Asymmetric Mannich reactions by α-silyl controlled aminomethylation of ketones

Article abstract of DOI:10.1055/s-2002-35998

An efficient, regio- and enantioselective synthesis of α-substituted β-amino ketones has been developed. Starting from simple ketones, enantiomerically pure α-silyl ketones 1a-j were prepared employing the SAMP/RAMP hydrazone methodology. The acyclic α-silyl ketones 1a-e were selectively converted to the silyl enol ethers (Z)-2a-e, whereas the cyclic α-silyl ketones 1f-j were obtained exclusively as the silyl enol ethers (E)-2f-j. In all cases the yields were virtually quantitative. Diastereoselective α-silyl controlled Mannich reaction with BF₃·Et₂O activated N,N-dibenzyl-N-methoxymethylamine afforded the α′-substituted β-amino ketones 3a-j in high yields (93-96%) and in one case good otherwise excellent diastereoselectivities (de 65, ≥96%). The configuration of the new stereogenic center follows from mechanistic considerations and was unambigously determined by NOE experiments with the major diastereoisomer (S,R)-3g and by X-ray crystal structure analysis of compound (S,R)-3c. Finally, the silyl group was removed with NH₄F-Bu₄NF in high yields (89-99%). The acyclic α-substituted β-amino ketones 4a-e were achieved in excellent enantiomeric excesses (ee 93-≥96%). During removal of the silyl group of the cyclic α-substituted β-amino ketones 4f-j racemisation could not be totally avoided (ee 32-89%).

Full text of DOI:10.1055/s-2002-35998

PAPER
2737
Asymmetric Mannich Reactions by -Silyl Controlled Aminomethylation of
Ketones
A
symmetric Mann
i
ic
h
Re
e
ctions by
t-Silyl
C
e
ontrolled A
r
minomethyla
E
tion of
K
etonesnders,* Johannes Adam, Stefan Oberbörsch, David Ward
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 18 September 2002
Dedicated to Professor Volker Jäger on the occasion of his 60th birthday.
modern variations lead in general to higher yields with
Abstract: An efficient, regio- and enantioselective synthesis of
-
shorter reaction times, deliver far less undesired side
products and allow kinetic control of the reaction, which
is important in asymmetric synthesis. On this basis
substituted -amino ketones has been developed. Starting from sim-
ple ketones, enantiomerically pure -silyl ketones 1a–j were pre-
pared employing the SAMP/RAMP hydrazone methodology. The
acyclic -silyl ketones 1a–e were selectively converted to the silyl diastereoselective5 or diastereo- and enantioselective6
enol ethers (Z)-2a–e, whereas the cyclic -silyl ketones 1f–j were
obtained exclusively as the silyl enol ethers (E)-2f–j. In all cases the
yields were virtually quantitative. Diastereoselective -silyl con-
methods for the preparation of Mannich bases have been
achieved.
The enantioselective catalytic Mannich reaction for the
synthesis of -amino ketones and aldehydes is a rather
new concept developed recently. Asymmetric Mannich
reactions with catalytically active chiral metal complexes
using N-aryl-, N-tosyl- or N-acylimino esters have been
developed,7 and in addition the proline catalysed asym-
metric reaction was realised recently.8
trolled Mannich reaction with BF3 Et2O activated N,N-dibenzyl-N-
methoxymethylamine afforded the -substituted -amino ketones
3a–j in high yields (93–96%) and in one case good otherwise excel-
lent diastereoselectivities (de 65, 96%). The configuration of the
new stereogenic center follows from mechanistic considerations
and was unambigously determined by NOE experiments with the
major diastereoisomer (S,R)-3g and by X-ray crystal structure anal-
ysis of compound (S,R)-3c. Finally, the silyl group was removed
with NH4F–Bu4NF in high yields (89–99%). The acyclic -substi-
tuted -amino ketones 4a–e were achieved in excellent enantiomer-
ic excesses (ee 93– 96%). During removal of the silyl group of the
cyclic -substituted -amino ketones 4f–j racemisation could not be
totally avoided (ee 32–89%).
In summary, various asymmetric Mannich-type but less
true Mannich reactions have been described and most of
them have been used for the synthesis of - or , -substi-
tuted -amino derivatives. Enantioselective methods for
the synthesis of -substituted Mannich bases are rare and
have been reported using the reaction of SMP-enamines
with iminium species9 or via a catalytic approach shown
by Shibasaki et al.,10 although many -substituted -ami-
no ketones and their derivatives have been shown to be
highly pharmacologically active compounds.3 Herein we
describe in detail our investigations on the asymmetric
synthesis of Mannich bases with a stereogenic center in
the -position employing the concept of efficient -silyl
controlled Mannich reactions.11
Virtually enantiomerically pure -silyl ketones12 were ac-
cessible using the highly regio- and enantioselective
SAMP–RAMP hydrazone method.13 Starting from methyl
ketones, acyclic -silyl ketones (S)-1a–e were produced
in a four-step procedure with enantiomeric excesses of
98% in 49–61% overall yields. Symmetrically substitut-
ed, cyclic ketones were transformed by a three-step reac-
Key words: asymmetric synthesis, aminomethylation, ketones,
enols, silicon, Mannich bases
The Mannich reaction for the synthesis of -amino ke-
tones or aldehydes has been the subject of investigations
since the early 20th century1 and so far has found a multi-
tude of applications in organic chemistry.2 The resulting
Mannich bases are of particular interest as pharmaceuti-
cally active compounds and as chiral building blocks in
the preparation of nitrogen-containing bioactive com-
pounds.3
In the last years progress has been made in asymmetric
Mannich-type reactions with ester or amide enolates for
the preparation of either - or , -substituted -amino es-
ters or acids.4 In comparison, intermolecular Mannich re-
actions for the asymmetric synthesis of -amino ketones
or aldehydes are less developed. One important innova-
tion in this particular reaction type are the use of separate-
ly or in situ prepared a1-reagents (e.g. iminium salts) and
the use of suitable reagents for d2-synthons (e.g. silyl enol
ethers, boron enolates or enamines) in aprotic solvents.2c
In comparison with the classical Mannich reaction these
tion sequence to
-silyl ketones (S)-1f–j with
enantiomeric excesses of 96% in 38–76% overall yields
(Scheme 1, Table 1).
The metalation of acyclic ketones (S)-1a–e with LDA and
addition of Me3SiCl generates silyl enol ethers of both E-
and Z-configuration. The geometrical uniformity of the -
silylated silyl enol ethers 2 is crucial for the stereoselec-
tivity, assuming that a virtually complete diastereofacial
selection arises from the directing dimethylthexylsilyl
group. Thus, the -silylated silyl enol ethers have to be
formed without racemisation and the acyclic ones with a
Synthesis 2002, No. 18, Print: 19 12 2002.
Art Id.1437-210X,E;2002,0,18,2737,2748,ftx,en;Z12602SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2738
D. Enders et al.
PAPER
Scheme 1 Entries to enantiopure -silyl ketones
clearly defined E- or Z-geometry. The acyclic -silyl ke-
tones (S)-1a–e were converted in virtually quantitative
yield to the (Z)-silyl enol ethers (Z,S)-2a–e by regioselec-
tive deprotonation with LDA and trapping of the (Z)-lith-
ium enolates with Me3SiCl in THF–HMPA at –95 °C.14
The Z/E-ratios (Z:E 50: 1) were determined by 1H NMR
spectroscopy [(S)-2a,b] and gas chromatography [(S)-2c–
e] (Table 1).
Scheme 2 Enantioselective synthesis of acyclic -amino ketones.
Reagents and conditions: a) LDA, THF, HMPA, Me3SiCl, –95 °C
r.t.; b) Bn2NCH2OCH3, BF3 Et2O, CH2Cl2, –85 °C
NH4F, Bu4NF, THF, –78 °C r.t.
–78 °C; c)
In the case of cyclic -silylated silyl ketones, an E-geom-
etry of the enolates is clearly defined but deprotonation of
cyclic ketones resulted in the formation of regioisomeric
-silylated silyl enol ethers. The achiral regioisomers
were observed in quantitative yield after 15 minutes using
LDA in THF. Finally, the silyl enol ethers (E,S)-2f–j
could be produced in virtually quantitative yields by add-
ing the silyl ketones to a solution of LDA and Me3SiCl in
THF at –95 °C (‘internal quench’, Table 1).
The application of the hygroscopic iminium salts can be
avoided by the in situ formation of the iminium ions or
similar reactive species.15 The aminoalkylation of the
crude silyl enol ethers with BF3 Et2O acitvated N,N-
dibenzyl-N-methoxymethylamine in CH2Cl2 at –85 °C,
aqueous workup and flash chromatography furnished the
desired -silylated -dibenzylaminomethyl ketones 3a–j
in excellent yields of 93–96% (Schemes 2 and 3,
Table 1 Asymmetric Mannich Reaction by -Silyl Controlled Aminomethylation of Ketones
R1
R2
Yield 1a
eeb
Yield 2
Z:Ec
Yield 3
ded
Yield 4
eee
(%)
(%)
(%)
(%)
(%)
(%)
(%)
a
b
c
d
e
f
n-Pr
i-Bu
p-BrBn
Bn
Me
Me
Me
Et
57
60
58
49
61
61
64
76
38
66
98
98
99
98
98
96
96
96
96
96
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
50:1
95
94
95
95
94
95
94
95
96
93
96
96
96
96
96
96
98
99
98
97
96
98
94
96
93
89
93
94
93
96
96
66
48
89
32
78
50:1
115:1
119:1
Bn
Bn
56:1
-(CH2)2-
–
–
–
–
–
g
h
i
-(CH2)3-
-(CH2)4-
65 ( 96)f
96
96
96
-CH2NBnCH2-
-OC(CH3)2O-
j
a Overall yields over four (1a–e) or three (1f–j) steps, respectively.
b Enantiomeric excesses were determined by gas chromatography of the corresponding -silyl alcohols on a chiral stationary phase ( -cyclo-
dextrin–polysiloxan) (1a–e) and by 1H NMR shift experiments (300 MHz) of the -silyl ketones using Eu(tfc)3 as chiral shift reagent in CDCl3
(f–j).
c Z/E-Ratios were determinated by 1H NMR spectroscopy (300 MHz) (2a,b) and gas chromatography (2c–e).
d Diastereomeric excesses were determined by 1H NMR spectroscopy (300 MHz).
e Enantiomeric excesses were determined by 1H NMR shift experiments [500 MHz (4a–c) and 300 MHz (4d–j)] of the -amino ketones using
(R)-(–)-9-anthryl-2,2,2-trifluoroethanol as chiral cosolvent in C6D6.
f After preparative HPLC.
Synthesis 2002, No. 18, 2737–2748 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Mannich Reactions by -Silyl Controlled Aminomethylation of Ketones
2739
Figure 2 Postulated transition states for the asymmetric Mannich
reactions
Scheme 3 Enantioselective synthesis of cyclic -amino ketones.
Reagents and conditions: a) LDA, THF, HMPA, Me3SiCl (internal
quench), –95 °C
–85 °C –78 °C; c) NH4F, Bu4NF, THF, –78 °C r.t.
r.t.; b) Bn2NCH2OCH3, BF3 Et2O, CH2Cl2,
from 89% up to 99%. The enantiomeric excesses were de-
terminated by 1H NMR spectroscopy using (R)-(–)-9-an-
thryl-2,2,2-trifluoroethanol as chiral cosolvent in C6D6.
For the acyclic -silylated -amino ketones 3a–e the
traceless removal of the silyl group furnished -substitut-
ed -amino ketones 4a–e in high enantiomeric excesses
(ee 93– 96%), whereas during the cleavage of the cyclic
compounds 3f–j partial racemisation could not be avoided
(ee 32–89%). The CH-acidity in the cyclic Mannich bases
seems to be higher than in the acyclic ones facilitating
Table 1). The diastereoisomeric excesses have been deter-
mined by 1H NMR spectroscopy and were virtually com-
plete (de 96%). The compound (S,R)-3g was obtained
with a diastereoisomeric excess of 65%. In this case the -
silylated -amino ketone (S,R)-3g could be separated by
preparative HPLC (de 96%).
The relative configuration was determined by X-ray crys- enolate formation and thus partial racemisation.
tal structure analysis of the acyclic compounds (S,R)-3c11
In summary, we have shown that cyclic and acyclic Man-
and by NOE experiments on the major diastereoisomer of
nich bases bearing a stereogenic center in the -position to
(S,R)-3g for the cyclic derivatives (Figure 1). The (S,R)-
the carbonyl group can be prepared regioselectively in
high enantiomeric purities and excellent overall yields by
the -silyl controlled Mannich reaction.
configuration follows from the known absolute configura-
tion of the -silylated ketones.12
Mps were measured with a Büchi 510 apparatus and are not correct-
ed. IR: Perkin Elmer FT 1750 spectrometer. 1H NMR spectra (300,
400, 500 MHz) and 13C NMR spectra (75, 100 MHz): Varian VXR
300, Varian Gemini 300, Varian Inova 400 and Varian VXR 500
spectrometer, internal standard TMS. MS: Varian MAT 212 and
Finnegan MAT SSQ 7000 spectrometer (EI 70 eV). Elemental anal-
yses: Heraeus CHN-O-RAPID and Elementar Vario EL. GC: Sie-
mens Sichromat 2 and 3, FID, using SE-54, OV1-CB, OV-5 or OV-
17 capilliary columns. Optical rotations: Perkin–Elmer P 241 pola-
rimeter. THF, CH2Cl2, diisopropylamine and HMPA were dried and
Figure 1 NOE connectivitiy in (S,R)-3g
distilled prior to use by standard procedures. Me3SiCl and BF3 Et2O
were freshly distilled prior to use. BuLi (1.6 M solution in hexane)
and Bu4NF (1 M solution in THF) were purchased from Merck and
Aldrich. The pH 6 buffer was purchased from Merck and the pH 7
buffer was prepared from 11.6 g NaOH and 68.0 g KH2PO4 in
1 L H2O. N,N-dibenzyl-N-methoxymethylamine was prepared by a
procedure reported in the literature.16 The -silylated ketones were
The almost complete diastereofacial selectivity can be ex-
plained by the transition states for acyclic and cyclic ke-
tones given in Figure 2. Thus, the bulky t-HexMe2Si-
group effects an efficient shielding of one face of the dou-
ble bond and the electrophile, which is an iminium spe- prepared according to reported procedures.12 All experiments were
performed under protection gas (argon).
cies, preferentially attacks from the other face, which
results in the observed configuration of the newly formed
Acyclic -Silylated Silyl Enol Ethers; General Procedure
stereogenic center.
To a solution of diisopropylamine (1.2 equiv) in anhyd THF (5 mL/
The -silylated -amino ketones 3a–j were converted to mmol amine), BuLi (1.2 equiv) was added at 0 °C. After stirring for
15 min anhyd HMPA (1.15 mL/mmol amine) was added and the so-
the corresponding -amino ketones 4a–j using Bu4NF in
lution was cooled to –95 °C. At this temperature the -silyl ketone
an NH4F suspension in THF at –95 °C. The yields ranged
(1 equiv diluted in 1 mL THF/mmol) was added dropwise. Then un-
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2740
D. Enders et al.
PAPER
diluted Me3SiCl (1.4 equiv) was added and the cooling bath was re-
moved. After warming up to r.t., the mixture was quenched by
addition of sat. aq NaHCO3. The aq layer was separated and extract-
ed with n-pentane (3 ). The combined organic layers were washed
with brine and dried (MgSO4). The crude -silylated silyl enol ether
was used for the next step without further purification. It is recom-
mended not to store the -silylated silyl enol ether because slow E–
Z-isomerisation can occur.
HRMS: m/z calcd for C18H40OSi2 (328.26, M+): 328.2617; found:
328.2617.
(–)-(Z)-1-{(1S)-1-[1,1-Dimethyl-1-(1,1,2-trimethylpropyl)silyl]-
3-methylbutyl}-1-propenyl (1,1,1-Trimethylsilyl) Ether [(Z,S)-
2b]
Reaction of -silyl ketone (S)-1b (0.78 g, 2.9 mmol) and Me3SiCl
(0.53 mL, 2.4 mmol) gave crude (Z,S)-2b.
Yield: 0.98 g (>99%); [ ]D24 –13.8 (c 1.09, CHCl3).
Cyclic -Silylated Silyl Enol Ethers; General Procedure
To a solution of diisopropylamine (1.1 equiv) in anhyd THF (3 mL/
mmol amine) BuLi (1.1 equiv) was added at 0 °C. After stirring for
15 min, the solution was cooled to –95 °C. At this temperature first
undiluted Me3SiCl (1.4 equiv) and then the -silyl ketone (1 equiv
diluted in 1 mL THF/mmol) were added dropwise. Then the cooling
bath was removed and after warming up to r.t. the mixture was
quenched by addition of sat. aq NaHCO3. The aq layer was separat-
ed and extracted with n-pentane (3 ). The combined organic layers
were washed with brine and dried (MgSO4). The crude -silylated
silyl enol ether was used for the next step without further purifica-
tion.
IR (film): 2956, 2867, 2602, 1654, 1466, 1409, 1390, 1378, 1365,
1351, 1334, 1301, 1253, 1234, 1202, 1155, 1119, 1103, 1052, 1034,
978, 950, 932, 870, 844, 791, 755, 683, 621, 607, 552, 505 cm–1.
1H NMR (300 MHz, CDCl3): = 0.02 (s, 3 H, SiCH3), 0.04 (s, 3 H,
SiCH3), 0.22 [s, 9 H, Si(CH3)3], 0.86 (s, 3 H, H3CCCH3), 0.87 (s, 3
H, H3CCCH3), 0.89 (d, 6 H, J = 6.6 Hz, H3CCHCH3), 0.92 (d, 3 H,
J = 6.6 Hz, H3CCHCH3), 0.93 (d, 3 H, J = 6.6 Hz, H3CCHCH3),
1.06 [m, 1 H, (CH3)2CHCHH], 1.52 (d, 3 H, J = 6.6 Hz, CHCH3),
1.65 [m, 1 H, (CH3)2CHCHH], 1.67 (m, 1 H, H3CCHCH3), 1.76
(sept, 1 H, J = 6.6 Hz, H3CCHCH3), 1.80 (dd, 1 H, J = 12.5, 2.2 Hz,
SiCH), 4.33 (q, 1 H, J = 6.6 Hz, = CH).
13C NMR (75 MHz, CDCl3):
= 4.5 (SiCH3), 3.9 (SiCH3), 1.2
Stereoselective Mannich Reaction; General Procedure
To a solution of N,N-dibenzyl-N-methoxymethylamine (1.15 equiv)
in CH2Cl2 (1 mL/mmol silyl enol ether) at –85 °C the -silylated si-
lyl enol ether (1 equiv diluted in 1 mL CH2Cl2/mmol) was added
dropwise. After 15 min stirring, BF3 Et2O (1.15 equiv) was added
and the mixture was slowly warmed up to –78 °C. After complete
conversion (TLC-control) the reaction was quenched with pH 7
buffer, allowed to warm to r.t. and extracted with CH2Cl2 (3 ). The
combined organic layers were dried (NaSO4) and concentrated in
vacuo.
[Si(CH3)3], 11.6 (CHCH3), 18.5 (CHCH3), 18.7 (CHCH3), 21.1
(CCH3), 21.2 (CCH3), 23.7 (CHCH3), 24.2 (CHCH3), 24.3
[C(CH3)2], 26.1 [C(CH3)2], 32.1 [CH(CH3)2], 34.2 (SiCH), 37.5
[(CH3)2CHCH2], 99.0 (=CH), 152.9 (=CO).
MS (EI, 70 eV): m/z (%) = 342 (1) [M+], 244 (5), 243 (22), 219 (4),
187 (4), 149 (9), 148 (18), 147 (100), 133 (8), 131 (5), 75 (5), 73
(62) [Me3Si+], 59 (4).
Anal. Calcd for C19H42OSi2 (342.72): C, 65.59; H, 12.35. Found: C,
65.19; H, 12.35.
Traceless Removal of the -Silyl Group; General Procedure
The -silylated Mannich base (1 equiv) was dissolved in anhyd
THF (10 mL THF/mmol) and cooled to –78 °C. At this temperature
solid NH4F (50 equiv) and Bu4NF (1.5 equiv; 1 M solution in THF)
was added and the resulting suspension was slowly warmed up to
r.t. Finally, the reaction was quenched by addition of pH 6 buffer,
extracted with n-pentane, dried (NaSO4) and concentrated in vacuo.
(+)-(Z)-1-{(1S)-2-(4-Bromophenyl)-1-[1,1-dimethyl-1-(1,1,2-tri-
methylpropyl)silyl]ethyl}-1-propenyl (1,1,1-Trimethylsilyl)
Ether [(Z,S)-2c]
Reaction of -silyl ketone (S)-1c (1.62 g, 4.0 mmol) and Me3SiCl
(0.71 mL, 4.8 mmol) gave crude (Z,S)-2c.
Yield: 2.34 g (>99%); [ ]D24 +1.8 (c 1.22, CHCl3).
IR (film): 3022, 2959, 2867, 2829, 2136 1764, 1662, 1488, 1466,
1404, 1392, 1379, 1365, 1341, 1315, 1252, 1224, 1184, 1167, 1127,
1085, 1073, 1051, 1012, 957, 937, 889, 874, 845, 834, 816, 801,
757, 709, 686, 658, 618, 550, 519, 502, 468 cm–1.
1H NMR (300 MHz, CDCl3): = –0.05 [s, 9 H, Si(CH3)3], 0.04 (s,
3 H, SiCH3), 0.06 (s, 3 H, SiCH3), 0.89 (d, J = 6.8 Hz, 3 H,
CH3CCH3), 0.89 (d, J = 6.8 Hz, 3 H, H3CCHCH3), 0.90 (s, 3 H,
H3CCHCH3), 0.90 (s, 3 H, H3CCCH3), 2.33 (d, J = 6.6 Hz, 3 H,
CHCH3), 1.79 (sept, J = 6.9 Hz, 1 H, H3CCHCH3), 1.94 (dd,
J = 12.4, 3.0 Hz, 1 H, BrC6H4CHH), 2.60 (dd, J = 14.8, 12.4 Hz, 1
H, BrC6H4CHH), 2.76 (dd, J = 14.7, 2.9 Hz, 1 H, SiCH), 4.36 (q,
J = 6.6 Hz, 1 H, =CH), 7.05 (d, J = 8.5 Hz, 2 H, CarH), 7.35 (d,
J = 8.5 Hz, 2 H, CarH).
13C NMR (75 MHz, CDCl3): = –4.2 (SiCH3), –3.5 (SiCH3), 1.5
[OSi(CH3)3], 12.0 (CHCH3), 19.0 (CHCH3), 19.3 (CHCH3), 21.6
(CCH3), 21.8 (CCH3), 24.9 [C(CH3)2], 34.6 [(CH3)2CH], 34.9
(BrC6H4CH2), 36.9 (SiCH), 100.8 (=CH), 119.8 (CarH), 131.1
(CarH), 131.5 (CarH), 142.4 (Car), 151.9 (=CO).
MS (EI, 70 eV): m/z (%) = 455/457 (0.4) [M+ – H], 355/357 (1),
297/299 (2), 213/215 (2), 169/171 (0.5), 147 (0.5), 144 (6) [t-
HexMe2Si+], 133 (6), 129/131 (3), 84 (3), 75 (21), 73 (100)
[Me3Si+], 66 (5), 59 (9).
(–)-(Z)-1-{(1S)-1-[1,1-Dimethyl-1-(1,1,2-trimethylpropyl)silyl]
butyl}-1-propenyl (1,1,1-Trimethylsilyl) Ether [(Z,S)-2a]
Reaction of -silyl ketone (S)-1a (0.54 g, 2.1 mmol) and Me3SiCl
(0.36 mL, 2.9 mmol) gave crude (Z,S)-2a.
Yield: 0.68 g (>99%); [ ]D24 –4.9 (c 1.07, CHCl3).
IR (film): 2957, 2870, 2601, 1655, 1586, 1465, 1410, 1391, 1378,
1346, 1296, 1252, 1232, 1206, 1157, 1127, 1100, 1067, 1033, 1011,
998, 970, 935, 869, 843, 794, 755, 684, 619, 550, 502 cm–1.
1H NMR (400 MHz, C6D6): = 0.11 [s, 9 H, Si(CH3)3], 0.20 (s, 3 H,
SiCH3), 0.21 (s, 3 H, SiCH3), 0.93 (d, 6 H, J = 6.8 Hz, H3CCHCH3),
0.93 (s, 3 H, H3CCCH3), 0.94 (t, 3 H, J = 6.6 Hz, CH2CH3), 0.95 (s,
3 H, H3CCCH3), 1.20–1.70 (m, 4 H, CH3CH2CHH, SiCH), 1.57 (d,
3 H, J = 6.8 Hz, CHCH3), 1.81 (sept, 1 H, J = 6.6 Hz, H3CCHCH3),
1.73 [dd, 1 H, J = 11.8, 2.8 Hz, (CH3CH2CHH)], 4.40 (q, 1 H,
J = 6.6 Hz, =CH).
13C NMR (100 MHz, C6D6):
= 4.3 (SiCH3), 3.5 (SiCH3), 1.3
[Si(CH3)3], 11.9 (=CHCH3), 14.3 (CH3CH2), 18.6 (CHCH3), 18.9
(CHCH3), 21.2 (CCH3), 21.4 (CCH3), 22.8 (CH3CH2), 24.5
[C(CH3)2], 31.1 (CH3CH2CH2), 34.6 [CH(CH3)2], 35.0 (SiCH), 99.5
(=CH), 153.0 (=CO).
MS (EI, 70 eV): m/z (%) = 328 (1) [M+], 230 (4), 229 (17), 149 (7),
148 (17), 147 (100) [t-HexMe2Si+], 74 (5), 73 (58) [Me3Si+].
Anal. Calcd for C22H39BrOSi2 (455.63): C, 58.00; H, 8.63. Found C,
57.96; H, 8.89.
Synthesis 2002, No. 18, 2737–2748 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Mannich Reactions by -Silyl Controlled Aminomethylation of Ketones
2741
(+)-(Z)-1-{(1S)-1-[1,1-Dimethyl-1-(1,1,2-trimethylpropyl)silyl]-
2-phenylethyl}-1-butenyl (1,1,1-Trimethylsilyl) Ether [(Z,S)-
2d]
Reaction of -silyl ketone (S)-1d (0.32 g, 1.0 mmol) and Me3SiCl
(0.18 mL, 1.4 mmol) gave crude (Z,S)-2d.
Yield: 0.30 g (>99%); [ ]D24 –1.5 (c 1.1, CHCl3).
IR (film): 3396, 2957, 2902, 2867, 2601, 2136, 1723, 1613, 1466,
1410, 1378, 1366, 1322, 1311, 1300, 1254, 1190, 1129, 1096, 1060,
987, 872, 843, 763, 684, 671, 624, 605, 558, 497, 465 cm–1.
1H NMR (300 MHz, CDCl3): = 0.06 (s, 3 H, SiCH3), 0.07 (s, 3 H,
SiCH3), 0.20 [s, 9 H, Si(CH3)3], 0.83 (d, J = 6.7 Hz, 3 H,
CH3CHCH3), 0.84 (d, J = 6.7 Hz, 3 H, H3CCHCH3), 0.86 (s, 3 H,
H3CCCH3), 0.87 (s, 3 H, H3CCCH3), 1.72 (sept, J = 6.7 Hz, 1 H,
H3CCHCH3), 1.84–2.26 (m, 5 H, SiCHCH2CH2), 4.44 (dd, J = 4.4,
2.4 Hz, 1 H, =CH).
Yield: 0.38 g (>99%); [ ]D24 +14.6 (c 1.02, CHCl3).
IR (film): 3085, 3063, 3027, 2959, 2903, 2870, 1937, 1797, 1659,
1603, 1494, 1465, 1455, 1391, 1377, 1356, 1300, 1252, 1187, 1167,
1125, 1107, 1073, 1049, 998, 971, 880, 845, 815, 735, 733, 698,
659, 653, 607, 573, 521, 503 cm–1.
1H NMR (300 MHz, CDCl3): = –0.10 [s, 9 H, Si(CH3)3], 0.06 (s,
3 H, SiCH3), 0.07 (s, 3 H, SiCH3), 0.85–0.93 (m, 15 H, CH3CCH3,
H3CCHCH3, CHCH3), 1.83 (sept, J = 6.9 Hz, 1 H, H3CCHCH3),
1.87–1.99 (m, 3 H, C6H5CHH, CHCH2CH3), 2.55 (dd, J = 14.8,
12.4 Hz, 1 H, C6H5CHH), 2.83 (dd, J = 14.6, 3.0 Hz, 1 H, SiCH),
4.32 (t, J = 6.9 Hz, 1 H, =CH), 7.08–7.26 (m, 5 H, CarH).
13C NMR (75 MHz, CDCl3): = –5.6 (SiCH3), –4.7 (SiCH3), 0.3
[OSi(CH3)3], 13.9 (CHCH2CH3), 17.9 (CHCH3), 18.0 (CHCH3),
18.6 (CHCH2CH3), 20.4 (CCH3), 20.5 (CCH3), 23.7 [C(CH3)2],
33.6 [(CH3)2CH], 34.1 (C6H5CH2), 35.7 (SiCH), 108.0 (=CH),
124.9 (p-CarH), 127.2 (o-CarH), 128.3 (m-CarH), 142.2 (Car), 149.2
(=CO).
13C NMR (75 MHz, CDCl3): = –4.7 (SiCH3), –3.8 (SiCH3), –0.1
[OSi(CH3)3], 18.4 (CHCH3), 18.6 (CHCH3), 20.2 (CCH3), 21.1
(CCH3), 24.8 [C(CH3)2], 25.6 (CH2CH2), 29.2 (CH2CH2), 33.2
(SiCH), 34.3 [(CH3)2CH], 99.3 (=CH), 157.9 (=CO).
MS (EI, 70 eV): m/z (%) = 299 (19) [M+ + 1], 231 (5), 229 (9), 228
(7), 227 (25), 225 (0.5) [M+ – Me3Si], 213 (5) [M+ – t-Hex], 171 (7),
157 (6), 155 (28) [M+ – t-HexMe2Si], 149 (22), 148 (16), 147 (100),
143 (6) [t-HexMe2Si+], 141 (17), 139 (6), 133 (22), 131 (6), 117 (8),
111 (6), 99 (5), 85 (11) [t-Hex+], 84 (7), 83 (6), 81 (6), 79 (7), 77 (7),
75 (8), 74 (11), 73 (85) [Me3Si+], 69 (8), 59 (19), 58 (6), 57 (9), 55
(10), 45 (13).
Anal. Calcd for C16H34OSi2 (298.62): C, 64.56; H, 11.48. Found: C,
64.19; H, 11.31.
MS (EI, 70 eV): m/z (%) = 390 (0.6) [M+], 291 (2), 147 (100), 133
(7), 84 (4), 73 (90) [Me3Si+], 66 (7), 59 (7), 45 (6).
(+)-(6R)-6-[1,1-Dimethyl-1-(1,1,2-trimethylpropyl)silyl]-1-cy-
clohexenyl (1,1,1-Trimethylsilyl) Ether [(E,R)-2g]
Reaction of -silyl ketone (R)-1g (0.25 g, 1.0 mmol) and Me3SiCl
(0.18 mL, 1.4 mmol) gave pure (E,R)-2g.
Anal. Calcd for C23H42OSi2 (390.76): C, 70.70; H, 10.83. Found C,
71.00; H, 10.85.
(+)-(Z)-1-{(1S)-1-[1,1-Dimethyl-1-(1,1,2-trimethylpropyl)silyl]-
2-phenylethyl}-3-phenyl-1-propenyl (1,1,1-Trimethylsilyl)
Ether [(Z,S)-2e]
Reaction of -silyl ketone (S)-1e (0.38 g, 1.0 mmol) and Me3SiCl
(0.18 mL, 1.4 mmol) gave crude (Z,S)-2e.
Yield: 0.31 g (>99%); [ ]D24 +26.5 (c 0.8, CHCl3).
IR (film): 3535, 3372, 3044, 2957, 2868, 2839, 2657, 1935, 1653,
1466, 1442, 1411, 1379, 1353, 1337, 1322, 1311, 1281, 1252, 1203,
1176, 1125, 1087, 1063, 1033, 988, 938, 907, 843, 808, 789, 761,
684, 651, 629, 607, 558, 519, 491 cm–1.
Yield: 0.46 g (>99%); [ ]D23 +17.1 (c 1.06, CHCl3).
IR (film): 3084, 3062, 3027, 2958, 2902, 2869, 1940, 1873, 1799,
1652, 1604, 1494, 1466, 1454, 1411, 1392, 1378, 1355, 1301, 1252,
1205, 1147, 1126, 1073, 1061, 1029, 986, 912, 874, 845, 815, 752,
731, 661, 523 cm–1.
1H NMR (300 MHz, CDCl3): = –0.06 [s, 9 H, Si(CH3)3], 0.07 (s,
3 H, SiCH3), 0.08 (s, 3 H, SiCH3), 0.90 (d, J = 6.7 Hz, 3 H,
CH3CHCH3), 0.91 (d, J = 6.7 Hz, 3 H, H3CCHCH3), 0.91 (s, 3 H,
H3CCCH3), 0.93 (s, 3 H, H3CCCH3), 1.83 (sept, J = 6.7 Hz, 1 H,
H3CCHCH3), 2.07 (dd, J = 12.8, 3.0 Hz, 1 H, CHHCHSi), 2.65 (dd,
J = 14.4, 12.8 Hz, 1 H, CHHCHSi), 2.90 (dd, J = 14.4, 3.0 Hz, 1 H,
SiCH), 3.25 (dd, J = 16.1, 7.1 Hz, 1 H, C6H5CHH), 3.34 (dd,
J = 16.1, 7.1 Hz, 1 H, C6H5CHH), 4.53 (t, J = 7.1 Hz, 1 H, =CH),
7.11–7.29 (m, 10 H, CarH).
13C NMR (75 MHz, CDCl3): = –5.0 (SiCH3), –3.9 (SiCH3), 0.9
[OSi(CH3)3], 18.5 (CHCH3), 18.6 (CHCH3), 21.3 (H3CCCH3), 24.4
[C(CH3)2], 32.3 (C6H5CH2), 34.3 [(CH3)2CH], 34.9 (CH2CHSi),
36.6 (SiCH), 105.5 (=CH), 125.5 (p-CarH), 125.7 (p-CarH), 128.0
(o-CarH), 128.1 (o-CarH), 128.4 (m-CarH), 129.0 (m-CarH), 142.4
(Car), 142.7 (Car), 151.5 (=CO).
MS (EI, 70 eV): m/z (%) = 452 (0.5) [M+], 368 (2) [M+ – t-Hex],
308 (1) [M+ – t-HexMe2Si], 278 (2), 220 (4), 147 (100), 133 (4), 91
(4), 84 (2), 73 (61) [Me3Si+], 59 (4).
1H NMR (300 MHz, CDCl3): = 0.04 (s, 3 H, SiCH3), 0.06 (s, 3 H,
SiCH3), 0.18 [s, 9 H, Si(CH3)3], 0.85 (d, J = 6.9 Hz, 3 H,
CH3CHCH3), 0.86 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 0.86 (s, 3 H,
CH3CCH3), 0.87 (s, 3 H, CH3CCH3), 1.74 (sept, J = 6.9 Hz, 1 H,
CH3CHCH3), 1.40–2.10 (m, 7 H, SiCHCH2CH2CH2), 4.69 (td,
J = 3.4, 1.4 Hz, 1 H, (=CH).
13C NMR (75 MHz, CDCl3): = –3.5 (SiCH3), –3.3 (SiCH3), 0.4
[OSi(CH3)3], 18.4 (CHCH3), 18.5 (CHCH3), 20.9 (CCH3), 21.3
(CCH3), 22.3 (CH2), 24.0 (CH2), 24.1 [C(CH3)2], 26.2 (CH2), 28.4
(SiCH), 34.2 [(CH3)2CH], 100.7 (=CH), 153.2 (=CO).
MS (EI, 70 eV): m/z (%) = 312 (1) [M+], 228 (5), 227 (12) [M+ – t-
Hex], 213 (16), 168 (7) [M+ – t-HexMe2Si], 149 (5), 148 (8), 147
(43), 143 (3) [t-HexMe2Si+], 135 (6), 134 (10), 133 (74), 85 (3) [t-
Hex+], 74 (11), 73 (100) [Me3Si+], 59 (12), 45 (7).
Anal. Calcd for C17H36OSi2 (312.64): C, 65.31; H, 11.61. Found C,
65.36; H, 11.75.
(+)-(7R)-7-[1,1-Dimethyl-1-(1,1,2-trimethylpropyl)silyl]-1-cy-
cloheptenyl (1,1,1-Trimethylsilyl) Ether [(E,R)-2h]
Reaction of -silyl ketone (R)-1h (0.25 g, 1.0 mmol) and Me3SiCl
(0.18 mL, 1.4 mmol) gave pure (E,R)-2h.
Yield: 0.33 g (>99%); [ ]D24 +77.8 (c 1.0, CHCl3).
Anal. Calcd for C28H44OSi2 (452.83): C, 74.27; H, 9.79. Found: C,
74.37; H, 9.77.
IR (film): 3042, 2957, 2926, 2868, 1647, 1466, 1447, 1412, 1391,
1378, 1365, 1334, 1315, 1303, 1252, 1227, 1214, 1190, 1148, 1119,
1087, 1062, 1035, 1017, 999, 953, 910, 887, 866, 843, 811, 760,
685, 651, 626, 607, 564, 506 cm–1.
1H NMR (300 MHz, CDCl3): = 0.08 (s, 3 H, SiCH3), 0.11 (s, 3 H,
SiCH3), 0.17 [s, 9 H, Si(CH3)3], 0.85 (d, J = 6.9 Hz, 6 H,
CH3CHCH3), 0.86 (s, 3 H, CH3CCH3), 0.87 (s, 3 H, CH3CCH3),
(–)-(5R)-5-[1,1-Dimethyl-1-(1,1,2-trimethylpropyl)silyl]-1-cy-
clopentenyl (1,1,1-Trimethylsilyl) Ether [(E,R)-2f]
Reaction of -silyl ketone (S)-1f (0.23 g, 1.0 mmol) and Me3SiCl
(0.18 mL, 1.4 mmol) gave pure (Z,S)-2f.
Synthesis 2002, No. 18, 2737–2748 ISSN 0039-7881 © Thieme Stuttgart · New York

2742
D. Enders et al.
PAPER
1.21–2.15 (m, 9 H, SiCHCH2CH2CH2CH2), 1.80 (sept, J = 6.9 Hz,
1 H, CH3CHCH3), 4.83 (dd, J = 8.8, 5.5 Hz, 1 H, =CH).
13C NMR (75 MHz, CDCl3): = –2.7 (SiCH3), –2.6 (SiCH3), 0.3
[OSi(CH3)3], 18.3 (CHCH3), 18.6 (CHCH3), 20.8 (CCH3), 21.0
(CCH3), 23.7 (CH2), 24.1 [C(CH3)2], 26.8 (CH2), 28.4 (CH2), 28.7
(CH2), 33.9 (SiCH), 34.6 [(CH3)2CH], 104.5 (=CH), 157.1 (=CO).
MS (EI, 70 eV): m/z (%) = 326 (0.3) [M+], 227 (5), 183 (1) [M+ – t-
HexMe2Si], 169 (12), 149 (9), 148 (13), 147 (95), 143 (1) [t-
HexMe2Si+], 133 (21), 94 (13), 85 (4) [t-Hex+], 84 (12), 79 (11), 75
(12), 74 (15), 73 (100) [Me3Si+], 59 (22), 45 (9).
13C NMR (100 MHz, CDCl3): = –5.3 (SiCH3), –3.8 (SiCH3), 0.2
[OSi(CH3)3], 17.6 (CHCH3), 19.2 (CHCH3), 20.0 (CCH3), 20.1
(CCH3), 21.6 (OOCCH3), 24.4 [C(CH3)2], 27.6 (OOCCH3), 34.3
[(CH3)2CH], 64.7 (SiCH), 96.8 (COO), 124.4 (=CH), 135.8 (=CO).
MS (EI, 70 eV): m/z (%) = 344 (0.5) [M+], 259 (9) [M+ – t-Hex],
202 (11), 201 (56) [M+ – t-HexMe2Si], 187 (8), 157 (21), 149 (14),
148 (16), 147 (100), 143 (2) [t-HexMe2Si+], 133 (29), 131 (5), 85
(5) [t-Hex+], 75 (7), 74 (8), 73 (50) [Me3Si+], 59 (13), 45 (7).
Anal. Calcd for C17H36O3Si2 (344.64): C, 59.25; H, 10.53. Found:
C, 59.57; H, 10.21.
Anal. Calcd for C18H38OSi2 (326.67): C, 66.18; H, 11.72. Found: C,
65.68; H, 11.65.
(–)-(2S,4R)-1-(Dibenzylamino)-4-[1,1-dimethyl-1-(1,1,2-trime-
thylpropyl)silyl]-2-methylheptan-3-one [(S,R)-3a]
Reaction of silyl enol ether (Z,S)-2a (1.00 g, 3.0 mmol), N,N-diben-
zyl-N-methoxymethylamine (0.83 g, 3.5 mmol) and BF3 Et2O (0.43
mL, 3.5 mmol) gave pure (S,R)-3a.
(–)-(3R)-1-Benzyl-3-[1,1-dimethyl-1-(1,1,2-trimethylpropyl)si-
lyl]-1,2,3,6-tetrahydro-4-pyridinyl (1,1,1-Trimethylsilyl) Ether
[(E,R)-2i]
Reaction of -silyl ketone (R)-1i (0.33 g, 1.0 mmol) and Me3SiCl
(0.18 mL, 1.4 mmol) gave pure (E,R)-2i.
Yield: 1.32 g (95%); [ ]D24 –67.6 (c 0.6, C6H6).
IR (KBr): 3085, 3060, 3026, 2978, 2958, 2907, 2873, 2829, 2809,
2719, 1945, 1808, 1680, 1640, 1543, 1483, 1451, 1407, 1386, 1365,
1341, 1326, 1314, 1303, 1284, 1263, 1253, 1193, 1155, 1120, 1099,
1085, 1071, 1047, 1029, 1012, 982, 966, 956, 938, 933, 913, 902,
878, 822, 807, 788, 747, 734, 699, 667, 609, 583, 512 cm–1.
1H NMR (300 MHz, CDCl3): = 0.01 (s, 3 H, SiCH3), 0.08 (s, 3 H,
SiCH3), 0.91 (m, 15 H, H3CCCH3, H3CCHCH3 H3CCHCH3,
CHCH3), 1.15 (d, J = 6.6 Hz, 3 H, CHCH3), 1.13–1.40 (m, 3 H,
CHHCH2CH3), 1.74 (sept, J = 6.9 Hz, 1 H, H3CCHCH3), 2.00 (m,
1 H, CHH), 2.26 (dd, J = 12.6, 10.2 Hz, 1 H, CHHN), 2.68 (m, 3 H,
SiCH, CHCHHN), 3.45 (d, J = 13.5 Hz, 2 H, NCH2Ph), 3.80 (d,
J = 13.5 Hz, 2 H, NCH2Ph), 7.26–7.43 (m, 10 H, CarH).
Yield: 0.30 g (>99%); [ ]D24 –24.3 (c 0.9, CHCl3).
IR (film): 3694, 3393, 3087, 3063, 3029, 2957, 2900, 2794, 2752,
1943, 1666, 1613, 1495, 1467, 1455, 1412, 1391, 1368, 1347, 1318,
1253, 1196, 1159, 1120, 1085, 1051, 1029, 1012, 986, 949, 914,
892, 841, 814, 779, 764, 699, 651, 607, 528, 497 cm–1.
1H NMR (300 MHz, CDCl3): = 0.03 (s, 3 H, SiCH3), 0.09 (s, 3 H,
SiCH3), 0.14 [s, 9 H, Si(CH3)3], 0.79 (d, J = 6.9 Hz, 3 H,
H3CCHCH3), 0.80 (s, 3 H, H3CCCH3), 0.81 (d, J = 6.9 Hz, 3 H,
H3CCHCH3), 0.84 (s, 3 H, H3CCCH3), 1.68 (sept, J = 6.9 Hz, 1 H,
H3CCHCH3), 1.78 (m, 1 H, SiCH), 2.61–2.73 (m, 3 H, NCH2CHSi,
NCHHCH), 2.95 (dddd, J = 14.7, 5.8, 3.7, 1.9 Hz, 1 H, NCHHCH),
3.27 (d, J = 12.8 Hz, 1 H, CHHPh), 3.61 (d, J = 12.8 Hz, 1 H, CHH-
Ph), 4.45 (t, J = 3.2 Hz, 1 H, =CH), 7.16–7.29 (m, 5 H, CarH).
13C NMR (75 MHz, CDCl3): = –3.5 (SiCH3), –2.3 (SiCH3), 0.8
[Si(CH3)3], 18.9 (H3CCH), 19.2 (CHCH3), 21.2 (H3CC), 21.6
(CCH3), 24.4 [(CH3)2C], 30.2 (SiCH), 34.7 [(CH3)2CH], 51.5
(NCH2CHSi), 54.3 (NCH2CH), 63.2 (NCH2Ph), 98.0 (=CH), 127.3
(p-CarH), 128.5 (o-CarH), 129.7 (m-CarH), 139.3 (Car), 152.5 (CO).
13C NMR (75 MHz, CDCl3):
= 4.4 (SiCH3), 2.3 (SiCH3), 14.8
(CHCH3), 16.3 (CH2CH3), 19.0 (H3CCCH3), 19.4 (H3CCCH3), 21.6
(H3CCHCH3), 22.1 (H3CCHCH3), 22.9 (H3CCHCH3), 24.8
(H3CCHCH3), 24.8 (CH2), 25.3 (H3CCCH3), 31.3 (CH2), 34.9
(H3CCHCH3), 44.8 (SiCH), 46.7 (CHCH2N), 55.8 (CHCH2N), 60.0
(CH2C6H5), 127.4 (CarH), 128.8 (CarH), 129.5 (CarH), 140.3 (Car),
215.9 (C=O).
MS (EI, 70 eV): m/z (%) = 374 (28) [M+
[CH2NBn2 ], 181 (6), 143 (7.3), 118 (24), 91 (91) [C7H7 ], 73 (21),
65 (7.4).
C7H7], 210 (100)
MS (EI, 70 eV): m/z (%) = 403 (6) [M+], 402 (9) [M+ – H], 388 (3)
[M+ – CH3], 390 (5), 334 (6), 333 (16), 332 (53), 320 (10), 319 (29),
318 (76) [M+ – t-Hex], 314 (1) [M+ – Me3Si], 312 (4) [M+ – C7H7],
267 (9), 266 (35), 261 (10), 260 (44) [M+ – t-HexMe2Si], 258 (16),
244 (5), 240 (8), 236 (7), 228 (9), 148 (12), 147 (74), 143 (6) [t-
+
+
Anal. Calcd for C30H47NOSi (465.80): C, 77.36; H, 10.57; N, 3.48.
Found: C, 77.02; H, 10.70; N, 3.33.
+
HexMe2Si+], 133 (5), 131 (5), 120 (16), 92 (6), 91 (72) [C7H7 ], 85
(4) [t-Hex+], 75 (5), 74 (9), 73 (100) [Me3Si+], 59 (12).
(–)-(2S,4R)-1-(Dibenzylamino)-4-[1,1-dimethyl-1-(1,1,2-trime-
thylpropyl)silyl]-2,6-dimethylheptan-3-one [(S,R)-3b]
Reaction of silyl enol ether (Z,S)-2b (1.00 g, 3.0 mmol), N,N-diben-
zyl-N-methoxymethylamine (0.83 g, 3.5 mmol) and BF3 Et2O (0.43
mL, 3.5 mmol) gave pure (S,R)-3b.
Anal. Calcd for C23H41NOSi2 (403.76): C, 68.42; H, 10.23; N, 3.47.
Found: C, 68.12; H, 10.45; N, 3.71.
(–)-(4S)-4-[1,1-Dimethyl-1-(1,1,2-trimethylpropyl)silyl]-2,2-
dimethyl-4H-1,3-dioxin-5-yl (1,1,1-Trimethylsilyl) Ether [(E,S)-
2j]
Reaction of -silyl ketone (S)-1j (0.27 g (1.0 mmol) and Me3SiCl
(0.18 mL, 1.4 mmol) gave pure (E,S)-2j.
Yield: 1.35 g (94%); [ ]D24 –71.6 (c 0.5, C6H6).
IR (KBr): 3082, 3059, 3025, 2978, 2958, 2906, 2873, 2828, 2809,
2719, 1942, 1808, 1680, 1640, 1543, 1483, 1451, 1407, 1386, 1365,
1341, 1326, 1311, 1302, 1284, 1262, 1253, 1192, 1155, 1120, 1098,
1085, 1071, 1047, 1029, 1012, 982, 966, 956, 938, 932, 913, 902,
877, 822, 807, 788, 747, 733, 699, 667, 609, 583 cm–1.
1H NMR (300 MHz, CDCl3): = 0.01 (s, 3 H, SiCH3), 0.08 (s, 3 H,
SiCH3), 0.90 (m, 12 H, H3CCCH3, H3CCHCH3 H3CCHCH3), 1.11
(d, J = 6.6 Hz, 3 H, CHCH3), 1.73 (sept, J = 6.9 Hz, 1 H,
H3CCHCH3), 2.70 (m, 2 H, CH2), 2.05–2.85 (m, 5 H, CH3CHCH3,
SiCH, CHCH2N), 3.39 (d, J = 13.5 Hz, 2 H, NCH2Ph), 3.85 (d,
J = 13.5 Hz, 2 H, NCH2Ph), 7.26–7.43 (m, 10 H, CarH).
Yield: 0.34 g (>99%); [ ]D24 –15.4 (c 1.1, CHCl3).
IR (film): 3532, 3369, 3080, 2959, 2905, 2871, 2802, 2603, 2374,
2343, 1782, 1667, 1599, 1465, 1411, 1369, 1292, 1254, 1200, 1171,
1128, 1053, 949, 889, 845, 781, 692, 666, 605, 572, 518, 495 cm–1.
1H NMR (400 MHz, CDCl3): = 0.09 (s, 3 H, SiCH3), 0.11 (s, 3 H,
SiCH3), 0.19 [s, 9 H, Si(CH3)3], 0.85 (d, J = 6.9 Hz, 3 H,
H3CCHCH3), 0.88 (d, J = 6.9 Hz, 3 H, H3CCHCH3), 0.88 (s, 3 H,
H3CCCH3), 0.94 (s, 3 H, H3CCCH3), 1.38 (s, 3 H, OOCCH3), 1.40
(s, 3 H, OOCCH3), 1.74 (sept, J = 6.9 Hz, 1 H, H3CCHCH3), 3.95
(d, J = 2.2 Hz, 1 H, =CH), 6.11 (d, J = 2.2 Hz, 1 H, SiCH).
13C NMR (75 MHz, CDCl3):
= 4.3 (SiCH3), 2.1 (SiCH3), 14.2
(CHCH3), 19.0 (H3CCCH3), 19.4 (H3CCCH3), 21.6 (H3CCHCH3),
22.1 (H3CCHCH3), 22.9 (H3CCHCH3), 24.8 (H3CCHCH3), 25.3
(H3CCCH3), 29.0 (H3CCHCH3), 34.9 (H3CCHCH3), 38.1 (CH2),
Synthesis 2002, No. 18, 2737–2748 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Mannich Reactions by -Silyl Controlled Aminomethylation of Ketones
2743
42.4 (SiCH), 46.6 (CHCH2N), 55.3 (CHCH2N), 60.0 (CH2C6H5),
13C NMR (75 MHz, CDCl3): = –4.1 (SiCH3), 2.1 (SiCH3), 13.1
127.5 (CarH), 127.6 (CarH), 129.5 (CarH), 140.3 (Car), 215.7 (C=O).
(CHCH2CH3), 19.0 (H3CCHCH3), 19.5 (H3CCHCH3), 21.6
(H3CCCH3), 21.8 (CHCH2CH3), 22.4 (H3CCCH3), 25.5
(H3CCCH3), 35.1 (H3CCHCH3), 35.3 (C6H5CH2CHSi), 48.6
(SiCH), 54.0 (CHCH2CH3), 55.0 (CHCH2N), 59.0 (CH2C6H5),
126.6 (CarH), 127.4 (CarH), 128.7 (CarH), 128.9 (CarH), 129.4
(CarH), 129.5 (CarH), 139.7 (Car), 143.7 (Car), 213.4 (C=O).
MS (EI, 70 eV): m/z (%) = 388 (19) [M+ C7H7], 241 (3), 210 (90)
+
+
[CH2NBn2 ], 181 (6), 157 (7), 141 (3), 118 (28), 91 (100) [C7H7 ],
73 (28), 65 (4), 42 (5).
Anal. Calcd for C31H49NOSi (479.80): C, 77.60; H, 10.29; N, 2.92.
Found: C, 77.40; H, 10.20; N, 3.18.
MS (EI, 70 eV): m/z (%) = 527 (0.4) [M+], 436 (5) [M+ C7H7], 210
+
(100), 181 (5), 118 (6), 91 (70) [C7H7 ], 73 (12).
(–)-(2S,4R)-1-(4-Bromophenyl)-5-(dibenzylamino)-2-[1,1-dime-
thyl-1-(1,1,2-trimethylpropyl)silyl]-4-methylpentan-3-one
[(S,R)-3c]
Anal. Calcd for C35H49NOSi (527.86): C, 79.64; H, 9.36; N, 2.65.
Found: C, 80.03; H, 9.33; N, 2.78.
Reaction of silyl enol ether (Z,S)-2c (1.37 g, 3.0 mmol), N,N-diben-
zyl-N-methoxymethylamine (0.83 g, 3.5 mmol) and BF3 Et2O (0.43
mL, 3.5 mmol) gave pure (S,R)-3c.
Yield: 1.86 g (95%); mp 74–75 °C; [ ]D24 –32.1 (c 1.0, C6H6).
(–)-(2R,4S)-2-Benzyl-1-(dibenzylamino)-4-[1,1-dimethyl-1-
(1,1,2-trimethylpropyl)silyl]-5-phenylpentan-3-one [(R,S)-3e]
Reaction of silyl enol ether (Z,S)-2e (0.27 g, 0.60 mmol), N,N-
dibenzyl-N-methoxymethylamine (0.17
g (0.70 mmol) and
IR (KBr): 3084, 3061, 3025, 2978, 2958, 2936, 2907, 2873, 2828,
2809, 2719, 1942, 1808, 1680, 1640, 1601, 1543, 1489, 1451, 1407,
1386, 1365, 1345, 1326, 1311, 1302, 1284, 1262, 1253, 1192, 1155,
1121, 1098, 1085, 1071, 1047, 1029, 1012, 982, 966, 956, 938, 932,
913, 902, 877, 822, 807, 788, 747, 733, 698, 666, 609, 583, 524, 512
cm–1.
BF3 Et2O (0.09 mL, 0.70 mmol) gave pure (R,S)-3e.
Yield: 0.33 g (94%); [ ]D24 –104.5 (c 1.1, CHCl3).
IR (film): 3084, 3062, 3027), 2958, 2869, 2827, 2797, 2716, 1945,
1873, 1806, 1749, 1688, 1603, 1585, 1494, 1453, 1407, 1391, 1379,
1366, 1314, 1253, 1192, 1156, 1120, 1087, 1075, 1029, 966, 938,
916, 874, 841, 829, 814, 771, 745, 699, 616, 603, 589, 552, 528, 497
cm–1.
1H NMR (300 MHz, CDCl3): = –0.70 (s, 3 H, SiCH3), –0.06 (s, 3
H, SiCH3), 0.78 (s, 3 H, H3CCCH3), 0.87 (d, J = 6.9 Hz, 6 H,
H3CCHCH3), 0.90 (s, 3 H, H3CCCH3),1.48 (m, 2 H, CHCH2N),
1.71 (sept, J = 6.9 Hz, 1 H, H3CCHCH3), 2.91 (d, J = 13.5 Hz, 2 H,
NCH2Ph), 2.67–3.19 (m, 6 H, 2 C6H5CH2, SiCH, COCH), 3.58 (d,
J = 13.5 Hz, 2 H, NCH2Ph), 7.02–7.31 (m, 20 H, CarH).
1H NMR (300 MHz, CDCl3):
= 0.02 (s, 3 H, SiCH3), 0.14 (s, 3
H, SiCH3), 0.93 (s, 3 H, H3CCCH3), 0.93 (d, J = 6.9 Hz, 6 H,
H3CCHCH3), 0.94 (d, J = 7.4 Hz, 3 H, CHCH3), 0.98 (s, 3 H,
H3CCCH3), 1.47 (m, 2 H, CHCH2N), 1.76 (sept, J = 6.9 Hz, 1 H,
H3CCHCH3), 2.49 (m, 1 H, COCH), 2.64 (dd, J = 13.5, 1.8 Hz, 1 H,
SiCH), 2.82 (dd, J = 12.1, 1.8 Hz, 1 H, BrC6H4CHH), 2.97 (d,
J = 13.5 Hz, 2 H, NCH2Ph), 3.11 (dd, J = 13.5, 12.1 Hz, 1 H,
BrC6H4CHH), 3.57 (d, J = 13.5 Hz, 2 H, NCH2Ph), 6.86–7.33 (m,
14 H, CarH).
13C NMR (75 MHz, CDCl3):
= 4.3 (SiCH3), 3.5 (SiCH3), 18.8
13C NMR (75 MHz, CDCl3):
=
5.0 (SiCH3), 3.2 (SiCH3), 12.9
(H3CCHCH3), 19.6 (H3CCHCH3), 21.3 (H3CCCH3), 22.4
(H3CCCH3), 25.4 (H3CCCH3), 34.1 (CHCH2C5H6), 35.1
(H3CCHCH3), 35.3 (C6H5CH2CHSi), 48.9 (SiCH), 54.7
(CHCH2N), 55.8 (CHCH2N), 59.1 (NCH2C6H5), 126.3 (p-CarH),
126.6 (p-CarH), 127.6 (p-CarH), 128.7 (o-CarH), 128.8 (o-CarH),
128.0 (o-CarH), 129.5 (m-CarH), 129.5 (m-CarH), 130.6 (m-CarH),
139.6 (Car), 142.1 (Car), 143.8 (Car), 211.9 (C=O).
(CHCH3), 18.6 (H3CCHCH3), 18.8 (H3CCHCH3), 21.3
(H3CCCH3), 21.5 (H3CCCH3), 24.8 (H3CCCH3), 33.8
(C6H5CH2CHSi), 34.6 (H3CCHCH3), 46.7(CHCH3), 48.2 (SiCH),
54.8 (CHCH2N), 58.6 (CH2C6H5), 119.7 (BrCar), 126.9 (CarH),
128.2 (CarH), 128.7 (CarH), 130.5 (CarH), 131.4 (CarH), 139.1 (Car),
142.1 (Car), 213.3 (C=O).
MS (EI, 70 eV): m/z (%) = 593/591 (0.08) [M+], 501/499 (1.5) [M+
C7H7], 210 (100) [CH2NBn2 ], 181 (5), 118 (5), 91 (70) [C7H7 ],
73 (11).
MS (EI, 70 eV): m/z (%) = 589 (1) [M+], 498 (4) [M+ C7H7], 210
(100), 181 (5), 118 (6), 91 (77) [C7H7 ], 73 (12).
+
+
+
Anal. Calcd for C40H51NOSi (589.94): C, 81.44; H, 8.71; N, 2.37.
Found: C, 81.37; H, 8.85; N, 2.85.
Anal. Calcd for C34H46BrNOSi (592.73): C, 68.90; H, 7.82; N 2.36.
Found: C, 68.62; H, 8.05; N, 2.51.
(–)-(2S,5R)-2-[(Dibenzylamino)methyl]-5-[1,1-dimethyl-1-
(1,1,2-trimethylpropyl)silyl]cyclopentan-1-one [(S,R)-3f]
Reaction of silyl enol ether (E,R)-2f (0.28 g, 1.00 mmol), N,N-
dibenzyl-N-methoxymethylamine (0.28 g, 1.15 mmol) and
BF3 Et2O (0.14 mL, 1.15 mmol) gave pure (S,R)-3f.
(–)-(2S,4R)-4-[(Dibenzylamino)methyl]-2-[1,1-dimethyl-1-
(1,1,2-trimethylpropyl)silyl]-1-phenylhexan-3-one [(S,R)-3d]
Reaction of silyl enol ether (Z,S)-2d (0.12 g, 0.32 mmol), N,N-
dibenzyl-N-methoxymethylamine (0.09 g, 0.37 mmol) and
BF3 Et2O (0.05 mL, 0.37 mmol) gave pure (S,R)-3d.
Yield: 0.41 g (95%); [ ]D24 –39.6 (c 1.1, CHCl3).
Yield: 0.16 g (95%); [ ]D24 –88.8 (c 1.0, CHCl3).
IR (film): 3786, 3531, 3404, 3085, 3062, 3027, 2958, 2870, 2795,
2714, 2602, 1947, 1873, 1807, 1713, 1640, 1602, 1585, 1494, 1452,
1412, 1379, 1367, 1317, 1291, 1252, 1187, 1151, 1128, 1089, 1069,
1029, 998, 978, 957, 932, 912, 873, 837, 808, 774, 746, 699, 661,
622, 605, 581, 477 cm–1.
1H NMR (300 MHz, CDCl3): = 0.00 (s, 3 H, SiCH3), 0.07 (s, 3 H,
SiCH3), 0.84 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 0.85 (d, J = 6.9 Hz,
3 H, CH3CHCH3), 0.85 (s, 3 H, CH3CCH3), 0.86 (s, 3 H,
CH3CCH3), 1.48 (m, 1 H, CHHCH2), 1.68 (sept, J = 6.9 Hz, 1 H,
CH3CHCH3), 1.77 (m, 1 H, CHHCH2), 1.92–2.02 (m, 2 H,
CH2CHH, SiCH), 2.18–2.34 (m, 2 H, CH2CHH, NCH2CH), 2.41
(dd, J = 12.6, 9.9 Hz, 1 H, NCHHCH), 2.74 (dd, J = 12.6, 3.6 Hz, 1
H, NCHHCH), 3.27 (d, J = 13.7 Hz, 1 H, CH2Ph), 3.77 (d, J = 13.7
Hz, 1 H, CH2Ph), 7.18–7.38 (m, 10 H, CarH).
IR (film): 3085, 3062, 3027, 2960, 2874, 2827, 2797, 2716, 1945,
1872, 1806, 1750, 1686, 1602, 1584, 1494, 1465, 1454, 1410, 1391,
1378, 1366, 1314, 1294, 1253, 1218, 1189, 1156, 1124, 1088, 1076,
1059, 1047, 1029, 1012, 969, 944, 913, 873, 843, 814, 758, 700,
1
668, 616, 515 cm .
1H NMR (300 MHz, CDCl3): = 0.02 (s, 3 H, SiCH3), 0.13 (s, 3 H,
SiCH3), 0.91 (s, 3 H, H3CCCH3), 0.93 (d, J = 6.9 Hz, 6 H,
H3CCHCH3), 0.99 (s, 3 H, H3CCCH3), 1.38–1.54 (m, 4 H,
CHCH2N, CHCH2CH3), 1.76 (sept, J = 6.9 Hz, 1 H, H3CCHCH3),
2.26 (m, 1 H, COCH), 2.76 (dd, J = 13.5, 1.8 Hz, 1 H, SiCH), 2.86
(d, J = 13.5 Hz, 2 H, NCH2Ph), 2.92 (dd, J = 12.1, 1.8 Hz, 1 H,
C6H5CHH), 3.16 (dd, J = 13.5, 12.1 Hz, 1 H, C6H5CHH), 3.45 (d,
J = 13.5 Hz, 2 H, NCH2Ph), 6.99–7.28 (m, 15 H, CarH).
Synthesis 2002, No. 18, 2737–2748 ISSN 0039-7881 © Thieme Stuttgart · New York

2744
D. Enders et al.
PAPER
13C NMR (75 MHz, CDCl3): = –4.5 (SiCH3), –4.4 (SiCH3), 18.3
(CHCH3), 18.4 (CHCH3), 20.8 (CCH3), 20.9 (CCH3), 23.9
[C(CH3)2], 24.1 (SiCHCH2), 30.2 (NCH2CHCH2), 34.2
[(CH3)2CH], 40.3 (SiCH), 49.2 (CHCH2), 53.8 (CHCH2N), 58.6
(NCH2Ph), 126.8 (p-CarH), 128.2 (o-CarH), 128.8 (m-CarH), 139.7
(Car), 221.5 (C=O).
1202, 1162, 1127, 1084, 1076, 1054, 1029, 1001, 970, 937, 919,
874, 837, 820, 808, 750, 699, 668, 625 cm–1.
1H NMR (300 MHz, CDCl3): = –0.02 (s, 3 H, SiCH3), 0.05 (s, 3
H, SiCH3), 0.82 (s, 3 H, CH3CCH3), 0.84 (s, 3 H, CH3CCH3), 0.86
(d, J = 6.7 Hz, 6 H, CH3CHCH3), 0.95–2.80 (m, 12 H,
CH2CH2CH2CH2, CHCH2N, SiCH), 1.76 (sept, J = 6.7 Hz, 1 H,
CH3CHCH3), 3.38 (d, J = 13.8 Hz, 2 H, NCH2Ph), 3.70 (d, J = 13.8
Hz, 2 H, NCH2Ph), 7.18–7.38 (m, 10 H, CarH).
13C NMR (75 MHz, CDCl3): = –3.8 (SiCH3), –3.3 (SiCH3), 18.3
(CHCH3), 18.6 (CHCH3), 20.6 (CCH3), 20.9 (CCH3), 24.4
[C(CH3)2], 26.4 (CH2), 30.1 (CH2), 30.2 (CH2), 30.5 (CH2), 34.0
[(CH3)2CH], 48.0 (CHCH2N), 49.3 (SiCH), 59.1 (NCH2), 60.0
(NCH2Ph), 126.9 (p-CarH), 128.2 (o-CarH), 128.9 (m-CarH), 139.9
(Car), 216.9 (C=O).
MS (EI, 70 eV): m/z (%) = 435 (0.1) [M+ – CH3], 420 (0.1) [M+ –
CH3], 350 (0.1) [M+ – t-Hex], 345 (5), 344 (21) [M+ – C7H7], 292
(0.1) [M+ – t-HexMe2Si], 225 (0.1) [M+ – CH2NBn2], 211 (8), 210
+
+
(45) [CH2NBn2 ], 197 (12), 196 (11) [NBn2 ], 155 (5), 154 (13),
153 (70), 143 (1) [t-HexMe2Si+], 120 (7), 118 (14), 106 (44), 92
+
+
(17), 91 (100) [C7H7 ], 85 (6) [t-Hex+], 79 (7), 77 (9) [C6H5 ], 75
(54), 73 (17), 65 (12), 59 (10).
Anal. Calcd for C28H41NOSi (435.72): C, 77.18; H, 9.48; N, 3.21.
Found: C, 77.00; H, 9.37; N, 3.53.
MS (EI, 70 eV): m/z (%) = 463 (0.1) [M+ – CH3], 378 (0.1) [M+ – t-
Hex], 373 (11), 372 (35) [M+ – C7H7], 320 (0.1) [M+ – t-HexMe2Si],
(–)-(2S,6R)-2-[(Dibenzylamino)methyl]-6-[1,1-dimethyl-1-
(1,1,2-trimethylpropyl)silyl]cyclohexan-1-one [(S,R)-3g]
Reaction of silyl enol ether (E,R)-2g (0.30 g, 1.00 mmol), N,N-
dibenzyl-N-methoxymethylamine (0.28 g, 1.15 mmol) and
BF3 Et2O (0.14 mL, 1.15 mmol) gave (S/R,R)-3g. Compound (S,R)-
3g has been enriched by preparative HPLC.
+
+
211 (17), 210 (100) [CH2NBn2 ], 196 (1) [NBn2 ], 181 (9), 143
(0.1) [t-HexMe2Si+], 118 (17), 92 (9), 91 (99) [C7H7 ], 85 (4) [t-
+
Hex+], 77 (1) [C6H5 ], 75 (9), 73 (16).
+
Anal. Calcd for C30H45NOSi (463.78): C, 77.69; H, 9.78; N, 3.02.
Found: C, 77.31; H, 9.54; N, 3.36.
Yield: 0.42 g (94%); [ ]D23 –141.2 (c 1.0, CHCl3).
(+)-(3R,5R)-1-Benzyl-3-[(dibenzylamino)methyl]-5-[1,1-dime-
thyl-1-(1,1,2-trimethylpropyl)silyl]-4-piperidinone [(R,R)-3i]
Reaction of silyl enol ether (E,R)-2i (0.42 g, 1.00 mmol), N,N-
dibenzyl-N-methoxymethylamine (0.28 g, 1.15 mmol) )and
BF3 Et2O (0.14 mL, 1.15 mmol) gave pure (R,R)-3i.
IR (film): 3676, 3347, 3085, 3062, 3026, 2952, 2866, 2829, 2795,
2714, 2601, 1946, 1872, 1807, 1681, 1602, 1585, 1494, 1452, 1410,
1391, 1379, 1366, 1341, 1293, 1252, 1218, 1167, 1133, 1105, 1066,
1053, 1027, 969, 939, 915, 873, 835, 812, 751, 699, 668, 614, 473
cm–1.
Yield: 0.52 g (96%); mp 66–67 °C; [ ]D24 +6.8 (c 1.1, CHCl3).
1H NMR (500 MHz, CDCl3): = –0.05 (s, 3 H, SiCH3), 0.08 (s, 3
H, SiCH3), 0.82 [s, 6 H, C(CH3)2], 0.83 (d, J = 7.0 Hz, 3 H,
CHCH3), 0.84 (d, J = 7.0 Hz, 3 H, CHCH3), 1.12 (m, 1 H,
NCH2CHCHH), 1.59 (m, 2 H, CH2CH2CH2), 1.72 (sept, J = 7.0 Hz,
1 H, CHCH3), 1.85 (m, 1 H, SiCHCHH), 1.97 (m, 1 H, SiCHCHH),
2.25 (m, 1 H, NCH2CH), 2.37 (m, 1 H, NCH2CHCHH), 2.40 (m, 1
H, SiCH), 2.48 (dd, J = 13.4, 9.8 Hz, CHHN), 2.83 (dd, J = 13.4,
4.0, 1H, CHHN), 3.36 (d, J = 13.7 Hz, 2 H, CH2Ph), 3.69 (d,
J = 13.7 Hz, 2 H, CH2Ph), 7.22 (m, 2 H, p- CarH), 7.29 (m, 4 H, m-
CarH), 7.35 (m, 4 H, o-CarH).
13C NMR (125 MHz, CDCl3): = –3.6 (SiCH3), –3.0 (SiCH3), 18.3
(CHCH3), 18.7 (CHCH3), 20.4 (CCH3), 20.8 (CCH3), 23.5
(CH2CH2CH2), 24.4 [C(CH3)2], 27.9 (SiCHCH2), 30.1
(NCH2CHCH2), 33.8 [(CH3)2CH], 42.4 (SiCH), 48.0 (CHCH2),
54.2 (CHCH2N), 59.7 (NCH2Ph), 126.8 (p-CarH), 128.1 (o-CarH),
128.8 (m-CarH), 139.8 (Car), 214.1 (C=O).
IR (film): 3660, 3351, 3085, 3062, 3028, 2957, 2871, 2796, 2755,
2713, 2249, 1947, 1877, 1807, 1686, 1602, 1585, 1545, 1494, 1435,
1391, 1379, 1364, 1350, 1321, 1289, 1252, 1201, 1150, 1116, 1088,
1074, 1045, 1028, 999, 952, 915, 874, 836, 814, 777, 747, 699, 668,
607, 511, 476 cm–1.
1H NMR (300 MHz, CDCl3): = 0.00 (s, 3 H, SiCH3), 0.14 (s, 3 H,
SiCH3), 0.78 (s, 3 H, CH3CCH3), 0.79 (s, 3 H, CH3CCH3), 0.81 (d,
J = 6.7 Hz, 3 H, H3CCH), 0.82 (d, J = 6.7 Hz, 3 H, H3CCH), 1.58
(m, 1 H, NCH2), 1.68 (sept, J = 6.7 Hz, 1 H, CH3CHCH3), 2.33–
2.49 (m, 3 H, NCH2), 2.55 (dd, J = 15.1, 4.0 Hz, 1 H, SiCH), 2.84
(m, 1 H, NCH2), 3.06 (m, 1 H, NCH2), 3.21 (d, J = 13.4 Hz, 2 H,
NCH2Ph), 3.30 (d, J = 12.8 Hz, 1 H, NCH2Ph), 3.38 (m, 1 H,
COCH), 3.70 (d, J = 13.4 Hz, 2 H, NCH2Ph), 3.64 (d, J = 12.8 Hz,
1 H, NCH2Ph), 7.08–7.43 (m, 15 H, CarH).
13C NMR (75 MHz, CDCl3): = –3.7 (SiCH3), –2.8 (SiCH3), 18.2
(H3CCH), 18.7 (H3CCH), 20.2 (H3CC), 20.9 (H3CC), 24.4
[(H3C)2C], 34.0 [(H3C)2CH], 42.8 (COCH), 47.8 (SiCH), 51.7
(NCH2), 55.9 (NCH2), 56.4 (NCH2), 59.4 (NCH2Ph), 62.6
(NCH2Ph), 126.8 (p-CarH), 127.2 (p-CarH), 128.1 (o-CarH), 128.3
(o-CarH), 128.9 (m-CarH), 129.3 (m-CarH), 138.6 (Car), 139.6 (Car),
211.4 (C=O).
MS (EI, 70 eV): m/z (%) = 434 (0.1) [M+ – CH3], 364 (0.1) [M+ – t-
Hex], 358 (8) [M+ – C7H7], 306 (0.1) [M+ – t-HexMe2Si], 239 (0.1)
+
+
[M+ – CH2NBn2], 210 (20) [CH2NBn2 ], 197 (9), 196 (8) [NBn2 ],
169 (6), 168 (17), 167 (75), 153 (5), 149 (12), 139 (10), 120 (7), 118
+
(10), 111 (5), 106 (44), 93 (6), 92 (19), 91 (100) [C7H7 ], 85 (8) [t-
+
Hex+], 79 (5), 77 (10) [C6H5 ], 75 (33), 73 (13), 65 (11), 59 (12), 58
MS (EI, 70 eV): m/z (%) = 344 (1) [M+ – NBn2], 259 (7), 258 (28),
(11), 57 (5), 51 (5), 45 (6).
+
+
210 (0.2) [CH2NBn2 ], 197 (8), 196 (7) [NBn2 ], 143 (1) [t-
Anal. Calcd for C29H43NOSi (449.75): C, 77.45; H, 9.64; N, 3.11.
Found: C, 77.22; H, 9.83; N, 3.29.
HexMe2Si+], 141 (21), 120 (6), 106 (33), 92 (16), 91 (100) [C7H7 ],
+
85 (5) [t-Hex+], 77 (5) [C6H5 ], 75 (8), 74 (6), 73 (9), 65 (11), 59
+
(11), 58 (9), 45 (7).
(–)-(2S,7R)-2-[(Dibenzylamino)methyl]-7-[1,1-dimethyl-1-
(1,1,2-trimethylpropyl)silyl]cycloheptan-1-one [(S,R)-3h]
Reaction of silyl enol ether (E,R)-2h (0.31 g, 1.00 mmol), N,N-
dibenzyl-N-methoxymethylamine (0.28 g, 1.15 mmol) and
BF3 Et2O (0.14 mL, 1.15 mmol) gave pure (S,R)-3h.
Anal. Calcd for C35H48N2OSi (540.86): C, 77.72; H, 8.94; N, 5.18.
Found: C, 77.28; H, 9.32; N, 5.21.
(–)-(4S,6S)-4-[(Dibenzylamino)methyl]-6-[1,1-dimethyl-1-
(1,1,2-trimethylpropyl)silyl]-2,2-dimethyl-1,3-dioxan-5-one
[(S,S)-3j]
Yield: 0.44 g (95%); [ ]D26 –134.3 (c 1.0, CHCl3).
IR (film): 3676, 3527, 3333, 3085, 3062, 3027, 2956, 2926, 2867,
2852, 2800, 2714, 2602, 2331, 1945, 1870, 1806, 1675, 1602, 1585,
1542, 1494, 1452, 1411, 1391, 1379, 1366, 1324, 1304, 1252, 1217,
Reaction of silyl enol ether (E,S)-2j (0.37 g, 1.00 mmol), N,N-
dibenzyl-N-methoxymethylamine (0.28 g, 1.15 mmol) and
BF3 Et2O (0.14 mL, 1.15 mmol) gave pure (S,S)-3j.
Synthesis 2002, No. 18, 2737–2748 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Mannich Reactions by -Silyl Controlled Aminomethylation of Ketones
2745
Yield: 0.45 g (93%); [ ]D24 –34.2 (c 1.1, CHCl3).
CH2COCHCH2), 3.44 (d, J = 13.5 Hz, 2 H, NCH2Ph), 3.61 (d,
J = 13.5 Hz, 2 H, NCH2Ph), 7.20–7.34 (m, 10 H, CarH).
IR (film): 3371, 3085, 3062, 3028, 2958, 2870, 2799, 2722, 2603,
2250, 1947, 1872, 1755, 1702, 1602, 1585, 1495, 1454, 1411, 1380,
1328, 1251, 1201, 1163, 1112, 1029, 964, 899, 873, 842, 816, 778,
746, 699, 668, 650, 609, 581, 500, 473 cm–1.
1H NMR (300 MHz, CDCl3): = 0.01 (s, 3 H, SiCH3), 0.04 (s, 3 H,
SiCH3), 0.83 (d, J = 6.7 Hz, 3 H, H3CCH), 0.84 (s, 3 H, H3CC), 0.85
(d, J = 6.7 Hz, 3 H, H3CCH), 0.88 (s, 3 H, H3CC), 1.42 (s, 3 H,
H3CCOO), 1.47 (s, 3 H, H3CCOO), 1.77 (sept, J = 6.7 Hz, 1 H,
H3CCH), 2.90–2.94 (m, 2 H, COCH2C), 3.68 (d, J = 13.8 Hz, 2 H,
CHHBn), 3.75 (d, J = 13.8 Hz, 2 H, CHHBn), 4.44–4.51 (m, 2 H,
COCH, SiCH), 7.18–7.41 (m, 10 H, CarH).
13C NMR (75 MHz, CDCl3): = –4.6 (SiCH3), –4.4 (SiCH3), 18.0
(H3CCH), 18.8 (H3CCH), 20.2 (H3CC), 20.6 (H3CC), 21.1
(OOCCH3), 24.3 [(H3C)2C], 28.9 (OOCCH3), 34.3 [(H3C)2CH],
55.0 (COCH2N), 58.0 (CH2Bn), 75.9 (COCH), 77.4 (SiCH), 126.9
(p-CarH), 128.1 (o-CarH), 129.3 (m-CarH), 139.4 (Car), 210.6 (C=O).
13C NMR (75 MHz, CDCl3):
= 15.8 (COCHCH3), 23.0
(CH3CHCH3), 23.1 (CH3CHCH3), 28.3 (CH3CHCH3), 32.9 (CH2),
39.6 (COCH2), 45.7 (CHCH2N), 57.9 (CHCH2N), 59.4 (CH2C6H5),
127.6 (CarH), 128.9 (CarH), 129.6 (CarH), 139.7 (Car), 214.8 (C=O).
MS (EI, 70 eV): m/z (%) = 337 (0.5) [M+], 210 (59) [CH2NBn2 ],
+
+
181 (6.5), 118 (3), 106 (4), 91 (100) [C7H7 ], 65 (12).
Anal. Calcd for C23H31NO (337.51): C, 81.85; H, 9.26; N, 4.15.
Found: C, 81.67; H, 9.31; N, 4.54.
(+)-(2R)-5-(4-Bromphenyl)-1-(dibenzylamino)-2-methylpen-
tan-3-one [(R)-4c]
Reaction of -silylated -amino ketone (S,R)-3c (0.30 g, 0.50
mmol), NH4F (0.93 g, 25 mmol) and Bu4NF (0.8 mL, 0.80 mmol; 1
M solution in THF) gave pure (R)-4c.
Yield: 0.22 g (98%); [ ]D24 +9.7 (c 0.6, C6H6).
MS (EI, 70 eV): m/z (%) = 482 (0.04) [M+], 467 (0.03) [M+ – CH3],
IR (film): 3397, 3085, 3062, 3026, 2967, 2933, 2800, 2716, 1950,
1894, 1809, 1708, 1602, 1489, 1453, 1404, 1371, 1251, 1217, 1126,
1102, 1073, 1073, 1029, 1012, 976, 909, 815, 756, 700, 668, 623,
510, 500 cm–1.
1H NMR (300 MHz, CDCl3): = 0.95 (d, J = 6.7 Hz, 3 H, CH3),
2.27–2.82 (m, 7 H, BrC6H4CH2CH2, COCHCH2), 3.38 (d, J = 13.5
Hz, 2 H, NCH2Ph), 3.61 (d, J = 13.4 Hz, 2 H, NCH2Ph), 6.97–7.39
(m, 14 H, CarH).
396 (0.07) [M+ – t-Hex], 338 (0.45) [M+ – t-HexMe2Si], 284 (0.13)
+
[M+ – NBn2], 211 (17), 210 (100) [CH2NBn2 ], 197 (6), 196 (6)
[NBn2 ], 181 (5), 157 (6), 143 (4) [t-HexMe2Si+], 142 (10), 141
+
+
(24), 113 (6), 106 (30), 99 (9), 92 (13), 91 (94) [C7H7 ], 85 (4) [t-
Hex+], 77 (4) [C6H5 ], 75 (12), 73 (18), 65 (8).
+
Anal. Calcd for C29H43NO3Si (481.75): C, 72.30; H, 9.00; N, 2.91.
Found: C, 72.04; H, 9.12; N, 3.44.
13C NMR (75 MHz, CDCl3): = 15.6 (CHCH3), 29.4 (BrC6H4CH2),
42.4 (COCH2), 45.9 (CHCH3), 57.9 (CHCH2N), 59.4 (CH2C6H5),
120.3 (BrCar), 127.7 (CarH), 128.8 (CarH), 129.6 (CarH), 130.9
(CarH), 132.0 (CarH), 139.6 (Car), 141.0 (Car), 213.1 (C=O).
(–)-(2R)-1-(Dibenzylamino)-2-methylheptan-3-one [(R)-4a]
Reaction of -silylated -amino ketone (S,R)-3a (0.23 g, 0.50
mmol), NH4F (0.93 g, 25 mmol) and Bu4NF (0.8 mL, 0.80 mmol; 1
M solution in THF) gave pure (R)-4a.
MS (EI, 70 eV): m/z (%) = 449/451 (0.5) [M+], 210 (91)
Yield: 0.16 g (98%); [ ]D24 –1.2 (c 0.5, C6H6).
+
+
[CH2NBn2 ], 181 (6.5), 91 (100) [C7H7 ], 65 (7).
IR (film): 3085, 3071, 3026, 2967, 2933, 2866, 2791, 1715, 1605,
1489, 1453, 1404, 1371, 1249, 1217, 1175, 1126, 1073, 1029, 976,
909, 815, 749, 700, 668, cm–1.
Anal. Calcd for C26H28BrNO (450.42): C, 69.33; H, 6.27; N, 3.11.
Found: C, 69.37; H, 6.65; N, 3.40.
1H NMR (300 MHz, CDCl3): = 0.88 (d, J = 6.9 Hz, 3 H, CH3),
0.99 (d, J = 6.9 Hz, 3 H, CHCH3), 1.25 (m, 2 H, CH2), 1.48 (m, 2 H,
CH2), 2.20–2.92 (m, 5 H, CH2COCHCH2), 3.44 (d, J = 13.5 Hz, 2
H, NCH2Ph), 3.61 (d, J = 13.5 Hz, 2 H, NCH2Ph), 7.20–7.34 (m, 10
H, CarH).
13C NMR (75 MHz, CDCl3): = 14.5 (CH2CH3), 15.7 (CHCH3),
23.0 (CH2CH3), 26.1 (COCH2CH2), 41.1 (COCH2), 57.9
(CHCH2N), 59.4 (CH2C6H5), 127.6 (CarH), 128.8 (CarH), 129.6
(CarH), 139.7 (Car), 214.7 (C=O).
(+)-(4R)-4-[(Dibenzylamino)methyl]-1-phenylhexan-3-one [(R)-
4d]
Reaction of -silylated -amino ketone (S,R)-3d (0.26 g, 0.50
mmol), NH4F (0.93 g, 25 mmol) and Bu4NF (0.8 mL, 0.80 mmol; 1
M solution in THF) gave pure (R)-4d.
Yield: 0.18 g (97%); [ ]D231.6 (c 0.8, CHCl3).
IR (film): 3399, 3085, 3062, 3027, 3003, 2960, 2930, 2874, 2799,
2717, 1948, 1875, 1808, 1711, 1603, 1585, 1495, 1453, 1370, 1255,
1156, 1125, 1067, 1029, 962, 934, 910, 875, 832, 796, 779, 749,
700, 620, 556, 509, 487 cm–1.
+
MS (EI, 70 eV): m/z (%) = 323 (1) [M+], 210 (67) [CH2NBn2 ], 181
+
(7), 118 (2.9), 106 (3.4), 91 (100) [C7H7 ], 65 (8).
1H NMR (300 MHz, CDCl3): = 0.73 (t, J = 7.4 Hz, 3 H, CH3),
Anal. Calcd for C22H29NO (323.48): C, 81.69; H, 9.04; N, 4.33.
Found: C, 81.57; H, 9.41; N, 4.66.
1.34–1.51 (m,
2
H, CH2CH3), 2.33–2.92 (m,
7
H,
CH2CH2COCHCH2N), 3.29 (d, J = 13.5 Hz, 2 H, NCH2Ph), 3.67 (d,
J = 13.5 Hz, 2 H, NCH2Ph), 7.12–7.32 (m, 15 H, CarH).
(–)-(2R)-1-(Dibenzylamino)-2,6-dimethylheptan-3-one [(R)-4b]
Reaction of -silylated -amino ketone (S,R)-3b (0.24 g, 0.50
mmol), NH4F (0.93 g, 25 mmol) and Bu4NF (0.8 mL, 0.80 mmol; 1
M solution in THF) gave pure (R)-4b.
13C NMR (75 MHz, CDCl3): = 12.4 (CH3), 23.9 (CH2CH3), 29.8
(PhCH2CH2CO), 43.5 (PhCH2CH2CO), 53.4 (COCH), 56.6
(CHCH2N), 59.3 (CH2Ph), 126.5 (p-CarH), 127.6 (p-CarH), 128.8
(o-CarH), 128.9 (o-CarH), 129.0 (m-CarH), 129.6 (m-CarH), 139.6
(Car), 142.0 (Car), 213.3 (C=O).
Yield: 0.16 g (94%); [ ]D24 –2.2 (c 0.4, C6H6).
IR (film): 3083, 3070, 3026, 2967, 2933, 2866, 2791, 1714, 1605,
1489, 1453, 1403, 1371, 1249, 1218, 1175, 1126, 1075, 1029, 976,
910, 815, 749, 701, 669, cm–1.
1H NMR (300 MHz, CDCl3): = 0.86 (d, J = 6.9 Hz, 3 H,
CH3CHCH3), 0.86 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 1.00 (d, J = 6.9
Hz, 3 H, COCHCH3), 1.40 (m, 3 H, CH2CH), 2.20–2.92 (m, 5 H,
+
MS (EI, 70 eV): m/z (%) = 385 (0.8) [M+], 211 (53) [CH2NBn2 ],
+
197 (22) [NBn2 ], 196 (16), 188 (36), 173 (6), 159 (9), 120 (8), 118
(6), 106 (51), 105 (16) [CH2CH2C6H5 ], 104 (9), 92 (17), 91 (100)
+
+
+
[C7H7 ], 84 (7), 83 (14), 79 (6), 77 (7) [C6H5 ], 65 (11), 55 (17).
Anal. Calcd for C27H31NO (385.55): C, 84.11; H, 8.10; N, 3.63.
Found: C, 83.79; H, 7.86; N, 3.81.
Synthesis 2002, No. 18, 2737–2748 ISSN 0039-7881 © Thieme Stuttgart · New York

2746
D. Enders et al.
PAPER
(–)-(2R)-2-Benzyl-1-(dibenzylamino)-5-phenylpentan-3-one
[(R)-4e]
1370, 1311, 1249, 1211, 1127, 1063, 1029, 973, 943, 911, 886, 840,
812, 735, 700, 648, 626, 584, 547, 500, 460 cm–1.
Reaction of -silylated -amino ketone (R,S)-3e (0.29 g, 0.50
mmol), NH4F (0.93 g, 25 mmol) and Bu4NF (0.8 mL, 0.80 mmol; 1
M solution in THF) gave pure (R)-4e.
Yield: 0.21 g (94%); [ ]D24 –2.8 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3):
CH2CH2CH2CH), 2.43 (dd, J = 12.2, 8.7 Hz, 1 H, NCH2), 2.82 (dd,
J = 12.2, 4.7 Hz, 1 H, NCH2), 3.34 (d, J = 13.8 Hz, 2 H CH2Ph),
3.76 (d, J = 13.8 Hz, 2 H, CH2Ph), 7.16–7.35 (m, 10 H, CarH).
= 1.23–2.58 (m, 9 H,
IR (KBr): 3405, 3085, 3062, 3027, 3003, 2926, 2800, 2717, 2249,
1949, 1876, 1807, 1710, 1603, 1584, 1548, 1495, 1453, 1368, 1331,
1254, 1206, 1178, 1156, 1125, 1075, 1029, 1003, 976, 910, 876,
830, 736, 699, 649, 622, 549, 489 cm–1.
13C NMR (75 MHz, CDCl3): = 23.9 (CH2), 27.7 (CH2), 31.9
(CH2), 41.5 (CH2C=O), 48.8 (CHCH2N), 53.5 (CHCH2N), 59.0
(NCH2Ph), 126.9 (p-CarH), 128.1 (o-CarH), 128.9 (m-CarH), 139.6
(Car), 213.0 (C=O).
1H NMR (400 MHz, CDCl3): = 2.24 (m, 1 H, CHH), 2.45 (dd,
J = 5.5, 12.9 Hz, 1 H, CHH), 2.55–2.77 (m, 5 H, 5 CHH), 2.79 (dd,
J = 9.1, 12.9 Hz, 1 H, CHH), 3.00 (tt, J = 8.8, 5.8 Hz, 1 H, COCH),
3.41 (d, J = 13.7 Hz, 2 H, NCHHPh), 3.62 (d, J = 13.7 Hz, 2 H,
NCHHPh), 6.98–7.31 (m, 20 H, CarH).
MS (EI, 70 eV): m/z (%) = 307 (2) [M+], 230 (1) [M+ – C6H5], 216
(9) [M+ – C7H7], 211 (12), 210 (83) [CH2NBn2 ], 197 (5) [NBn2 ],
181 (8), 118 (5), 111 (19) [M+ – NBn2], 106 (19), 97 (2) [M+ –
+
+
+
+
CH2NBn2], 92 (10), 91 (100) [C7H7 ], 77 (2) [C6H5 ], 67 (8), 65
(10).
13C NMR (100 MHz, CDCl3): = 29.0 (CHCH2C6H5), 36.6
(CH2CH2C6H5), 45.3 (CH2CH2C6H5), 52.8 (COCH), 56.4
(CHCH2N), 59.0 (NCH2C6H5), 125.9 (CarH), 126.2 (CarH), 127.1
(CarH), 128.2 (CarH), 128.3 (CarH), 128.5 (CarH), 128.7 (CarH),
129.0 (CarH), 138.9 (Car), 139.4 (Car), 141.3 (Car), 212.3 (C=O).
Anal. Calcd for C21H25NO (307.43): C, 82.04; H, 8.20; N, 4.56.
Found: C, 81.66; H, 8.40; N, 4.70.
(–)-(S)-2-[(Dibenzylamino)methyl]-1-cycloheptanone [(S)-4h]
Reaction of -silylated -amino ketone (S,R)-3h (0.23 g, 0.50
mmol), NH4F (0.93 g, 25 mmol) and Bu4NF (0.8 mL, 0.80 mmol; 1
M solution in THF) gave pure (S)-4h.
MS (EI, 70 eV): m/z (%) = 250 (16) [M+ – NBn2], 197 (10) [NBn2 ],
+
196 (7), 171 (7), 159 (12), 146 (5), 145 (11), 141 (5), 131 (7), 129
(7), 120 (6), 118 (8), 117 (22), 116 (7), 115 (21), 106 (47), 105 (8)
Yield: 0.15 g (93%); [ ]D24 –50.9 (c 0.4, CHCl3).
+
+
[CH2CH2C6H5 ], 104 (6), 92 (17), 91 (100) [C7H7 ], 89 (5), 79 (8),
IR (film): 3382, 3084, 3061, 3027, 2928, 2853, 2796, 2715, 1949,
1875, 1810, 1701, 1601, 1585, 1494, 1453, 1370, 1345, 1318, 1245,
1206, 1170, 1156, 1128, 1102, 1075, 1028, 973, 936, 876, 863, 828,
734, 700, 648, 622, 500, 452 cm–1.
+
78 (6), 77 (12) [C6H5 ], 65 (21), 51 (10).
Anal. Calcd for C32H33NO (447.62): C, 85.87; H, 7.43; N, 3.13.
Found: C, 85.46; H, 7.32; N, 2.79.
1H NMR (300 MHz, CDCl3):
CH2CH2CH2CH2CH2CH, NCHH), 3.43 (dd, J = 18.8, 13.8 Hz, 1 H,
NCHH), 3.48 (d, J = 13.8 Hz, 2 H CH2Ph), 3.56 (d, J = 13.8 Hz, 2
H CH2Ph), 7.16–7.34 (m, 10 H, CarH).
13C NMR (75 MHz, CDCl3): = 24.6 (CH2), 28.0 (CH2), 28.7
(CH2), 29.5 (CH2), 42.4 (CH2C=O), 50.7 (CHCH2N), 55.7
(CHCH2N), 59.1 (NCH2Ph), 126.9 (p-CarH), 128.1 (o-CarH), 128.9
(m-CarH), 139.6 (Car), 215.3 (C=O).
= 1.08–2.75 (m, 12 H,
(–)-(S)-2-[(Dibenzylamino)methyl]-1-cyclopentanone [(S)-4f]
Reaction of -silylated -amino ketone (S,R)-3f (0.22 g, 0.50
mmol), NH4F (0.93 g, 25 mmol) and Bu4NF (0.8 mL, 0.80 mmol; 1
M) solution in THF) gave pure (S)-4f.
Yield: 0.14 g (95%); mp 59 °C; [ ]D24 –14.6 (c 0.5, CHCl3).
IR (film): 3453, 3084, 3062, 3027, 2970, 2935, 2872, 2799, 2715,
1952, 1875, 1810, 1735, 1602, 1585, 1494, 1452, 1406, 1382, 1351,
1318, 1296, 1262, 1203, 1156, 1119, 1069, 1028, 1003, 971, 926,
870, 846, 825, 746, 700, 611, 580, 526, 494, 475 cm–1.
1H NMR (300 MHz, CDCl3): = 1.49–2.09 (m, 3 H, CH2CH2CH),
2.00 (m, 1 H, COCH), 2.16–2.42 (m, 3 H, H2CCOCH, CH2CH2CH),
2.44 (dd, J = 12.1, 9.7 Hz, 1 H, NCH2), 2.74 (dd, J = 12.1, 3.7 Hz,
1 H, NCH2), 3.33 (d, J = 13.8 Hz, 2 H CH2Ph), 3.76 (d, J = 13.8 Hz,
2 H CH2Ph), 7.18–7.38 (m, 10 H, CarH).
MS (EI, 70 eV): m/z (%) = 321 (1) [M+], 244 (0.4) [M+ – C6H5], 230
+
(5) [M+ – C7H7], 211 (10), 210 (67) [CH2NBn2 ], 197 (6), 196 (6)
+
[NBn2 ], 125 (1) [M+ – NBn2], 118 (5), 111 (0.4) [M+ – CH2NBn2],
+
106 (25), 105 (8), 92 (12), 91 (100) [C7H7 ], 81 (6), 79 (5), 77 (7)
+
[C6H5 ], 67 (6), 65 (12), 55 (9), 51 (5).
Anal. Calcd for C22H27NO (321.46): C, 82.20; H, 8.47; N, 4.36.
Found: C, 82.04; H, 8.39; N, 4.72.
13C NMR (75 MHz, CDCl3):
= 20.6 (CHCH2CH2), 29.1
(CHCH2CH2), 38.4 (CH2C=O), 47.9 (CHCH2N), 53.7 (CHCH2N),
58.6 (NCH2Ph), 126.9 (p-CarH), 128.2 (o-CarH), 128.8 (m-CarH),
139.5 (Car), 220.8 (C=O).
(+)-(3S)-1-Benzyl-3-[(dibenzylamino)methyl]-4-piperidinone
[(S)-4i]
Reaction of -silylated -amino ketone (R,R)-3i (0.16 g, 0.30
mmol), NH4F (0.56 g, 15 mmol) and Bu4NF (0.5 mL, 0.50 mmol; 1
M solution in THF) gave pure (S)-4i.
MS (EI, 70 eV): m/z (%) = 293 (0.5) [M+], 210 (9) [M+ – CH2NBn2],
+
202 (1) [M+ – C7H7], 197 (18) [NBn2 ], 196 (15), 120 (10), 106 (77),
+
+
96 (19) [M+ – NBn2], 91 (100) [C7H7 ], 83 (2) [CH2NBn2 ], 79 (5),
Yield: 0.11 g (92%); [ ]D25 +1.9 (c 0.5, CHCl3).
+
77 (6) [C6H5 ], 73 (6), 68 (10), 67 (11), 65 (15), 61 (5), 55 (6), 51
IR (film): 3646, 3406, 3085, 3061, 3027, 3004, 2929, 2798, 2715,
2249, 1951, 1877, 1811, 1713, 1678, 1602, 1585, 1494, 1470, 1453,
1418, 1390, 1364, 1349, 1324, 1288, 1265, 1192, 1131, 1075, 1056,
1028, 1002, 974, 910, 866, 842, 823, 736, 700, 648, 620, 550, 515,
488, 467 cm–1.
(5), 45 (5).
Anal. Calcd for C20H23NO (293.41): C, 81.87; H, 7.90; N, 4.77.
Found: C, 81.62; H, 8.06; N, 4.67.
(–)-(S)-2-[(Dibenzylamino)methyl]-1-cyclohexanone [(S)-4g]
Reaction of -silylated -amino ketone (S,R)-3g (0.22 g, 0.50
mmol), NH4F (0.93 g, 25 mmol) and Bu4NF (0.8 mL, 0.80 mmol; 1
M solution in THF) gave pure (S)-4g.
1H NMR (300 MHz, CDCl3): = 2.05 (dd, J = 11.5, 8.4 Hz, 1 H,
CHCHHN), 2.21 (m, 1 H, COCHH), 2.38–2.50 (m, 3 H, NCH2,
NCH2), 2.73 (m, 1 H, NCH2), 2.80 (ddd, J = 10.4, 5.0, 2.0 Hz, 1 H,
COCHH), 2.94 (dd, J = 12.9, 5.6 Hz, 1 H, CHCHHN), 3.14 (ddd,
J = 11.5, 5.2, 2.1 Hz, 1 H, CHCH2N), 3.35 [d, J = 13.2 Hz, 2 H,
N(CHHPh)2], 3.44 (d, J = 13.5 Hz, 1 H, NCHHPh), 3.53 [d,
J = 13.3 Hz, 2 H, N(CHHPh)2], 3.62 (d, J = 13.5 Hz, 1 H, NCHH-
Ph), 7.16–7.41 (m, 15 H, CarH).
Yield: 0.15 g (98%); [ ]D24 –41.6 (c 0.3, CHCl3).
IR (film): 3515, 3397, 3084, 3061, 3027, 3004, 2934, 2860, 2829,
2796, 2715, 2249, 1950, 1877, 1809, 1708, 1601, 1585, 1494, 1451,
Synthesis 2002, No. 18, 2737–2748 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Mannich Reactions by -Silyl Controlled Aminomethylation of Ketones
2747
13C NMR (75 MHz, CDCl3): = 40.7 (COCH2), 48.2 (COCH), 51.8
(NCH2CH2), 53.5 (NCH2CH), 57.0 (Bn2NCH2CH), 58.6
[N(CH2Ph)2], 61.8 (NCH2Ph), 126.9 (2 p-CarH), 127.3 (p-CarH),
128.1 (2 o-CarH), 128.3 (o-CarH), 128.9 (m-CarH), 129.0 (2 m-CarH),
138.3 (Car), 139.4 (2 Car), 210.8 (C=O).
(3) (a) Kleemann, A.; Engel, J. In Pharmazeutische Wirkstoffe;
Sucker, H.; Fuchs, P. E., Eds.; Thieme: Stuttgart, 1987.
(b) Traxler, P.; Trinks, U.; Buchdunger, E.; Mett, H.; Meyer,
T.; Müller, M.; Regenass, U.; Rösel, J.; Lydon, N. J. Med.
Chem. 1995, 38, 2441. (c) Dimmock, J. R.; Sidhu, K. K.;
Chen, M.; Reid, R. S.; Allen, T. M.; Kao, G. Y.; Truitt, G. A.
Eur. J. Med. Chem. 1993, 28, 313. (d)Shiozawa, A.; Narita,
K.; Izumi, G.; Kurashige, S.; Sakitama, K.; Ishikawa, M.
Eur. J. Med. Chem. 1995, 30, 85. (e) Wanner, K. T.;
Praschak, I.; Nagel, U. Arch. Pharm. 1990, 323, 335.
(4) (a) Vicario, J. L.; Badía, D.; Carrillo, L. Org. Lett. 2001, 3,
773. (b) Vicario, J. L.; Badía, D.; Carrillo, L. J. Org. Chem.
2001, 60, 9030. (c) Davis, F. A.; Zhou, P.; Chen, B.-C.
Chem. Soc. Rev. 1998, 27, 13. (d) Saito, S.; Hatanaka, K.;
Yamamoto, H. Tetrahedron 2001, 57, 875. (e) Saito, S.;
Hatanaka, K.; Yamamoto, H. Org. Lett. 2000, 2, 1891.
(f) Allef, P.; Kunz, H. Tetrahedron: Asymmetry 2000, 11,
375. (g) Müller, R.; Goesmann, H.; Waldmann, H. Angew.
Chem. Int. Ed. 1999, 38, 184; Angew. Chem. 1999, 111,
166. (h) Müller, R.; Röttele, H.; Henke, H.; Waldmann, H.
Chem. Eur. J. 2000, 6, 2032. (i) Kanazawa, A. M.; Jean
Noël, D.; Greene, A. E. J. Org. Chem. 1994, 59, 1238.
(j) Kise, N.; Ueda, N. J. Org. Chem. 1999, 64, 7511.
(k) Shono, T.; Kise, N.; Sanda, F.; Ohi, S.; Yoshioka, K.
Tetrahedron Lett. 1989, 30, 1253. (l) Kawakami, T.;
Ohtake, H.; Arakawa, H.; Okachi, T.; Imada, Y.; Murahashi,
S.-I. Chem. Lett. 1999, 795. (m) Corey, E. J.; Decicco, C. P.;
Newbold, R. C. Tetrahedron Lett. 1991, 39, 5287.
MS (EI, 70 eV): m/z (%) = 307 (1) [M+ – C7H7], 210 (1)
+
+
[CH2NBn2 ], 201 (8) [M+ – NBn2], 197 (10) [NBn2 ], 196 (7), 124
+
(5), 120 (5), 110 (17), 106 (37), 92 (22), 91 (100) [C7H7 ], 77 (5)
[C6H5 ], 65 (16).
+
Anal. Calcd for C27H30N2O (398.55): C, 81.37; H, 7.59; N, 7.03.
Found: C, 80.87; H, 7.90; N, 7.23.
(–)-(4S)-4-[(Dibenzylamino)methyl]-2,2-dimethyl-1,3-dioxan-5-
one [(S)-4j]
Reaction of -silylated -amino ketone (S,S)-3j (0.14 g, 0.30
mmol), NH4F (0.56 g, 25 mmol) and Bu4NF (0.5 mL, 0.50 mmol; 1
M solution in THF) gave pure (S)-4j.
Yield: 0.09 g (89%); [ ]D24 –7.2 (c 0.3, CHCl3).
IR (film): 3473, 3085, 3062, 3028, 2989, 2939, 2882, 2831, 2800,
2720, 2250, 1950, 1875, 1792, 1746, 1631, 1603, 1586, 1495, 1453,
1375, 1327, 1291, 1252, 1224, 1202, 1176, 1162, 1134, 1094, 1028,
974, 912, 879, 844, 736, 700, 649, 624, 609, 563, 538, 524, 471
cm–1.
1H NMR (300 MHz, CDCl3): = 1.42 (s, 3 H, CH3), 1.49 (s, 3 H,
CH3), 2.71 (dd, J = 14.4, 8.4 Hz, 1 H, CHCHHN), 3.16 (dd, J = 4.4,
2.6 Hz, 1 H, CHCHHN), 3.64 (d, J = 13.7 Hz, 2 H, CHHPh), 3.75
(d, J = 13.7 Hz, 2 H, CHHPh), 3.94 (d, J = 17.0 Hz, 1 H, COCHH),
4.23 (d, J = 17.0 Hz, 1 H, COCHH), 4.49 (ddd, J = 8.3, 2.7, 1.5 Hz,
1 H, CHCH2N), 7.18–7.39 (m, 5 H, CarH).
(n) Ishihara, K.; Funahashi, M.; Hanaki, N.; Miyata, M.;
Yamamoto, H. Synlett 1994, 963. (o) Ishihara, K.;
Yamamoto, H. Eur. J. Org. Chem. 1999, 527. (p) Ishitani,
H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119,
7153. (q) Ishitani, H.; Kitazawa, T.; Kobayashi, S.
13C NMR (75 MHz, CDCl3): = 23.6 (CH3), 24.0 (CH3), 51.8
(CHCH2N), 58.7 (NCH2Ph), 66.7 (COCH2), 74.9 (COCH), 100.8
[(H3C)2COO], 126.9 (p-CarH), 128.2 (o-CarH), 128.8 (m-CarH),
139.4 (Car), 208.7 (C=O).
Tetrahedron Lett. 1999, 40, 2161. (r) Ishitani, H.; Ueno, M.;
Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180.
(5) (a) Seebach, D.; Betschart, C.; Schiess, M. Helv. Chim. Acta
1984, 67, 1593. (b) Nolen, E. G.; Aliocco, A.; Broody, M.;
Zuppa, A. Tetrahedron Lett. 1991, 32, 73. (c) Nolen, E. G.;
Aliocco, A.; Vitarius, J.; McSorley, K. J. Chem. Soc., Chem.
Commun. 1990, 1532. (d) Arend, M.; Risch, N. Synlett
1997, 974. (e) Arend, M.; Risch, N. Angew. Chem. Int. Ed.
Engl. 1994, 33, 2422; Angew. Chem. 1994, 106, 2531.
(f) Arend, M.; Risch, N. Angew. Chem., Int. Ed. Engl. 1995,
34, 1639; Angew. Chem.; 1995, 107: 2861. (g) Zarghi, J.;
Reza Naimi-Jamal, M.; Webb, S. A.; Balalaie, S.; Saidi, M.
R.; Ipaktschi, J. Eur. J. Org. Chem. 1998, 197.
MS (EI, 70 eV): m/z (%) = 324 (0.4) [M+ – CH3], 211 (9), 210 (50)
+
[M+ – CH2NBn2], 197 (4) [NBn2 ], 181 (5), 143 (0.4) [M+ – NBn2],
+
+
106 (29), 92 (11), 91 (100) [C7H7 ], 77 (2) [C6H5 ], 65 (10).
Anal. Calcd for C21H25NO3 (339.43): C, 74.31; H, 7.42; N, 4.13.
Found: C, 73.98; H, 7.32; N, 4.59.
Acknowledgements
This work was supported by Deutsche Forschungsgemeinschaft
(Leibniz prize, Sonderforschungsbereich 380, Transferbereich 11)
and the Fonds der Chemischen Industrie. We thank Grünenthal
GmbH, Degussa AG, BASF AG, Bayer AG and Wacker Chemie for
donations of chemicals.
(h) Katritzky, A. R.; Harris, P. A. Tetrahedron 1990, 46,
987. (i) Saidi, M. R.; Heydari, A.; Ipaktschi, J. Chem. Ber.
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S. J. Org. Chem. 1988, 52, 2617. (k) Agami, C.; Bihan, D.;
Puchot-Kadouri, C. Tetrahedron 1996, 27, 9079.
(l) Frauenrath, H.; Arenz, T.; Raabe, G.; Zorn, M. Angew.
Chem., Int. Ed. Engl. 1993, 32, 83; Angew. Chem. 1993, 105,
74. (m) Tanino, K.; Takahashi, M.; Murayama, K.;
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Synthesis 2002, No. 18, 2737–2748 ISSN 0039-7881 © Thieme Stuttgart · New York