Efficient catalysts for asymmetric Mannich reactions

Article abstract of DOI:10.1039/c3ob40681d

Efficient chiral catalysts for direct asymmetric three-component Mannich reactions of ketones, aldehydes and an amine (p-anisidine) have been developed. The corresponding β-amino carbonyl compounds (Mannich adducts) were obtained in good chemical yields a

Full text of DOI:10.1039/c3ob40681d

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Efficient catalysts for asymmetric Mannich reactions
Michał Rachwalski,*a,b Tim Leenders,a Sylwia Kaczmarczyk,c Piotr Kiełbasiński,c
Stanisław Leśniakb and Floris P. J. T. Rutjesa
Cite this: Org. Biomol. Chem., 2013, 11,
4207
Efficient chiral catalysts for direct asymmetric three-component Mannich reactions of ketones, aldehydes
and an amine (p-anisidine) have been developed. The corresponding β-amino carbonyl compounds
(Mannich adducts) were obtained in good chemical yields and excellent enantio- and diastereoselecti-
vities. The reaction conditions have been optimized by invoking ultrasonication and the influence of
some structural moieties of the catalysts on the chemical yield and stereoselectivity of the Mannich
products has been evaluated.
Received 5th April 2013,
Accepted 1st May 2013
DOI: 10.1039/c3ob40681d
www.rsc.org/obc
same year, Sebesta and co-workers introduced L-proline-
derived sulfonamides as very efficient catalysts in the Mannich
Introduction
The synthesis of chiral, enantiomerically pure compounds is reaction of cyclohexanone with N-PMP-protected α-imino ethyl-
an important aspect of synthetic organic chemistry due to the glyoxylate in different solvents.13 More recently, Maruoka and
importance of single stereoisomers in industrial sectors (e.g. co-workers reported a stereocontrolled synthesis of vicinal di-
pharma and food). As a result, the design and synthesis of amines by asymmetric Mannich reaction of N-protected
appropriate catalysts for asymmetric reactions is crucial to be aminoacetaldehydes.14
able to create chiral products in a highly enantioselective
manner.
In the past few years, we designed a series of chiral organo-
catalysts, containing hydroxyl, sulfinyl and amino moieties,
The asymmetric Mannich reaction is synthetically useful for with two stereogenic centers, one located on the sulfinyl sulfur
the construction of nitrogen-containing chiral molecules.1,2 An atom and the other on the carbon atom in the amine moiety15
efficient proline-promoted three-component Mannich reaction (Fig. 1). These catalysts were shown to efficiently catalyze
was developed by List et al.3,4 Similar results concerning various enantioselective reactions for asymmetric carbon–
proline-catalyzed Mannich reactions were described by Barbas carbon bond formation. In particular, the catalysts containing
and co-workers,5 albeit the latter approach involved the use of secondary amines turned out to be useful for the stereo-
preformed imines.
selective nitroaldol (Henry) reaction,16 the aza-Henry reaction17
Recent developments on asymmetric Mannich reactions and the asymmetric direct aldol reaction.18
include asymmetric catalysis using enantiopure scandium(III),6,7
The ones bearing chiral aziridinyl substituents proved
copper,8,9 and palladium complexes.10 Nevertheless, the efficient for enantioselective diethylzinc and phenylethynylzinc
majority of Mannich reactions are still based on enamine additions to aldehydes,19,20 and enantioselective conjugate
catalysis and new examples keep emerging, thereby continu- Michael addition of diethylzinc to enones.21 Moreover, it was
ously increasing the scope. List et al. developed a method for possible to access both enantiomeric products of these reac-
the one-pot asymmetric synthesis of diaminoaldehydes with tions using readily available enantiopure diastereomeric cata-
very high stereoselectivities from acetaldehyde and various lysts. Following up on the aforementioned results, we decided
N-Boc imines.11 One year later, an enantioselective route to
carbamate- and benzoate-protected β-aminoaldehydes and
β-amino acids was reported by Zhao and co-workers.12 In the
aRadboud University Nijmegen, Institute for Molecules and Materials,
Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
E-mail: m.rachwalski@science.ru.nl; Fax: +31 243653393; Tel: +31 243653202
bUniversity of Łódź, Faculty of Chemistry, Department of Organic and Applied
Chemistry, Tamka 12, 91-403 Łódź, Poland. E-mail: mrach14@wp.pl;
Fax: +48 0426655162; Tel: +48 0426355767
cCentre of Molecular and Macromolecular Studies, Polish Academy of Sciences,
Department of Heteroorganic Chemistry, Sienkiewicza 112, 90-363 Łódź, Poland
Fig. 1 Enantiopure sulfoxide-based catalysts bearing chiral amines.
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to apply our catalysts in three-component Mannich reactions
using the standard enamine-mediated Mannich conditions.4
Table 1 Screening of catalysts 3
Results and discussion
Synthesis and screening of the ligands
Five chiral catalysts 3a–e, derived from (−)-cis-myrtanylamine
(a), (−)-(S)- and (+)-(R)-1-(1′-naphthyl)ethylamine (b and c,
respectively) and (−)-(S)- and (+)-(R)-phenylethylamine (d and e,
respectively), were synthesized as described previously
(Scheme 1).15 In order to study the catalytic activity of the cata-
lysts in the asymmetric three-component Mannich reaction,
we chose the process involving hydroxyacetone, p-anisidine
and p-nitrobenzaldehyde (Table 1) as a benchmark reaction.
Initially, standard Mannich conditions were applied (DMSO as
solvent, room temperature) using 35 mol% of catalyst 3c. Since
the reaction proceeded rather slowly, a catalytic amount
(15 mol%) of acetic acid was added. This resulted after 48 h in
the formation of the corresponding Mannich adduct in good
ee (around 80%), but unsatisfactory chemical yield (approxi-
mately 40%). In order to enhance the reaction rate, we were
inspired by a publication from the Kantam group,22 who
demonstrated an advantageous effect of ultrasound treatment
on Mannich reactions both in terms of yield and ee. Thus, the
reaction was repeated under identical conditions, but now sub-
jected also to ultrasound. Gratifyingly, after 1 h, TLC showed
complete conversion of the reaction. The results for the other
catalysts are collected in Table 1.
Product 4
eeb (%)
drc
a
Entry
Catalyst
Yield [%]
[α]D
1
2
3
4
5
3a
3b
3c
3d
3e
62
80
85
58
60
−2.0
+3.3
−3.5
+1.9
−2.0
57
91
97
54
56
13 : 1
18 : 1
20 : 1
12 : 1
13 : 1
a In chloroform (c = 1). b Determined by chiral HPLC for the major
diastereoisomer. c Based on 1H NMR data of the crude product.
Catalysts 3b and c have the same absolute configuration at the
sulfinyl sulfur atom (R) and opposite configurations on the
amine moieties ((S) and (R), respectively) leading to opposite
enantiomers of product 4. The slight differences in ee between
entries 2 and 3 might be explained in terms of ‘matched’ and
‘mismatched’ interactions with the stereogenic sulfinyl center.
An additional experiment using lower catalyst 3c loading
(10 mol%) was performed and the corresponding Mannich
adduct 4 was obtained in lower chemical yield and ee (79%
and 88%, respectively).
It shows that catalyst 3a, bearing the (−)-cis-myrtanylamine
moiety and catalysts 3d–e (bearing (−)-(S)- and (+)-(R)-phenyl-
ethylamine), exhibited only moderate catalytic activity in this
process (entries 1, 4 and 5, respectively). On the other hand,
catalysts 3b and c, containing the enantiomeric 1-(1′-naphthyl)-
ethylamine moieties, appeared more effective (entries 2 and 3),
providing product 4 in high yield and excellent ee. Considering
the outcome, we assume that the main stereocontrol is exerted
by the stereogenic centers located on the amine moieties.
Asymmetric Mannich reactions in the presence of catalyst 3c
On the basis of the screening results, we decided to determine
the scope of the activity of catalyst 3c. It was therefore applied
in asymmetric three-component Mannich reactions involving
acetone (R = H) or hydroxyacetone (R = OH) as ketone, various
aldehydes and p-anisidine as starting materials under identical
reaction conditions as in the screening experiments
(Scheme 2). The results of these Mannich transformations are
shown in Table 2.
Inspection of Table 2 makes it clear that catalyst 3c efficien-
tly catalyzes the title reaction leading to the appropriate
Mannich adducts 4–12. Only in the case of entry 2, where an
aliphatic aldehyde was applied, the corresponding chiral
product was obtained in lower chemical yield and lower
enantioselectivity (65 and 78%, respectively). In the other
entries, the enantiopure Mannich adducts were formed in
high chemical yields (82–93%), excellent enantioselectivities
(94–99% ee) and generally high diastereoselectivities. In the
reaction of hydroxyacetone and p-methoxybenzaldehyde (entry
Scheme 1 Synthesis of catalysts 3a–c.
Scheme 2 Mannich reaction promoted by catalyst 3c.
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Table 2 Asymmetric Mannich reactions promoted by catalyst 3c
Characterization
eeb (%) drc
4 : 1
a
Entry Mannich product
1
Yield (%) [α]D
92
+2.1 89
2
3
91
+8.2 91
6 : 1
Scheme 3 Catalysts 13, 14, 15 and 19.
85
−3.5 97
20 : 1
4
5
65
82
+7.6 78
—
—
+11.2 95
Scheme 4 Synthesis of catalyst 13.
6
7
91
93
−13.5 99
15 : 1
15 : 1
involving treatment with trifluoroacetic anhydride in the pres-
ence of sodium iodide in acetone at 0 °C (Scheme 4).
+1.0 96
The acetylated derivative 14 was synthesized as described
previously.15 Sulfone 15 was obtained by oxidation of catalyst
3c with m-CPBA. Diamine 19 was synthesized starting from bis
(hydroxymethylphenyl)sulfide 16, which upon PCC-mediated
oxidation24 of the diol to dialdehyde 17, oxidation to the sulf-
oxide 18 with m-CPBA and subsequent reductive amination25
with the aid of sodium triacetoxyborohydride gave the final
diamine structure 19 in an overall yield around 60%
(Scheme 5).
8
9
86
90
+52.6 94
9 : 1
3 : 1
−1.4 65
All amines 13–15 and 19 were tested as catalysts under the
optimal Mannich conditions using hydroxyacetone, p-nitro-
benzaldehyde and p-anisidine as starting materials (Table 3).
Table 3 clearly shows that modification of the catalyst,
either by the protection of the alcohol (entry 2), or removal of
a In chloroform (c = 1). b Determined by chiral HPLC for the major
diastereoisomer. c Based on 1H NMR data of the crude product.
9), the product was formed in good chemical yield, but with a
lower ee value. Similar findings for L-proline-catalyzed
Mannich reaction were reported in the literature.4
Influence of hydroxyl and sulfinyl groups on the
stereochemistry of the process
In order to verify the influence of the sulfinyl and hydroxy mo-
ieties on the stereochemical outcome and chemical yield of
the Mannich reactions, compounds 13–15 and 19 were syn-
thesized (Scheme 3).
Compound 13 contains the sulfide instead of the sulfinyl
moiety and was obtained in 40% yield from catalyst 3c using a
mild reduction method as described by Oae and Drabowicz23 Scheme 5 Synthesis of catalyst 19.
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Table 3 Studies on the influence of the sulfinyl and hydroxy groups
Table 4 Asymmetric Mannich reactions promoted by catalyst 19
Product 4
Characterization
a
a
Entry
Catalyst
Yield (%)
[α]D
eeb (%)
drc
9 : 1
9 : 1
7 : 1
Entry Mannich product
1
Yield (%) [α]D
eeb (%) drc
1
2
3
4
13
14
15
19
62
58
52
94
−1.8
−1.9
−1.7
−3.6
50
53
48
99
96
+2.2 89
4 : 1
20 : 1
a In chloroform (c = 1). b Determined by chiral HPLC for the major
2
3
95
+8.6 91
6 : 1
diastereoisomer. c Based on 1H NMR data of the crude product.
the sulfinyl stereogenic center by reduction or oxidation
(entries 1 and 3, respectively), leads to the corresponding
Mannich adduct in moderate chemical yield and considerably
lower enantiomeric excess. These data show that, although the
main stereocontrol is exerted by the stereogenic centers
located on the amine moiety (vide supra), the combination of
the free alcohol and the sulfinyl moiety in the catalyst has a
positive effect on the enantioselectivity of the title reaction. On
the other hand, replacement of the hydroxy group by a chiral
amine moiety, to produce the diamino derivative 19, caused an
enhancement in chemical yield and stereoselectivity of the
Mannich product (entry 4). As the absolute configuration of
both amino moieties is the same, the sulfinyl group is not a
stereogenic centre anymore, which again shows the more deci-
sive role of the stereogenic centre located in the amine part of
the catalyst in the stereoselectivity of the reaction. Hence,
diamine catalysts seem to be more efficient than amino alco-
hols in asymmetric three-component Mannich reactions.
94
−3.6 99
20 : 1
4
5
70
88
+8.2 84
—
—
+11.7 99
6
7
95
98
−13.5 99
15 : 1
15 : 1
+1.0 98
8
9
91
90
+54.3 97
9 : 1
3 : 1
Asymmetric Mannich reactions in the presence of catalyst 19
Since catalyst 19 exhibited the highest efficiency in terms of
chemical yield and stereoselectivity of the chiral Mannich
product, we decided to reassess all the substrates from Table 2
and subjected them to the title reaction under optimized con-
ditions (Scheme 6).
−1.4 65
The results of these transformations are shown in Table 4.
Inspection of Table 4 clearly shows that all the results in
terms of chemical yield and stereoselectivities have been
improved by the use of diamine catalyst 19.
a In chloroform (c = 1). b Determined by chiral HPLC for the major
diastereoisomer. c Based on 1H NMR data of the crude product.
efficient in effecting asymmetric three-component Mannich
reactions. By systematically modifying the catalyst, we showed
that the chiral amine moiety had the largest influence on the
stereochemistry of the reaction. The introduction of a second
chiral amine moiety in the catalyst improved both chemical
yield and stereoselectivity of the asymmetric Mannich process.
Conclusions
Efficient chiral catalysts bearing two stereogenic centers, one
located on the sulfinyl sulfur atom and the other on the
carbon atom in the chiral amine moiety, were found to be
Experimental section
General information
Unless otherwise specified, all the reagents were purchased
from commercial suppliers and used as received. Reactions
were followed using thin layer chromatography (TLC) on silica
Scheme 6 Mannich reaction promoted by catalyst 19.
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gel-coated plates (Merck 60 F254) with the indicated solvent (CH2O), 125.22 (Car), 125.43 (Car), 126.81 (Car), 127.34 (Car),
mixture. Detection was performed with UV-light. Optical 127.52 (Car), 127.75 (Car), 128.33 (Car), 128.54 (Car), 129.13
rotations were determined with a Perkin Elmer 241 polari- (Car), 129.22 (Car), 129.85 (Car), 130.12 (Car), 130.32 (Car),
meter. NMR spectra were recorded on a Bruker DMX 300 131.10 (Car), 133.72 (Cq ar), 134.12 (Cq ar), 136.72 (Cq ar), 137.93
spectrometer at 300 MHz in CDCl3. Chemical shifts are given (Cq ar), 138.56 (Cq ar), 138.63 (Cq ar), 140.0 (Cq ar); HRMS (ESI)
in ppm with respect to tetramethylsilane (TMS) as an internal calcd for C26H24NO3S: 431.3267; found: 431.3264 (M + H).
standard. Coupling constants are reported as J-values in Hz.
High resolution mass spectra were recorded on a JEOL
AccuTOF (ESI) or a MAT900 (EI, CI and ESI). The enantiomeric
Synthesis of catalyst 19
excess (ee) values were determined by chiral HPLC (Chiralpak Bis(hydroxymethylphenyl)sulfide 16 was synthesized according
AD-H).
to the procedure described previously.15 The next step leading
to dialdehyde 17 was performed by following the procedure
described by Hsu and co-workers.24 A mixture of pyridinium
Synthesis of catalysts 3a–e
Chiral diastereomeric catalysts 3a–e and 14 were synthesized chlorochromate (PCC) (6.86 g, 31.5 mmol) in dry dichloro-
according to procedures described previously.15
methane (42 mL) was added dropwise to a solution of 16
(2.02 g, 8.23 mmol) in dry dichloromethane (30 mL). After stir-
ring at room temperature for 4 h, the reaction mixture was fil-
Synthesis of catalyst 13
Catalyst 13 was synthesized using a procedure described by tered. The residue was washed with dichloromethane (3 ×
Drabowicz and Oae.23 A round-bottom flask was charged with 20 mL) and diethyl ether (20 mL). The filtrate and washings
acetone (3 mL), catalyst 3c (200 mg, 0.48 mmol) and sodium were combined and concentrated in vacuo to give 17 as a
1
iodide (174 mg, 1.16 mmol). The flask was immersed in an ice yellowish solid (1.7 g, 85%), m.p. 97 °C; H NMR (CDCl3): δ =
bath (0 °C) and an acetone solution of trifluoroacetic anhy- 7.15 (d, J = 6.0 Hz, 2H), 7.40–7.51 (m, 4H), 7.95 (dd, J = 6.0,
dride (264 mg, 1.25 mmol, 0.175 mL) was slowly added with 3.0 Hz, 2H), 10.35 (s, 1H).
stirring. After 0.5 h, TLC showed completion of the reduction
Oxidation of the sulfide 17 to the corresponding sulfoxide
of the sulfoxide. After acetone has been evaporated, water was 18 was performed by following a procedure described by
added and the mixture was extracted with diethyl ether (7 mL). Daines et al.26 Sulfide (dialdehyde) 17 (1.5 g, 6.20 mmol) was
The ether extract was washed with a sodium thiosulfate solu- dissolved in dry dichloromethane (15 mL) and cooled to 0 °C.
tion and water. Upon evaporation of ether from the dried MCPBA (1.33 g, 6.55 mmol) was added and the solution was
extract, virtually pure sulfide was obtained. Final purification stirred for 30 min at room temperature. After this time the
was performed by filtration through a short silica gel column reaction mixture was diluted with ethyl acetate, washed with
with heptane as an eluent to yield 13 (77 mg, 40%) as a yellow- saturated aqueous NaHCO3 and brine, and dried over anhy-
1
ish oil. [α]D = −24.6 (CHCl3, c = 1); H NMR (CDCl3): δ = 1.44 drous MgSO4. After evaporation of the solvent the crude
(d, J = 6.0 Hz, 3H), 2.80 (br s, 2H), 3.85 (s, 2H), 4.65 (s, 2H), mixture was purified via column chromatography on silica gel
4.55 (q, J = 6.0 Hz, 1H), 7.10–8.13 (m, 15H); 13C NMR (CDCl3): using a mixture of ethyl acetate with heptane (in gradient) as
δ = 22.16 (CH3), 50.21 (CH), 57.64 (CH2N), 63.52 (CH2O), an eluent to afford the desired sulfoxide as yellowish foam
124.38 (Car), 124.87 (Car), 125.38 (Car), 126.12 (Car), 126.35 (1.20 g, 75%); 1H NMR (CDCl3): δ = 7.57–7.61 (m, 2H),
(Car), 126.78 (Car), 127.1 (Car), 127.37 (Car), 127.48 (Car), 127.95 7.98–8.01 (m, 2H), 8.08–8.10 (m, 2H), 10.7 (s, 1H).
(Car), 128.38 (Car), 129.88 (Car), 130.52 (Car), 131.54 (Car),
Reductive amination of dialdehyde (sulfoxide) 18 was
131.67 (Car), 132.19 (Car), 132.78 (Car), 133.56 (Car), 133.59 carried out using a method described by Abdel-Magid et al.25
(Car), 134.76 (Car), 134.79 (Car), 142.68 (Car); HRMS (ESI) calcd Dialdehyde 18 (0.8 g, 4.40 mmol) and (+)-(R)-1-(1′-naphthyl)-
for C26H25NOS: 400.3624; found: 400.3628 (M + H).
ethylamine (1.50 g, 8.77 mmol) were dissolved in anhydrous
THF (30 mL) and then treated with sodium triacetoxyboro-
hydride (2.61 g, 12.31 mmol). The reaction mixture was stirred
Synthesis of catalyst 15
Catalyst 3c (0.10 g, 0.24 mmol) was dissolved in dry dichloro- at room temperature for 2 h. Finally, the mixture was
methane (10 mL) and MCPBA (0.17 g, 0.98 mmol) was added quenched by adding a saturated aqueous solution of NaHCO3,
and the solution was stirred for 24 h at room temperature. and the product was extracted with ethyl acetate. The extract
After this time the reaction mixture was washed with 5% was dried over anhydrous MgSO4, and the solvent was evapor-
aqueous Na2CO3, extracted with dichloromethane and dried ated to give the crude product. Column chromatography on
over anhydrous MgSO4. After evaporation of the solvent the silica gel (ethyl acetate with heptane in gradient as an eluent)
crude mixture was purified via column chromatography on provided the catalyst 19 as a yellowish oil (2.21 g, 88%); [α]D
=
1
silica gel using a mixture of ethyl acetate with heptane (in gra- −47.3 (CHCl3, c = 1); H NMR (CDCl3): δ = 1.41 (d, J = 6.9 Hz,
dient) as an eluent to afford the corresponding sulfone 15 as 6H), 3.95 (s, 2H), 4.29 (q, J = 6.0 Hz, 2H), 6.89–8.01 (m, 22H);
yellowish foam (0.078 g, 78%); [α]D = −8.3 (CHCl3, c = 1); 13C NMR (CDCl3): δ = 22.48 (2CH3), 49.10 (2CH), 60.34
1H NMR (CDCl3): δ = 1.93 (d, J = 6.9 Hz, 3H), 4.44–4.62 (m, (2CH2N), 123.92 (2Car), 124.32 (2Car), 125.63 (2Car), 126.15
4H), 5.89 (q, J = 6.9 Hz, 1H), 7.10–8.10 (m, 15H); 13C NMR (2Car), 126.82 (2Car), 127.10 (2Car), 127.62 (2Car), 127.95 (2Car),
(CDCl3): δ = 20.9 (CH3), 39.91 (CH), 60.91 (CH2N), 61.75 128.42 (2Car), 128.57 (2Car), 130.11 (2Car), 131.24 (2Car), 134.23
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(2Car), 135.72 (2Car), 137.23 (2Car), 141.52 (2Car); HRMS (ESI)
calcd for C38H36N2OS: 569.3579; found: 569.3584 (M + H).
(3S,4R)-4-(4-Bromophenyl)-3-hydroxy-4-(4-methoxyphenyl-
amino)butan-2-one (10), a yellowish oil; H NMR (CDCl3): δ =
1
2.35 (s, 3H), 3.27 (br s, 1H), 3.65 (s, 3H), 3.95 (br s, 1H), 4.42
(d, J = 1.0 Hz, 1H), 4.90 (d, J = 1.0 Hz, 1H), 6.48–6.51 (m, 2H),
6.61–6.67 (m, 2H), 7.39–7.45 (m, 2H), 7.50–7.54 (m, 2H). Other
Asymmetric three-component Mannich reaction – general
procedure
A round-bottom flask containing a mixture of the catalyst spectroscopic data are in agreement with the literature.4
(0.15 mmol), p-anisidine (0.123 g, 1 mmol), ketone (2 mL in
(3S,4R)-3-Hydroxy-4-(4-methoxyphenylamino)-4-phenylbutan-
1
the case of acetone and 0.74 g, 10 mmol in the case of hydro- 2-one (11), a colorless solid; H NMR (CDCl3): δ = 2.35 (s, 3H),
xyacetone), glacial acetic acid (10 μL, 0.15 mmol) and an alde- 3.30 (br s, 1H), 3.62 (s, 3H), 4.38 (br s, 1H), 4.42 (d, J = 1.0 Hz,
hyde (1.1 mmol) in DMSO (8 mL) was immersed in an 1H), 4.86 (d, J = 1.0 Hz, 1H), 6.42–6.48 (m, 2H), 6.65–6.71 (m,
ultrasonic bath and was sonicated for 1 h at room temperature. 2H), 7.24–7.28 (m, 2H), 7.31–7.37 (m, 2H). Other spectroscopic
After this time, a phosphate buffer solution (pH 7.4) was data are in agreement with the literature.4
added and the mixture was extracted with ethyl acetate. After
(3S,4R)-3-Hydroxy-4-(4-methoxyphenyl)-4-(4-methoxyphenyl-
1
drying with anhydrous MgSO4 and evaporation of the solvent, amino)butan-2-one (12), a yellowish oil; H NMR (CDCl3): δ =
the crude mixture was subjected to column chromatography 2.33 (s, 3H), 3.35 (br s, 1H), 3.72 (s, 3H), 3.83 (s, 3H), 4.28 (br
(heptane with ethyl acetate in gradient as an eluent) to afford s, 1H), 4.44 (d, J = 2.0 Hz, 1H), 4.95 (d, J = 2.0 Hz, 1H),
chiral Mannich products 4–10. The values of their chemical 6.52–6.58 (m, 2H), 6.71–6.76 (m, 2H), 6.92–6.98 (m, 2H),
yields, optical rotations, ee’s and dr’s are collected in Tables 7.38–7.45 (m, 2H). Other spectroscopic data are in agreement
1–3, respectively.
with the literature.4
(3S,4R)-3-Hydroxy-4-(4-methoxyphenylamino)-4-(2-methoxy-
1
phenyl)butan-2-one (4), a yellow oil; H NMR (CDCl3): 2.37 (s,
3H), 3.71 (s, 3H), 3.78 (br s, 1H), 3.99 (s, 3H), 4.40 (br s, 1H),
4.57 (d, J = 2.0 Hz, 1H), 5.39 (d, J = 2.0 Hz, 1H), 6.48–6.51 (m,
Acknowledgements
2H), 6.68–6.97 (m, 2H), 6.86–6.97 (m, 2H), 7.22–7.32 (m, 2H). We gratefully acknowledge general financial support from the
Other spectroscopic data are in agreement with the Netherlands Organisation for Scientific Research (NWO-CW),
literature.27
in particular, the ACTS IBOS programme. Part of the work was
(3S,4R)-3-Hydroxy-4-(4-methoxyphenylamino)-4-(3-methyl- financially supported by the Polish Ministry of Science and
1
phenyl)butan-2-one (5), yellowish foam; H NMR (CDCl3): 2.33 Higher Education, Grant No. N N204 131140 for PK.
(s, 3H), 2.37 (s, 3H), 3.72 (s, 3H), 3.77 (br s, 1H), 4.34 (br s,
1H), 4.43 (d, J = 2.6 Hz, 1H), 4.87 (d, J = 2.6 Hz, 1H), 6.52–6.54
(m, 2H), 6.70–6.72 (m, 2H), 7.08–7.29 (m, 4H). Other spectro-
Notes and references
scopic data are in agreement with the literature.27
(3S,4R)-3-Hydroxy-4-(4-methoxyphenylamino)-4-(4-nitrophe-
nyl)butan-2-one (6), yellowish foam; H NMR (CDCl3): δ = 2.38
1 (a) J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M.
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29; (b) A. Ting and S. E. Schaus, Eur. J. Org. Chem., 2007,
5797; (c) S. Hoekman, J. M. M. Verkade and F. P. J. T.
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R. Mahrwald, Springer, Heidelberg, pp. 343–378.
2 For general reviews on organocatalysis, see e.g.: Asymmetric
organocatalysis, ed. A. Berkessel and H. Gröger, Wiley-VCH,
Weinheim, 2005; Enantioselective organocatalysis, ed.
P. I. Dalko, Wiley-VCH, Weinheim, 2007.
1
(s, 3H), 3.62 (s, 3H), 3.88 (br s, 1H), 4.25 (br s, 1H), 4.40 (d, J =
1.0 Hz, 1H), 5.00 (d, J = 1.0 Hz, 1H), 6.49–6.50 (m, 2H),
6.68–6.74 (m, 2H), 7.51–7.53 (m, 2H), 8.25–8.27 (m, 2H). Other
spectroscopic data are in agreement with the literature.4
(R)-4-(4-Methoxyphenylamino)oct-7-en-2-one (7), a yellow
oil; 1H NMR (CDCl3): δ = 1.58–1.65 (m, 2H), 2.12 (s, 3H),
2.51–2.74 (m, 2H), 3.49 (br s, 1H), 3.75–3.80 (m, 1H), 3.75 (s,
3H), 4.94–5.05 (m, 2H), 5.75–5.85 (m, 1H), 6.52–6.54 (m, 2H),
6.75–6.57 (m, 2H). Other spectroscopic data are in agreement
with the literature.4
3 B. List, J. Am. Chem. Soc., 2000, 122, 9336.
4 B. List, P. Pojarliev, W. T. Biller and H. J. Martin, J. Am.
Chem. Soc., 2002, 124, 827.
(R)-4-(4-Methoxyphenylamino)-6-phenylhexan-2-one (8),
a
yellow oil; 1H NMR (CDCl3): δ = 1.85 (m, 2H), 2.12 (s, 3H),
2.52–2.83 (m, 4H), 3.49 (br s, 1H), 3.74–3.76 (m, 1H), 3.75 (s,
3H), 6.49–6.52 (m, 2H), 6.74–6.76 (m, 2H), 7.18–7.25 (m, 3H),
7.26–7.30 (m, 2H). Other spectroscopic data are in agreement
with the literature.4
5 W. Notz, S. Watanabe, N. S. Chowdari, G. Zhong,
J. M. Betancort, F. Tanaka and C. F. Barbas III, Adv. Synth.
Catal., 2004, 346, 1131.
6 C. Xiao-Hua, G. Hui and X. Bing, Eur. J. Chem., 2012, 3,
258.
(3S,4R)-3-Hydroxy-4-(4-methoxyphenylamino)-4-(4-cyanophenyl)-
butan-2-one (9), yellowish foam; H NMR (CDCl3): δ = 2.30 (s,
7 Q. Zhang, Y. H. Hui, X. Zhou, L. L. Lin, X. H. Liu and
X. M. Feng, Adv. Synth. Catal., 2010, 352, 976.
1
3H), 3.25 (br s, 1H), 3.60 (s, 3H), 3.85 (br s, 1H), 4.40 (d, J = 1.0
Hz, 1H), 4.92 (d, J = 1.0 Hz, 1H), 6.42–6.47 (m, 2H), 6.60–6.63
(m, 2H), 7.45–7.48 (m, 2H), 7.54–7.60 (m, 2H). Other spectro-
scopic data are in agreement with the literature.4
8 G. Liang, M.-C. Tong, H. Y. Tao and C.-J. Wang, Adv. Synth.
Catal., 2010, 352, 1851.
9 T. Arai, A. Mishiro, E. Matsumura, A. Awata and
M. Shirasugi, Chem.–Eur. J., 2012, 18, 11219.
4212 | Org. Biomol. Chem., 2013, 11, 4207–4213
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