Hz, 1H, o-CHArS), 6.89 (ddd, JH,H¼7.7,
(minor enantiomer)] ee: 99%. IR:
n
¼3425, 2961, 2918, 2848, 1702,
4
3
7.9 Hz, JH,H¼1.3 Hz, 1H, p-CHArS), 6.61 (ddd, JH,H¼7.7, 7.7 Hz,
4JH,H¼1.2 Hz, 1H, p-CHArN), 6.47 (dd, 3JH,H¼7.9 Hz, 4JH,H¼1.2 Hz, 1H,
1590, 1486, 1306, 756, 629 cmꢁ1
.
1H NMR (500 MHz, CDCl3):
d
¼1.19e1.32, 1.37e1.49, 1.50e1.84, 1.86e1.94 [m, 10H, 5CH2], 2.12 [s,
3
o-CHArN), 3.62 (dd, JH,H¼8.6, 3.7 Hz, 1H, CH), 2.72 (dd,
3H, CH3], 2.75 [dd, 1H, CH2CO, 2J¼18.2 Hz, 3J¼9.5 Hz], 2.85 [dd, 1H,
CH2CO, 2J¼18.2 Hz, 3J¼9.5 Hz], 3.60e3.65 [m, 1H, NCH], 4.76 [br s,
1H, NH], 6.47 [d, 1H, o-CHArN, 3J¼7.7 Hz], 6.62 [dd, 1H, p-CHArN,
3J¼7.4, 7.4 Hz], 6.89 [dd, 1H, p-CHArS, 3J¼7.4, 7.4 Hz], 6.98 [d, 1H, o-
2JH,H¼17.1 Hz, JH,H¼3.7 Hz, 1H, CHCH2CO), 2.67 (dd, JH,H¼17.1 Hz,
3
2
3JH,H¼8.6 Hz, 1H, CHCH2CO), 2.25 (dd, JH,H¼16.3 Hz, JH,H¼7.2 Hz,
1H, CH2CH(CH3)2), 2.25 (dd, 2JH,H¼16.3 Hz, 3JH,H¼6.9 Hz, 1H,CH2CH
(CH3)2), 2.15e2.04 (m, 1H, CH(CH3)2), 1.41 (s, 3H, CH3), 1.29 (s, 3H,
CH3), 0.89e0.87 (m, 6H, CH(CH3)2) ppm. 13C NMR (125 MHz, CDCl3)
2
3
CHArS, 3J¼7.7 Hz] ppm. 13C NMR (125 MHz, CDCl3):
¼21.41, 21.92,
d
25.70, 30.93, 36.41, 34.83, 45.65, 47.02, 54.16, 114.95, 115.65, 117.83,
125.41, 127.72, 139.01, 208.77 ppm. MS (CI, iso-butane): m/z(%)¼
276.0 (100) [MH]þ.
d
¼210.72, 138.98, 127.45, 125.48, 117.83, 115.35, 115.19, 54.97, 52.64,
45.74, 42.01, 29.69, 25.78, 24.61, 22.52, 22.45 ppm. MS (CI, iso-bu-
tane): m/z(%)¼278.3 (100) [MH]þ. HRMS (CI, iso-butane): calcd for
[C16H24NOS]þ 278.1579; found 278.1579.
4.4.8. (R)-1-(3,4-Dihydrospiro[benzo[b][1,4]thiazine-2,10-cyclo-
hexan]-3-yl)butan-2-one (2h). Following GP A the corresponding
spiro-thiazine (1.38 mmol, 300 mg), DMSO (9.0 mL), water (1.5 mL),
(S)-proline (0.42 mmol, 47.7 mg) and ethylmethylketone (2.99 g)
were used. The reaction was performed for 3 days at room tem-
perature before performing the purification by chromatography.
The product was isolated as colourless oil (170.0 mg, 0.587 mmol,
43%). TLC: Rf¼0.79 (solvent: methylene chloride). The enantiomeric
excess was determined by chiral HPLC [column: Chiralpak AS, sol-
4.4.5. (R)-1-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]thiazine-3-yl)-
3-methylbutan-2-one (2e). Following GP
A the corresponding
benzothiazine (0.282 mmol, 50 mg), DMSO (3.2 mL), water
(0.3 mL), (S)-proline (0.056 mmol, 6.5 mg) and 3-methylbutan-2-
one (0.8 mL) were used. The product was isolated as colourless oil
(3.7 mg, 0.014 mmol, 5%). TLC: Rf¼0.78 (solvent: methylene chlo-
ride). The enantiomeric excess could not be determined. IR:
n
¼3401, 2964, 2924, 1706, 1592, 1483, 1366, 743, 631 cmꢁ1. 1H NMR
vent: iso-propanol/n-hexane (10:90), flow: 1.0 mL minꢁ1
tR¼4.8 min (major enantiomer), tR¼6.8 min (minor enantiomer)]
ee: 95%. IR:
¼3425, 2928, 2850, 1704, 1588, 1485, 1311, 751,
674 cmꢁ1 1H NMR (500 MHz, CDCl3):
;
3
4
(500 MHz, CDCl3)
d
¼6.94 (dd, JH,H¼7.6 Hz, JH,H¼1.3 Hz, 1H, o-
CHArS), 6.88 (ddd, 3JH,H¼7.5, 7.9 Hz, 4JH,H¼1.3 Hz, 1H, p-CHArS), 6.61
n
3
4
(ddd, JH,H¼7.5, 7.6 Hz, JH,H¼0.9 Hz, 1H, p-CHArN), 6.46 (dd,
3JH,H¼7.9 Hz, 4JH,H¼0.9 Hz, 1H, o-CHArN), 3.61 (dd, 3JH,H¼7.4, 4.2 Hz,
1H, CH), 2.77 (dd, 2JH,H¼17.0 Hz, 3JH,H¼4.2 Hz, 1H, CHCH2), 2.73 (dd,
.
d
¼1.02 [dd, 3H, CH2CH3,
3J¼7.3, 7.3 Hz], 1.20e1.31, 1.38e1.49, 1.50e1.84, 1.87e1.94 [m, 10H,
5CH2], 2.30e2.46 [m, 2H, CH2CH3], 2.71 [dd, 1H, CH2CO, 2J¼17.8 Hz,
3J¼2.5 Hz], 2.85 [dd, 1H, CH2CO, 2J¼17.8 Hz, 3J¼9.7 Hz], 3.64 [dd, 1H,
2JH,H¼17.0 Hz, JH,H¼7.4 Hz, 1H, CHCH2), 2.60e2.51 (m, 1H, CH
3

552
K. Schulz et al. / Tetrahedron 67 (2011) 546e553
NCH, 3J¼2.5, 9.7 Hz], 4.62 [br s, 1H, NH], 6.44 [d, 1H, o-CHArN,
3J¼7.7 Hz], 6.60 [dd, 1H, p-CHArN, 3J¼7.4, 7.7 Hz], 6.88 [ddd, 1H, p-
CHArS, 3J¼7.4, 7.7 Hz, 4J¼1.0 Hz], 6.97 [dd, 1H, o-CHArS, 3J¼7.7 Hz,
4J¼1.0 Hz] ppm. 13C NMR (125 MHz, CDCl3):
¼7.64, 21.44, 21.99,
d
25.77, 34.81, 36.48, 36.87, 44.34, 47.13, 54.25, 114.70, 115.35, 117.61,
125.37, 127.65, 139.23, 211.66 ppm. MS (CI, iso-butane): m/z(%)¼
290.1 (100) [MH]þ. HRMS (CI, iso-butane): calcd for [C18H20NOS]þ
290.1579; found 290.1577.
4.4.9. (R)-1-(2,2-Dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)
propan-2-one (2i). Following GP A the corresponding oxazine
(0.31 mmol, 50.2 mg), DMSO (3.2 mL), water (0.28 mL), (S)-proline
(0.06 mmol, 7.3 mg) and acetone (0.8 mL) were used. The reaction
was conducted at 0 ꢀC for 7 days before performing the purification
by chromatography. The product was isolated as colourless oil
(46.6 mg, 0.21 mmol, 69%). TLC: Rf¼0.80 (solvent: methylene
chloride). The enantiomeric excess was determined by chiral HPLC
[column: Chiralpak AS, solvent: ethanol/n-hexane (10:90), flow:
1.0 mL minꢁ1; tR¼5.3 min (major enantiomer), tR¼15.4 min (minor
enantiomer)] ee: 99%. IR:
n
¼3382, 2979, 2925, 1653, 1479, 1385,
755 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d
¼1.24 [s, 3H, CH3], 1.33 [s,
3H, CH3], 2.17 [s, 3H, COCH3], 2.53 [dd, 1H, CH2, 2J¼17.8 Hz,
3J¼10.5 Hz], 2.73 [dd, 1H, CH2, 2J¼17.8 Hz, 3J¼2.2 Hz], 3.50 [dd, 1H,
NCH, 3J¼10.5 Hz, 3J¼2.2 Hz], 4.47 [br s, 1H, NH], 6.55e6.58 [m, 1H,
o-CHArN], 6.65 [ddd, 1H, p-CHArN, 3J¼7.6, 7.5 Hz, 4J¼1.1 Hz],
6.72e6.77 [m, 2H, p-CHArO, o-CHArO] ppm. 13C NMR (125 MHz,
CDCl3):
d
¼22.51, 25.46, 30.65, 44.23, 52.79, 74.45, 115.23, 116.83,
118.74, 120.99, 131.76, 142.23, 208.05 ppm. MS (CI, iso-butane): m/z
(%)¼220.2 (100) [MH]þ. HRMS (CI, iso-butane): calcd for
[C18H20NOS]þ 220.1338; found 220.1338.
4.4.10. (R)-1-(2,2-Dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-
yl)butan-2-one (2j). Following GP A the corresponding oxazine
(0.31 mmol, 50.2 mg), DMSO (3.2 mL), water (0.28 mL), (S)-proline
(0.06 mmol, 7.3 mg) and acetone (0.8 mL) were used. The reaction
was conducted at 0 ꢀC for 7 days before performing the purification
by chromatography. The product was isolated as colourless oil
(11.4 mg, 0.05 mmol, 16%). TLC: Rf¼0.75 (solvent: methylene chlo-
ride). The enantiomeric excess was determined by chiral HPLC
[column: Chiralpak AS, solvent: ethanol/n-hexane (2:98), flow:
1.0 mL minꢁ1; tR¼6.4 min (major enantiomer), tR¼19.0 min (minor
Fig. 1. Atomic force microscopy (AFM) images of a monolithic polymer disc. Both items
show the identical region in 2D-picture (left side) and relief modellation (right) on
identical scale.
washed with water and brine, dried over MgSO4 and dried in vacuo.
The product was obtained as a yellow oil (2.68 g, 7.7 mmol, 60%).
The analytical data was in accordance to that reported in the
literature.22
enantiomer)] ee: 99%. IR:
n
¼3383, 2977, 2935, 1710, 1500, 1306,
744 cmꢁ1 1H NMR (500 MHz, CDCl3):
.
d
¼1.07 [dd, 3H, CH2CH3,
4.4.12. Polystyrene-supported (S)-proline (8). The polymeric mix-
ture contained 40 mol % of the polymerizable compounds: (2S,4R)-
1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid 7,
styrene, divinylbenzene and 60 mol % of the porogenic agents:
toluene and 1-dodecanol, the radical initiator AIBN was added in
1 wt % (related to polymerizable compounds). The 40 mol %
polymerizable compounds were composed of: 7.5 mol % of (2S,4R)-
1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid,
72.0 mol % of styrene and 20.5 mol % of divinylbenzene (80%,
technical grade). The 60 mol % porogenic agents were composed of:
70 mol % 1-dodecanol and 30 mol % toluene. The components were
mixed in the following order: 1. monomer; 2. styrene; 3. toluene; 4.
divinylbenzene; 5. 1-dodecanol; 6. AIBN. After addition of all
components, the mixture was thoroughly homogenized. After-
wards the slightly yellow liquid was filled into column formed
moulds, the moulds were capped and placed in an oil bath which
was tempered to 70 ꢀC for 24 h. After this time the moulds were
broken and the column formed polymer was cut into discs, washed
in a Soxhlet-extractor with THF for 3 h and oven-dried at 60 ꢀC.
Deprotection step: 0.5 g of the polymer were given into 15 mL of
a mixture of CH2Cl2/trifluoracetic acid (4:1) and mixed for 2 h in an
ice bath. The reaction mixture was stirred for an additional hour
while warming to room temperature. After this 25 mL MeOH/NEt3
3J¼7.3, 7.3 Hz], 1.25 [s, 3H, CH3], 1.34 [s, 3H, CH3], 2.38e2.54 [m, 3H,
CH2CH3, CH2CO], 2.71 [dd, 1H, CH2CO, 2J¼17.6 Hz, 3J¼2.2 Hz], 3.51
[dd, 1H, CH, 3J¼10.6, 2.2 Hz], 4.51 [br s, 1H, NH], 6.58 [dd, 1H, o-
CHArN, 3J¼8.1 Hz, 4J¼1.3 Hz], 6.66 [ddd, 1H, p-CHArN, 3J¼7.7, 7.6 Hz,
4J¼1.3 Hz], 6.73e6.78 [m, 2H, p-CHArO, o-CHArO] ppm. 13C NMR
(125 MHz, CDCl3):
d
¼7.62, 22.51, 25.52, 36.68, 42.95, 52.96, 74.58,
115.27, 116.88, 118.79, 121.03, 131.81, 142.30, 210.92 ppm. MS (CI,
iso-butane): m/z(%)¼234.2 (100) [MH]þ. HRMS (CI, iso-butane):
calcd for [C18H20NOS]þ 234.1494; found 234.1495.
4.4.11. (2S,4R)-1-(tert-Butoxycarbonyl)-4-(4-vinylbenzyloxy)pyrroli-
dine-2-carboxylic acid (7). To a solution of (2S,4R)-1-(tert-butox-
ycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (12.9 mmol,
3.00 g,) in dry THF (90 mL) was added NaH (26.4 mmol, 1.00 g, 60%
suspension in oil) in dried THF (20 mL) at 0 ꢀC under argon atmo-
sphere. The mixture was stirred for 1.5 h. Then p-vinyl-benzyl-
chloride (19.4 mmol, 3.04 mL) was added dropwise via syringe at
0
ꢀC, subsequently a spatula tip potassium iodide was added. The
reaction mixture was heated to 50 ꢀC for 66 h. The reaction was
quenched with ice water. The resulting yellow liquid was washed
twice with hexanes, the aqueous phase was acidified to pH 2 with
KHSO4-solution (10%) under ice cooling. The aqueous phase was
extracted with ethyl acetate four times, the organic phase was
(49:1) were added and the mixture was stirred for
2 h.

K. Schulz et al. / Tetrahedron 67 (2011) 546e553
553
Lett. 2006, 8, 1533e1535; (c) Zhuang, W.; Saaby, S.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2004, 43, 4476e4478; Angew. Chem. 2004, 116, 4576e4578; (d)
Jiang, B.; Dong, J. J.; Si, Y. G.; Zhao, X. L.; Huang, Z. G.; Xu, M. Adv. Synth. Catal.
Subsequently the polymer was washed in a Soxhlet-extractor with
THF for 3 h and oven-dried at 60 ꢀC, to afford the polymer templates
which were subjected to the reaction conditions. IR (cmꢁ1): Back-
ground polymer without catalyst: 3026, 2923, 1602, 1493, 1452,
905, 758; Loaded Polymer: 3026, 2923, 1705, 1602, 1452, 1180, 905,
758 (Fig. 1).
€
2008, 350, 1360e1366; (e) Hahn, B. T.; Frohlich, R.; Harms, K.; Glorius, F. Angew.
Chem., Int. Ed. 2008, 47, 9985e9988; Angew. Chem. 2008, 120, 10134e10137.
€
7. For syntheses of this compounds ee for example: (a) Groger, H.; Martens, J.
€
Sulfur Lett. 1995, 19, 197e206; (b) Groger, H.; Manikowski, J.; Martens, J. Phos-
phorous, Sulfur, Silicon Relat. Elem. 1996, 116, 123e132.
8. (a) Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, A.; Takayama, K.; Yoden, T.; Uchida,
W.; Asano, M.; Fujita, S.; Yanagisawa, I.; Fujikura, T. Chem. Pharm. Bull. 1996, 44,
103e114; (b) Kobayashi, T.; Strobeck, M.; Schwartz, A.; Mori, Y. Eur. J. Pharmacol.
1997, 332, 313e320; (c) Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, A.; Yoden, T.;
Yamagiwa, Y.; Yanagisawa, I.; Shibanuma, T.; Nohira, H. Bioorg. Med. Chem.
2000, 8, 393e404; (d) Okuyama, K.; Kiuchi, S.; Okamoto, M.; Narita, H.; Kudo, Y.
Eur. J. Pharmacol. 2000, 398, 209e216; (e) Cecchetti, V.; Calderone, V.; Tabarrini,
O.; Sabatini, S.; Filipponi, E.; Testai, L.; Spogli, R.; Martinotti, E.; Fravolini, A. J.
Med. Chem. 2003, 46, 3670e3679; (f) Trapani, G.; Reho, A.; Morlacchi, F.; La-
trofa, A.; Marchini, P.; Venturi, F.; Cantalamessa, F. Farmaco, Ed. Sci. 1985, 40,
369e376; (g) Armenise, D.; Trapani, G.; Stasi, F.; Morlacchi, F. Arch. Pharm.
(Weinheim) 1998, 331, 54e58; (h) Hayakawa, I.; Atarashi, S.; Yokohama, S.;
Imamura, M.; Sakano, K.; Furukawa, M. Antimicrob. Agents Chemother. 1986, 29,
163e164; (i) Atarashi, S.; Tsurumi, H.; Fujiwara, T.; Hayakawa, I. J. Heterocycl.
Chem. 1991, 28, 329e331; (j) Hirata, T.; Saito, H.; Tomioka, H.; Sato, K.; Jidoi, J.;
Hosoe, K.; Hidaka, T. Antimicrob. Agents Chemother. 1995, 39, 2295e2303.
9. For a recent review about heterogeneous asymmetric catalysis see: (a) Heit-
baum, M.; Glorius, F.; Escher, I. Angew. Chem., Int. Ed. 2006, 45, 4732e4762;
Angew. Chem. 2006, 118, 4850e4881.
Acknowledgements
We thank the Central analytic section of the University of Old-
enburg for retrieving NMR and MS data and S. Pust for AFM-mi-
croscopy measurements. K.S. gratefully acknowledges the Heinz
€
Neumuller-Stiftung for a doctoral fellowship.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.10.079.
References and notes
10. For a review: (a) Corma, A.; Garcia, H. Top. Catal. 2008, 48, 8e31.
11. (a) France, S.; Bernstein, D.; Weatherwax, A.; Lectka, T. Org. Lett. 2005, 7,
3009e3012.
1. For reviews on metal-free catalysis see: (a) Dalko, P. I.; Moisan, L. Angew. Chem.,
Int. Ed. 2001, 40, 3726e3748; Angew. Chem. 2001, 113, 3840e3864; (b) Dalko, P.
I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138e5175; Angew. Chem. 2004,
116, 5248e5286; (c) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719e724; (d)
List, B. Tetrahedron 2002, 58, 5573e5590; (e) Limbach, M. Chem. Biodivers. 2006,
3, 119e132; (f) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
5606e5655; (g) Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int., Ed. 2006, 45,
1520e1543; Angew. Chem. 2006, 118, 1550e1573; (h) Marcia de Figuieredo, R.;
Christmann, M. Eur. J. Org. Chem. 2007, 2575e2600.
12. See 6a and b.
13. CCDC 798107 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.
14. For applications of 3b as auxiliary, ligand or catalyst see: (a) Mehler, T.; Behnen,
W.; Wilken, J.; Martens, J. Tetrahedron: Asymmetry 1994, 5, 185e188; (b) Ya-
maguchi, M.; Shiraishi, T.; Igarashi, Y.; Hirama, M. Tetrahedron Lett. 1994, 35,
8233e8236; (c) Levina, A.; Muzart, J. Tetrahedron: Asymmetry 1995, 6, 147e156;
(d) Thomassigny, C.; Prim, D.; Greck, C. Tetrahedron Lett. 2006, 47, 1117e1119;
(e) Zhang, H.; Mitsumori, S.; Utsumi, N.; Imai, M.; Garcia-Delgado, N.; Mifsud,
M.; Albertshofer, K.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III. J.
Am. Chem. Soc. 2008, 130, 875e886.
15. See 14c and: (a) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew. Chem.
, Int. Ed. 2003, 42, 4233e4237; (b) Wang, H.; Pei, W. W.; Sun, G. B.; Ye, W. P.
Chin. Chem. Lett. 2004, 15, 14196e21422; (c) Steiner, D. D.; Mase, N.; Barbas, C. F.,
III. Angew. Chem., Int. Ed 2005, 44, 3706e3710; (d) Kumar, A.; Maurya, R. A.
Tetrahedron 2007, 63, 1946e1952; (e) Vishnumaya, M. R.; Singh, V. K. J. Org.
Chem. 2009, 74, 4289e4297; (f) Chua, P. J.; Tan, B.; Zhong, G. Green Chem. 2009,
11, 543e547.
2. (a) Eder, U.; Sauer, R.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10,
496e497; Angew. Chem. 1971, 83, 492e493; (b) Hajos, Z. G.; Parrish, D. R. J. Org.
Chem. 1974, 39, 1615e1621; (c) Woodward, R. B.; Logusch, E.; Nambiar, K. P.;
Sakan, K.; Ward, D. E.; Auyeung, B. W.; Balaram, P.; Browne, L. J.; Card, P. J.;
Chen, C. H.; Chenevert, R. B.; Fliri, A.; Frobel, K.; Gais, H. J.; Garratt, D. G.;
Hayakawa, K.; Heggie, W.; Hesson, D. P.; Hoppe, D.; Hoppe, I.; Hyatt, J. A.; Ikeda,
D.; Jacobi, P. A.; Kim, K. S.; Kobuke, Y.; Kojima, K.; Krowicki, K.; Lee, V. J.; Leutert,
T.; Malchenko, S.; Martens, J.; Matthews, R. S.; Ong, B. S.; Press, J. B.; Rajanbabu,
T. V.; Rousseau, G.; Sauter, H. M.; Suzuki, M.; Tatsuta, K.; Tolbert, L. M.;
Truesdale, E. A.; Uchida, I.; Ueda, Y.; Uyehara, T.; Vasella, A. T.; Vladuchick, W.
C.; Wade, P. A.; Williams, R. M.; Wong, H. N. C. J. Am. Chem. Soc. 1981, 103,
3210e3213 for an early review; (d) Drauz, K.; Kleemann, A.; Martens, J. Angew.
Chem., Int. Ed. Engl. 1982, 21, 584e608; Angew. Chem. 1982, 94, 590e613; (e)
List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395e2396; (f)
Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386e7387; (g) Ahrendt, K. A.;
Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243e4244; (h)
Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
9874e9875; (i) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611e3614; (j) Enders,
D.; Seki, A. Synlett 2002, 26e28; (k) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett.
2001, 3, 2423e2425; (l) Northrup, A. B.; Macmillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798e6799.
16. (a) Martens, J.; Luebben, S. Arch. Pharm. (Weinheim, Ger.) 1991, 324, 59e60; (b)
Grondal, C.; Enders, D. Tetrahedron 2005, 62, 329e337.
17. (a) Clark, J. H. Green Chem. 1999, 1, 1e8; (b) Anastas, P. T.; Kirchhoff, M. M. Acc.
Chem. Res. 2002, 35, 686e694.
18. For excellent recent reviews see: (a) Gruttadauria, M.; Giacalone, F.; Noto, R.
Chem. Soc. Rev. 2008, 37, 1666e1688; (b) Kristensen, T. E.; Hansen, T. Eur. J. Org.
Chem. 2010, 3179e3204 references therein; further selected examples; (c)
Manabe, K.; Kobayashi, S. Adv. Synth. Catal. 2002, 344, 270e273; (d) Youk, S. H.;
Oh, S. H.; Rho, H. S.; Lee, J. E.; Lee, J. W.; Song, C. E. Chem. Commun. 2009,
2220e2222; (e) Rodriguez-Llansola, F.; Miravet, J. F.; Escuder, B. Chem. Commun.
€
3. For recent reviews discussing enamine- and iminium-catalysis see: (a) Erkkila,
A.; Majander, I.; Pikho, P. M. Chem. Rev. 2007, 107, 5416e5470; (b) Mukherjee,
S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471e5569; (c)
Bertelsen, S.; Nielsen, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46,
7356e7359.
4. (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336e9337; (b) List, B.; Pojarliev, P.;
Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827e833.
€
2009, 7303e7305; (f) Zambouli, A.; Rahier, N. J.; Gehringer, M.; Cattoen, X.;
Niel, G.; Bied, C.; Moreau, J. J. E.; Wong Chi Man, M. Tetrahedron: Asymmetry
2009, 20, 2880e2885; (g) Rueping, M.; Sugiono, E.; Steck, A.; Theissmann, A.
Adv. Synth. Catal. 2010, 352, 281e287; (h) Hagiwara, H.; Kuroda, T.; Hoshi, T.;
Suzuki, T. Adv. Synth. Catal. 2010, 352, 909e916; (i) Revell, J. D.; Gantenbein, D.;
Krattiger, P.; Wennemers, H. Biopolymers (Pept. Sci.) 2006, 84, 105e113.
5. Selected examples: (a) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126,
5356e5357; (b) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int.
Ed. 2004, 43, 1566e1568; (c) Yang, J. W.; Chandler, C.; Stadler, M.; Kampen, D.;
List, B. Nature 2008, 452, 453e455; (d) Giera, D. S.; Sickert, M.; Schneider, C.
Org. Lett. 2008, 10, 4259e4262; (e) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.;
Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 199e201; (f) Bernardi, L.; Gothelf, A.
S.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583e2591; (g) Zhang,
H.; Syed, S.; Barbas, C. F., III. Org. Lett. 2010, 12, 708e711; (h) Mitsumori, S.;
Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem.
19. For similar approaches see: (a) Kondo, K.; Yamano, T.; Takemoto, K. Makromol.
Chem. 1985, 186, 1781e1785; (b) Giacalone, F.; Gruttadauria, M.; Mossuto
Marculescu, A.; Noto, R. Tetrahedron Lett. 2007, 48, 255e259; (c) Giacalone, F.;
Gruttadauria, M.; Mossuto Marculescu, A.; D’Anna, F.; Noto, R. Catal. Commun.
2008, 9, 1477e1481; (d) Doyaguez, E. G.; Calderon, F.; Sanchez, F.; Fernandez-
Mayoralas, A. J. Org. Chem. 2007, 72, 9353e9356; (e) Alza, E.; Rodríguez-Escrich,
ꢂ
C.; Sayalero, S.; Bastero, A.; Pericas, M. A. Chem.dEur. J. 2009, 15, 10167e10172.
ꢁ
ꢁ
20. (a) Svec, F.; Frechet, J. M. J. Chem. Mater. 1995, 7, 707e715; (b) Svec, F.; Frechet,
J. M. J. Ind. Eng. Chem. Res. 1999, 38, 34e48; (c) Burguete, M. I.; Fraile, J. M.;
Garcia, J. I.; García-Verdugo, E.; Luis, S. V.; Mayoral, J. A. Org. Lett. 2000, 2,
3905e3908.
ꢁ
Soc. 2006, 128, 1040e1041; (i) Cordova, A.; Watanabe, S.-I.; Tanaka, F.; Notz, W.;
Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1866e1867; (j) Rodríguez, B.; Bolm,
C. J. Org. Chem. 2006, 71, 2888e2891; (k) Hayashi, Y.; Tsuboi, W.; Ashimine, I.;
Urushima, T.; Shoji, M.; Sakai, K. Angew. Chem., Int. Ed. 2003, 42, 3677e3680.
6. (a) Itoh, T.; Yokaya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2003, 5,
4301e4304; (b) Itoh, T.; Yokaya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org.
21. He, R.; Toy, P. H.; Lam, Y. Adv. Synth. Catal. 2008, 350, 54e60.
22. Gruttadauria, M.; Giacalone, F.; Mossuto Marculescu, A.; Meo, P. L.; Riela, S.;
Noto, R. Eur. J. Org. Chem. 2007, 4688e4698.