Direct organocatalytic enantioselective α-aminomethylation of ketones

Article abstract of DOI:10.1016/j.tet.2005.08.113

The scope and limitations of the direct organocatalytic asymmetric α-aminomethylation of ketones are disclosed. The proline-catalyzed classical Mannich reactions between unmodified ketones, aqueous formaldehyde and aromatic amines furnished the desired Ma

Full text of DOI:10.1016/j.tet.2005.08.113

Tetrahedron 62 (2006) 357–364
Direct organocatalytic enantioselective a-aminomethylation
of ketones
*
´ ´
´
Ismail Ibrahem, Weibiao Zou, Jesus Casas, Henrik Sunden and Armando Cordova
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Received 30 May 2005; revised 8 August 2005; accepted 31 August 2005
Available online 3 October 2005
Abstract—The scope and limitations of the direct organocatalytic asymmetric a-aminomethylation of ketones are disclosed. The proline-
catalyzed classical Mannich reactions between unmodified ketones, aqueous formaldehyde and aromatic amines furnished the desired
Mannich bases in high yield with up to O99% ee. Moreover, methyl alkyl ketones were regioselectively a-aminomethylated at the
methylene carbon affording the corresponding Mannich products with up to O99% ee. In addition, the proline-catalyzed one-pot three-
component reaction between p-anisidine, aqueous formaldehyde and 4,4-dimethyl-2-cycloxehen-1-one furnished the corresponding bicyclic
aza-Diels–Alder adduct with O99% ee.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
complexes.10 Recently, Shibasaki and Matsunaga,11 and
Trost and co-workers12 developed di-nuclear zinc organo-
metallic complexes as catalyst for the direct catalytic
enantioselective Mannich-type reactions between hydroxy-
arylketones and preformed imines. In addition, Jørgensen
and co-workers have developed elegant direct asymmetric
Mannich reactions involving activated ketones as donors
and chiral copper(II) bisoxazoline (BOX) complexes as
catalysts.13 The rapidly growing research in organocatalysis
has also led to development of several amino acid catalyzed
stereoselective reactions.14 List reported the first one-pot
three-component Mannich reaction between in situ gener-
ated imines and unmodified ketones as donors.15 This initial
report led to the development of several novel Mannich-type
reactions by several groups that are catalyzed by amino acid
derivatives.16 More recently, we developed the first direct
organocatalytic one-pot three-component Mannich reaction
involving aldehydes as nucleophiles.17 Moreover, Jacobsen,18
Terada,19 Akiyama20 and Jørgensen21 have reported
excellent catalytic asymmetric Mannich-type reactions
that are catalyzed by organocatalysts.
The classical Mannich reaction,1 in which an aminomethyl
group is introduced in the a-position to a carbonyl
compound, is an important transformation in organic
chemistry.2 The resulting Mannich bases are of particular
interest due to their use as synthetic building blocks and
precursors of pharmaceutically valuable g-amino alcohols
for different therapeutic areas.2 However, there are only a
few enantioselective a-aminomethylation reactions that
have been developed and most of them are diastereoselec-
tive employing chiral auxiliaries or enantiomerically pure
substrates.3 For example, Enders and co-workers have
developed excellent diastereoselective a-aminomethylation
reactions.4
The initial stoichiometric and indirect stereoselective
Mannich-type reactions utilize preformed chiral enol
equivalents or imines.5 Thus, the first successful example
of catalytic asymmetric additions of preformed enolates to
imines by Kobayashi and co-workers was an important
advancement.6 These results inspired the research and
development of several catalytic indirect stereoselective
Mannich reactions catalyzed by organometallic
complexes.7–9 Shibasaki and co-workers reported the first
example of direct catalytic enantioselective Mannich-type
reactions that were catalyzed by heterobimetallic
The first attempt to catalyze the one-pot three-component
direct catalytic a-aminomethylation reaction of a ketone
was reported by Shibasaki and co-workers.10 In this
reaction, the desired Mannich base was isolated in 16%
yield and 64% ee. Inspired by this initial attempt and our
interest in amino acid catalysis,22 we most recently
disclosed the first organocatalytic a-aminomethylation of
ketones.23 Herein, we present the scope and limitations
of this one-pot three-component reaction, which also led to
Keywords: Asymmetric catalysis; Proline derivatives; Ketones; a-Amino-
methylation; Classical Mannich reaction.
Corresponding author. Tel.: C46 8 162479; fax: C46 8 154908;
e-mail addresses: acordova@organ.su.se; acordova1a@netscape.net
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.113

358
I. Ibrahem et al. / Tetrahedron 62 (2006) 357–364
the discovery of the first one-pot three-component aza-
Diels–Alder reaction.24
and enantioselectivities. We initially investigated the
proline-catalyzed reaction between cyclohexanone 1a,
aqueous formaldehyde 2 and para-anisidine that yields
Mannich product 3a as a model system (Eq. 1).
2. Results and discussion
The focus of our project was to develop a direct amino acid-
catalyzed classical one-pot three-component Mannich
reaction between aqueous formaldehyde, aromatic amines
and ketones to furnish chiral Mannich bases in high yields
(1)
Table 1. Selected examples from the solvent screena
We conducted the reaction in different organic solvents and
found that the highest enantioselectivity as well as
efficiency was obtained in DMSO (Table 1).
In this solvent, p-methoxyphenyl (PMP) protected Mannich
base 3a is isolated in high yield with O99% ee. Increasing
the equivalents of ketone 1a from two to ten significantly
increased the enantioselectivity as well as the rate of the
reaction in DMF (Entry 5). Importantly, we found that the
Mannich bases should be purified by neutral aluminium
oxide column chromatography since they racemize upon
silica-gel column chromatography.
Entry
Solvent
Time (h)
Yield (%)b
ee (%)c
1
3
4
5
6
DMSO
NMP
DMF
DMF
16
33
33
14d
94
87
80
61d
87
O99
77
87
98d
25
Acetonitrile 33
a Experimental conditions: a mixture of 1a (2 mmol, 2 equiv), p-anisidine
(1.1 mmol), 2 (1 mmol) and (S)-proline was stirred at room temperature
for 16 h. The crude product obtained after aqueous work-up was purified
by column chromatography.
In addition to proline, we also investigated other organo-
catalysts ability to mediate the model reaction (Table 2).
All the investigated catalysts catalyzed the reaction and
furnished the desired Mannich base 3a in high yield.
However, (S)-proline-catalyzed the reaction with the high-
est stereoselectivity under the set reaction conditions.
b Isolated yield of the pure products after neutral aluminum oxide
chromatography.
c Determined by chiral-phase HPLC analyses.
d Ten equivalents ketone 1a was used.
Table 2. Catalyst screened for the direct asymmetric a -hydroxymethylation of ketone 1aa
Entry
1
Catalyst
Time (h)
16
Yield (%)b
94
ee (%)c
(S)-proline
O99
3
4
33
33
71
92
!5
!5
5
6
33
17
62
96
!5
51
a Experimental conditions: a mixture of 1a (2 mmol, 2 equiv), p-anisidine (1.1 mmol), 2 (1 mmol) and chiral organocatalyst was stirred at room temperature for
16–33 h. The crude product obtained after aqueous work-up was purified by column chromatography.
b Isolated yield of the pure products after neutral aluminum oxide chromatography.
c Determined by chiral-phase HPLC analyses.

I. Ibrahem et al. / Tetrahedron 62 (2006) 357–364
359
Table 3. Proline-catalyzed one-pot three-component direct a-aminomethylation fo different ketonesa
3/30
Entry
1
Ketone
Product
Yield (%)b
ee (%) of 3c
90
O99
1a
3a
2
85
O99
1b
1c
1d
3b
3c
3
4
84d
O99d
85e
O99f
3d
5
80
2:1
O99
3e
3e0
RZn-pent
1e
84
6
7
94
72
4:1
6:1
3f
3f0
1f
RZCH2CHZCH2
O99
1g
3g
3g0
RZn-hept
8
60d,g
70d,g
1h
3h
a Experimental conditions: a mixture of 1 (2 mmol, 2 equiv), p-anisidine (1.1 mmol), 2 (1 mmol) and (S)-proline was stirred at room temperature for 16–17 h.
The crude product obtained after aqueous work-up was purified by column chromatography.
b Isolated yield of the pure products after neutral aluminum oxide chromatography.
c Determined by chiral-phase HPLC analyses.
d Proline (30 mol%) was used.
e Trans/cis 3:1.
f
ee of the trans-isomer.
g Purified by silica-gel column chromatography.

360
I. Ibrahem et al. / Tetrahedron 62 (2006) 357–364
Table 4. Direct catalytic one-pot three-component a-aminomethylation reactions with different aromatic aminesa
Entry
1
Ar
Product
Yield (%)b
ee (%)c
90
O99
3a
3i
2
45
O99
3
4
71
92
O99
O99
3j
3k
a Experimental conditions: a mixture of 1 (2 mmol, 2 equiv), aniline (1.1 mmol), 2 (1 mmol) and (S)-proline was stirred at room temperature for 16–24 h. The
crude product obtained after aqueous work-up was purified by column chromatography.
b Isolated combined yield after neutral aluminum oxide chromatography.
c Determined by chiral-phase HPLC analyses.
Based on these results and the practical aspects of
employing proline catalysis we decided to investigate the
proline-catalyzed one-pot three-component direct catalytic
asymmetric Mannich reactions for a set of different aliphatic
ketones (Table 3).
ketones can be synthesized in moderate to high yield with
almost absolute stereocontrol.
We also investigated the proline-catalyzed direct asym-
metric one-pot three-component a-aminomethylation of
aldehydes (Scheme 1). However, under all the reaction
conditions tested the self-Mannich adducts were formed
with excellent stereoselectivity and only trace amounts of
the desired product was detected. Thus, in this case, proline
exhibited a high chemoselectivity for the formation of the
self-Mannich adduct.
The reactions proceeded smoothly, and the corresponding
Mannich bases 3a–3h were isolated in high yield with up to
O99% ee. For example, the proline-catalyzed a-amino-
methylation of dihydroxyacetone phosphate mimic 1c
furnished aminosugar 3c in 84% yield with O99% ee.25
The reactions exhibited excellent chemoselectivity and no
aldol adducts could be detected. Moreover, reactions with
linear ketones were regioselective and the a-aminomethyl-
ation occurred predominantly at the methylene carbon
atoms of the ketones. The amino acid-catalyzed one-pot
three-component reaction was also extended to other
aromatic amines than p-anisidine (Table 4).
The high efficiency and stereoselectivity of the amino acid
catalyzed direct catalytic asymmetric a-aminomethylation
The proline-catalyzed reactions between substituted ani-
lines, aqueous formaldehyde and cyclohexanone 1a yielded
the corresponding Mannich bases 3i–3k in 45–92% yield
with O99% ee, respectively. Thus, a-aminoarylated
Scheme 2. Proline-catalyzed one-pot three-component asymmetric aza-
Diels–Alder reaction.
Scheme 1. Chemoselectivity in the proline-catalyzed asymmetric a-aminomethylation of aldehydes.

I. Ibrahem et al. / Tetrahedron 62 (2006) 357–364
361
Scheme 3. Asymmetric synthesis of diacetylated cis-6 and trans-6.
reactions of ketones inspired us to investigate the reactions
between aqueous formaldehyde, p-anisidine and a,b-
unsaturated cyclic ketones. The transformations constitute
the first examples of direct catalytic asymmetric aza-Diels–
Alder reactions.24 For example, the proline-catalyzed
aza-Diels–Alder reaction between p-anisidine, aqueous
formaldehyde and 2-cyclohexenone 1h furnished the aza-
Diels–Alder product 4a in 75% yield and O99% ee
(Scheme 2).
elaboration in wet solvents and in the presence of air. In
addition, other proline-derivatives including dipeptides
catalyzed the reaction. The proline-catalyzed one-pot
three-component a-aminomethylation of ketones opens up
a new entry for the construction of pharmaceutically active
Mannich bases.
3. Experimental
3.1. General
The absolute configuration of the amino acid derived
Mannich bases was determined by converting Mannich
product 3a into the known diacetylated amino alcohol 6
(Scheme 3). Thus, a-aminomethylated ketone 3a was
reduced with NaBH4 in situ to the corresponding mono-
protected amino alcohol 5, which was isolated in 88% yield,
over the two steps, with dr 1:1 (trans/cis) and O99%ee.
Removal of the p-methoxyphenyl (PMP) group under
oxidative conditions followed by acetylation afforded the
cis- and trans-diacetylated amino alcohols 6 in 72%
combined yield. The optical rotation of the cis-isomer and
comparison with the literature revealed that the absolute
configuration of the product was cis-(1S,2S)-6 ([a]2d5C50.2
(c 1.0, MeOH), [a]2d5C55.9 (c 0.8, MeOH)26).
Chemicals and solvents were either purchased puriss p.A.
from commercial suppliers or purified by standard tech-
niques. For thin-layer chromatography (TLC), silica gel
plates Merck 60 F254 were used and compounds were
visualized by irradiation with UV light and/or by treatment
with a solution of phosphomolybdic acid (25 g),
Ce(SO4)2$H2O (10 g), concd H2SO4 (60 mL), and H2O
(940 mL) followed by heating or by treatment with a
solution of p-anisaldehyde (23 mL), concd H2SO4 (35 mL),
acetic acid (10 mL), and ethanol (900 mL) followed by
heating. Flash chromatography was performed using silica
gel Merck 60 (particle size 0.040–0.063 mm), 1H NMR and
13C NMR spectra were recorded on Varian AS 400.
Chemical shifts are given in d relative to tetramethylsilane
(TMS), the coupling constants J are given in Hz. The spectra
were recorded in CDCl3 as solvent at room temperature,
TMS served as internal standard (d 0 ppm) for 1H NMR, and
CDCl3 was used as internal standard (d 77.0 ppm) for 13C
NMR. HPLC was carried out using a Waters 2690
Millennium with photodiode array detector. Optical
rotations were recorded on a Perkin Elmer 241 Polarimeter
(lZ589 nm, 1 dm cell). High resolution mass spectra were
recorded on an IonSpec FTMS mass spectrometer with a
DHB-matrix.
On the basis of the absolute configuration, we propose
transition-state model I to account for the regio- and
enantio-selectivity of the a-aminomethylation reaction of
unmodified substituted ketones (Fig. 1). Hence, (S)-proline
derivative forms an enamine with the ketone that is attacked
by the imine from its Si-face providing (2S)-a-aminomethyl-
ated ketones. This is in accordance with the transition states
of previously reported proline-catalyzed Mannich reactions,
in which a Si-facial attack occurs.15–17
3.2. Typical experimental procedure for the direct
asymmetric a-aminomethylation of ketones
To a vial containing 2 (1 mmol, 36% aqueous solution),
aniline (1.1 mmol) and a catalytic amount of (S)-proline
(10 or 30 mol%) in DMSO (4 mL) was added the ketone 1
(2 mmol). After 20 h of vigorously stirring the reaction was
quenched by addition of aqueous NH4Cl and the aqueous
phase was extracted three times with EtOAc. The combined
organic layers were dried with MgSO4, which was
subsequently removed by filtration. Next, the solvent was
removed under reduced pressure following purification of
the crude product mixture by neutral aluminum oxide
Figure 1. Transition state models evoked to account for the enantioselec-
tivity of the (S)-proline-catalyzed reaction.
In summary, our catalytic enantioselective one-pot three-
component a-aminomethylation of various ketones repre-
sents a direct approach for the construction of nearly
enantiomerically pure Mannich bases in high yield. The
reactions were simply performed without tedious

362
I. Ibrahem et al. / Tetrahedron 62 (2006) 357–364
column chromatography (EtOAc/pentane 1:10) to afford
a-aminomethylated ketone 3. The ee of the ketones was
determined by chiral-phase HPLC analysis (Daicel Chiral-
pak AD column, lZ244 nm, v 0.5 mL/min, hex/i-PrOH).
CDCl3) d (ppm): 25.1, 28.0, 32.3, 42.5, 45.6, 50.0, 56.1,
114.9, 115.2, 142.2, 152.6, 213.6; HPLC (Daicel Chiralpak
AD, hexanes/i-PrOH 98:2, flow rate 0.5 mL/min, lZ
254 nm): major isomer: tRZ25.40 min; minor isomer:
tRZ26.98 min; [a]2D5C6.1 (c 1.1, CHCl3).
3.2.1. (2S)-(4-Methoxyphenylamino-methyl)-cyclohexa-
none 3a. Yellow solid (219 mg), 94% 1H NMR
(400 MHz, CDCl3) d (ppm): 1.49 (m, 1H, CH [Cy]), 1.67
(m, 2H, CH2 [Cy]), 1.90 (m, 1H, CH [Cy]), 2.10 (m, 2H,
CH2 [Cy]), 2.35 (m, 2H, CH2 [Cy]), 2.65 (m, 1H, CHC]O),
3.05 (dd, JZ13.3, 4.7 Hz, 1H, CHHN), 3.37 (dd, JZ13.3,
7.8 Hz, 1H, CHHN), 3.74 (s, 3H, OCH3), 6.59 (m, 2H,
ArH), 6.77 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3) d
(ppm): 25.1, 28.0, 32.3, 42.5, 45.6, 50.0, 56.1, 114.9, 115.2,
142.2, 152.6, 213.6; HPLC (Daicel Chiralpak AD, hexanes/
i-PrOH 96:4, flow rate 0.5 mL/min, lZ254 nm): major
isomer: tRZ44.31 min; minor isomer: tRZ58.79 min;
[a]2D5C4.6 (c 2, CHCl3); MALDI-TOF MS: 256.1008;
C14H19NO2 (MCNaC: calcd 256.1313).
1
3.2.6. Compound 3f. Yellow oil, 219 mg, 94% H NMR
(400 MHz, CDCl3) d (ppm): 2.16 (s, 3H, CH3C]O), 2.27
(m, 1H, CHCH]CH2), 2.47 (m, 1H, CHCH]CH2), 3.93
(m, 1H, CHCH2), 3.20 (dd, JZ12.8, 4.8 Hz, 1H, CHHN),
3.35 (dd, JZ12.9, 8.3 Hz, 1H, CHHN), 3.74 (s, 3H, OCH3),
5.10 (m, 2H, CH2]CH), 5.75 (m, 1H, CH2]CH), 6.57 (d,
JZ8.9 Hz, 2H, ArH), 6.77 (d, JZ8.9 Hz, 2H, ArH); 13C
NMR (100 MHz, CDCl3) d (ppm): 30.1, 34.1, 45.8, 51.8,
56.0, 114.7, 115.2, 117.8, 135.0, 142.0, 152.7, 211.3; HPLC
(Daicel Chiralpak AD, hexanes/i-PrOH 98:2, flow rate
0.5 mL/min, lZ254 nm): major isomer: tRZ43.40 min;
minor isomer: tRZ47.20 min; [a]2D5C3.6 (c 2.5, CHCl3).
1
3.2.7. Compound 3g. Yellow oil (220 mg, 72%) H NMR
3.2.2. Compound (2S)-3b. 248 mg, 85% 1H NMR
(400 MHz, CDCl3) white solid d (ppm): 1.99 (m, 2H, CH2
[Cy]), 2.08 (m, 2H, CH2 [Cy]), 2.38 (m, 1H, CH [Cy]), 2.65
(m, 1H, CH [Cy]), 2.95 (m, CH, [Cy]), 3.10 (dd, JZ13.2,
4.7 Hz, 1H, CHHN), 3.33 (dd, JZ13.2, 7.3 Hz, 1H,
CHHN), 3.73 (s, 3H, OCH3), 4.00 (m, 4H, 2!OCH2),
6.56 (m, 2H, ArH), 6.77 (m, 2H, ArH); 13C NMR
(100 MHz, CDCl3) d (ppm): 34.4, 38.4, 38.7, 44.8, 45.9,
55.7, 64.6, 107.2, 142.1, 152.2, 211.8; HPLC (Daicel
Chiralpak AD, hexanes/i-PrOH 98:2, flow rate 0.5 mL/min,
lZ254 nm): major isomer: tRZ148.04 min; minor isomer:
tRZ160.40 min; [a]2D5K2.0 (c 1.0, CHCl3).
(400 MHz, CDCl3) d (ppm): 0.88 (t, JZ6.7 Hz, 3H), 1.28
(m, 12H), 2.15 (s, 3H), 2.82 (m, 1H), 3.17 (dd, JZ12.8,
4.6 Hz, 1H), 3.32 (dd, JZ12.9, 8.6 Hz, 1H), 3.73 (s, 3H),
6.56 (d, JZ8.9 Hz, 2H), 6.77 (d, JZ9.1 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d (ppm): 14.2, 22.8, 27.5, 29.2, 29.8,
29.9, 32.0, 46.2, 52.6, 114.5, 115.1, 120.0, 142.2, 152.5,
212.3; HPLC (Daicel Chiralpak AD, hexanes/i-PrOH 99:1,
flow rate 0.5 mL/min, lZ254 nm): major isomer: tRZ
41.50 min; minor isomer: tRZ43.10 min; [a]2D5C2.0 (c 1.4,
CHCl3).
1
3.2.8. Compound 3h. Yellow oil (126 mg, 60%) H NMR
(400 MHz, CDCl3) d (ppm): 2.17 (s, 3H, CH3), 3.76 (s, 3H,
OMe), 4.56 (dd, JZ5.5, 7.8 Hz, 1H, CHOH), 4.86 (d, JZ
2.5 Hz, 1H, CH2NHAr), 5.04 (d, JZ2.5 Hz, 1H, CH2-
NHAr), 6.60 (d, JZ9.0 Hz, 2H), 6.85 (d, JZ9.0 Hz, 2H);
13C NMR (100 MHz, CDCl3) d (ppm): 26.5, 50.6, 55.9,
83.7, 114.9, 115.8, 140.4, 153.6, 209.5; HPLC (Daicel
Chiralpak AD, hexanes/i-PrOH 90:10, flow rate 0.5 mL/
min, lZ254 nm): major isomer: tRZ18.97 min; minor
isomer: tRZ23.53 min; [a]2D5K9.4 (c 1, CHCl3).
3.2.3. Compound (2S)-3c. 223 mg, 84% 1H NMR
(400 MHz, CDCl3) yellowish oil d (ppm): 1.44 (s, 3H,
Me), 1.96 (s, 3H, Me), 3.29 (m, 1H), 3.37 (m, 1H), 3.73 (s,
3H, OMe), 4.0 (d, JZ17.8 Hz, 1H), 4.27 (d, JZ17.8 Hz,
1H), 4.43 (m, 1H), 6.65 (d, JZ8.9 Hz, 2H, ArH), 6.78 (d,
JZ8.9 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3) d
(ppm): 23.8, 24.2, 44.5, 55.8, 66.8, 73.4, 101.1, 115.0,
115.4, 141.7, 152.9, 208.9; (Daicel Chiralpak AD, hexanes/
i-PrOH 98:2, flow rate 0.5 mL/min, lZ254 nm): major
isomer: tRZ44.63 min; minor isomer: tRZ54.14 min;
[a]2D5K129.3 (c 2.5, CHCl3).
3.2.9. Compound 3i. Yellow solid (148 mg, 45%) 1H NMR
(400 MHz, CDCl3) d (ppm): 1.49 (m, 1H, CH [Cy]), 1.67
(m, 2H, CH2 [Cy]), 1.90 (m, 1H, CH [Cy]), 2.10 (m, 2H,
CH2 [Cy]), 2.35 (m, 2H, CH2 [Cy]), 2.65 (m, 1H, CHC]O),
3.07 (dd, JZ13.3, 4.5 Hz, 1H, CH2NHAr), 3.37 (dd, JZ
13.6, 7.8 Hz, 1H, CH2NHAr), 6.36 (d, JZ8.8 Hz, 2H, ArH),
7.39 (d, JZ8.8 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3)
d (ppm): 25.1, 28.0, 32.2, 42.5, 44.0, 49.9, 115.4, 117.4,
138.0, 147.8, 213.3; HPLC (Daicel Chiralpak AD, hexanes/
i-PrOH 98:2, flow rate 0.5 mL/min, lZ254 nm): major
isomer: tRZ53.80 min; minor isomer: tRZ78.80 min;
[a]2D5C2.2 (c 1.1, CHCl3).
3.2.4. Compound trans-(2S)-3d. (3dC3d0, 210.2 mg,
85%) yellow solid, major diastereomer: 1H NMR
(400 MHz, CDCl3) d (ppm): 1.0 (d, JZ6.3 Hz, 3H,
CHCH3), 1.29 (m, 1H, CH [Cy]), 1.71 (m, 2H, CH2 [Cy]),
2.01 (m, 2H, CH2 [Cy]), 2.35 (m, 2H, CH2 [Cy]), 2.7 (m,
1H, CH [Cy]), 3.05 (m, H, CHHN), 3.35 (m, 1H, CHHN),
3.73 (s, 3H, OCH3), 6.56 (m, 2H, ArH), 6.77 (m, 2H, ArH);
13C NMR (100 MHz, CDCl3) d (ppm): 21.2, 31.7, 35.6,
40.2, 41.6, 45.0, 48.6, 55.7, 114.4, 114.9, 142.2, 152.1,
213.4; HPLC (Daicel Chiralpak AD, hexanes/i-PrOH 96:4,
flow rate 0.5 mL/min, lZ254 nm): major isomer: tRZ
48.8 min; minor isomer: tRZ52.9 min.
3.2.10. Compound 3j. Yellow solid (200 mg, 71%) 1H
NMR (400 MHz, CDCl3) d (ppm): 1.49 (m, 1H, CH [Cy]),
1.67 (m, 2H, CH2 [Cy]), 1.90 (m, 1H, CH [Cy]), 2.10 (m,
2H, CH2 [Cy]), 2.35 (m, 2H, CH2 [Cy]), 2.65 (m, 1H,
CHC]O), 3.07 (dd, JZ13.3, 4.5 Hz, 1H, CH2NHAr), 3.37
(dd, JZ13.4, 7.7 Hz, 1H, CH2NHAr), 6.45 (d, JZ8.9 Hz,
2H, ArH), 7.21 (d, JZ8.9 Hz, 2H, ArH); 13C NMR
(100 MHz, CDCl3) d (ppm): 25.1, 27.9, 32.2, 42.4, 44.1,
1
3.2.5. Compound 3e. Yellow oil 211 mg, 80% H NMR
(400 MHz, CDCl3) d (ppm): 0.80 (m, 3H), 1.30 (m, 8H),
2.15 (s, 3H), 2.82 (m, 1H), 3.17 (dd, JZ12.8, 4.7 Hz, 1H),
3.32 (dd, JZ12.8, 8.6 Hz, 1H), 3.73 (s, 3H), 6.56 (d, JZ
9.1 Hz, 2H), 7.26 (d, JZ9.1 Hz, 2H); 13C NMR (100 MHz,

I. Ibrahem et al. / Tetrahedron 62 (2006) 357–364
363
45.0, 109.0, 114.7, 132.1, 147.3, 213.3; HPLC (Daicel
Chiralpak AD, hexanes/i-PrOH 98:2, flow rate 0.5 mL/min,
lZ254 nm): major isomer: tRZ45.22 min; minor isomer:
tRZ63.04 min; [a]2D5K5.6 (c 1.0, CHCl3).
were dried (MgSO4), evaporated and, after purification by
column chromatography, the corresponding reduced alco-
hols 5 (trans/cis 1:1) were obtained (82%, 193 mg).
Subsequent acetylation for 2 h in CH2Cl2 (10 mL) using
Ac2O (10 equiv, 1 mL) and catalytic 4,40-dimethylamino-
pyridine (DMAP), extraction with water, drying with
MgSO4 and evaporation of the organic phase, and
purification by column chromatography afforded the cis-
monoacetylated compound. This compound was dissolved
in MeOH (2 mL) and added to and an oxidant solution of
iodobenzene acetate (1.5 g, 4.5 mmol in 15 mL of MeOH)
over 30 min, the reaction allowed to stir for an additional
30 min and then acidified with 1 N HCl (30 mL) and
allowed to stir for 1.5 h. The reaction mixture was washed
with CH2Cl2 (2!30 mL) and the combined organics were
back extracted with 0.1 N HCl (20 mL). CH2Cl2 was added
to the combined acidic aqueous layers with vigorous stirring
to yield a biphasic system. The reaction was brought to
pHw10–11 with solid Na2CO3. After 1.5 h the two layers
were separated and the aqueous phase was extracted with
CH2Cl2 (2!30 mL). The combined organics were dried
with MgSO4 and concentrated. The oil obtained was
dissolved in CH2Cl2 (5 mL), and Ac2O (1 mL) and catalytic
DMAP were added. After 2 h, the reaction was extracted
with water, the organic phase dried and evaporated, and then
purified by column chromatography, obtaining the pure cis-
2-aminocyclohexanol diacetylated with 40% yield (86 mg).
1
3.2.11. Compound 3k. Yellow solid (187 mg, 92%) H
NMR (400 MHz, CDCl3) d (ppm): 1.49 (m, 1H, CH [Cy]),
1.67 (m, 2H, CH2 [Cy]), 1.90 (m, 1H, CH [Cy]), 2.10 (m,
2H, CH2 [Cy]), 2.35 (m, 2H, CH2 [Cy]), 2.65 (m, 1H,
CHC]O), 3.12 (dd, JZ13.5, 4.7 Hz, 1H, CH2NHAr), 3.44
(dd, JZ13.5, 7.7 Hz, 1H, CH2NHAr), 6.6 (d, JZ8.4 Hz,
2H, ArH), 6.70 (m, 1H, ArH), 7.18 (m, 2H, ArH); 13C NMR
(100 MHz, CDCl3) d (ppm): 25.0, 27.9, 32.2, 42.4, 43.9,
49.9, 113.0, 117.4, 129.4, 148.2, 213.3; HPLC (Daicel
Chiralpak AD, hexanes/i-PrOH 98:2, flow rate 0.5 mL/min,
lZ254 nm): major isomer: tRZ35.86 min; minor isomer:
tRZ30.95 min; [a]2D5C7.5 (c 2.4, CHCl3).
3.3. Typical experimental procedure for the direct
catalytic aza-Diels–Alder reactions
To a vial containing aqueous formaldehyde (1 mmol, 36%
aqueous solution), aniline (1.1 mmol) and a catalytic
amount of (S)-proline (30 mol%) in DMSO (4 mL) was
added the 4,4-dimethyl-2-cyclohexen-1-one 1h (2 mmol).
After 24–37 h of vigorously stirring at 50 8C the reaction
was quenched by directly purifying the reaction mixture
by silica-gel column chromatography (EtOAc/pentane-
mixtures) to afford the desired aza-Diels–Alder products 4
(194.5 mg, 75%). Alternatively the reactions can also be
quenched by addition of aqueous NH4Cl. The aqueous
phase was extracted three times with EtOAc. The combined
organic layers were dried with MgSO4, which was
subsequently removed by filtration. Next, the solvent was
removed under reduced pressure following purification of
the crude product mixture by neutral aluminum oxide
column chromatography (EtOAc/pentane-mixtures) to fur-
nish pure 4 as a yellow solid. The ee of the aza-Diels–alder
products 4 were determined by chiral-phase HPLC analysis
(Daicel AD column, lZ244 nm, vZ0.5 mL/min, Hex/IPA)
or chiral-phase GC analyses.
N,O-diacetylated-cis-(1S, 2S)-2-aminomethyl-1-cyclohexa-
nol 6. H NMR (400 MHz, CDCl3) d (ppm): 1.24 (m, 9H,
1
4!CH2 and CHCH2N), 1.97 (s, 3H, CH3), 2.09 (s, 3H,
CH3), 2.95 (m, 1H, CHHNH), 3.53 (m, 1H, CHHNH), 4.58
(m, 1H, CHOOCH3), 6.13 (br s, 1H, NH); [a]2D5C50.2 (c
1.0, MeOH).
Acknowledgements
A. C. thanks the Swedish Research Council, Lars Hierta
Foundation, Carl-Trygger Foundation and Wenner-Gren
Foundation for financial support.
3.3.1. Compound 4a. 1H NMR (CDCl3) d 1.08 (s, 3H), 1.10
(s, 3H), 1.77 (d, JZ2.98 Hz, 2H), 2.47 (dd, JZ18.7, 3.4 Hz
1H), 2.62 (m, 1H), 2.68 (dd, JZ18.9, 2.3 Hz 1H), 3.48 (d,
JZ2.5 Hz, 2H), 3.75 (m, 1H), 3.76 (s, 3H), 6.61 (d, JZ
9.2 Hz, 2H), 6.84 (d, JZ9.2 Hz, 2H); 13C NMR d 28.8
(CH3), 30.2 (CH3), 36.1 (C), 38.9 (CH2), 41.3 (CH), 46.0
(CH2), 47.9 (CH2), 56.1 (CH3), 58.5 (CH), 112.1 (CH),
115.5 (CH3), 141.1, 151.4, 214.0; HPLC (Daicel Chiralpak
AD, hexanes/i-PrOH 99:1, flow rate 1.2 mL/min, lZ
254 nm): major isomer: tRZ24.94 min; minor isomer:
tRZ27.31 min; [a]DK71.8 (c 1.7, CHCl3); MALDI-TOF
MS: 256.1689; C16H22NO2 (MCHC: calcd 261.1683). Mp
71–73 8C.
References and notes
¨
1. Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, 647.
2. Excellent reviews see: (a) Kleinmann, E. F. In Trost, B. M.,
Flemming, I., Eds.; Comprehensive Organic Synthesis;
Pergamon: New York, 1991; Vol. 2. (b) Arend, M.;
Westerman, N.; Risch, N. Angew. Chem., Int. Ed. 1998, 37,
1044. (c) Denmark, S.; Nicaise, O. J.-C. In Jacobsen, E. N.,
Pfaltz, A., Yamomoto, H., Eds.; Comprehensive asymmetric
catalysis; Springer: Berlin, 1999; Vol. 2, p 93. (d) Tramontini,
M.; Angiolini, L. Tetrahedron 1990, 46, 1791. (e) Hellmann,
H.; Optiz, G. a-Aminoalkylierung; Chemie: Weinheim, 1960;
p 1. (f) Blicke, F. F. Org. React. 1942, 1, 303. (g) Brewster,
J. H.; Eliel, E. L. Org. React. 1953, 7, 99. (h) For examples,
see: Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
Ed.; Wiley-VCH: Weinheim, 1997.
3.4. Experimental procedure for protective group
removal and the preparation of cis-6
To the reaction mixture (Table 3, entry 1), 5 mL of MeOH
was added, and then 10 equiv of NaBH4 at 0 8C. After
15 min, 15 mL of brine was added, and the mixture
extracted with EtOAc (2!25 mL). The organic phases
3. (a) Risch, N.; Esser, A. Liebigs Ann. Chem. 1992, 233.
(b) Risch, N.; Arend, M. In Mu¨ller, E., Ed.; Houben-Weyl:

364
I. Ibrahem et al. / Tetrahedron 62 (2006) 357–364
Methoden der Organischen Chemie; Thieme: Stuttgart, 1995; Porjaliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc.
Vol. E21b, p 1908. (c) Vinkovic, V.; Sunjic, V. Tetrahedron
1997, 53, 689.
4. (a) Enders, D.; Ward, D.; Adam, J.; Raabe, G. Angew. Chem.,
2002, 124, 827.
16. (a) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F.,
´
III Tetrahedron Lett. 2001, 42, 199. (b) Cordova, A.; Notz, W.;
Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem.
´
Soc. 2002, 124, 1842. (c) Cordova, A.; Watanabe, S.-i.;
Tanaka, F.; Notz, W.; Barbas, C. F., III J. Am. Chem. Soc.
¨
Int. Ed. 1996, 35, 981. (b) Enders, D.; Oberborsch, S.; Adam,
J.; Ward, D. Synthesis 2002, 18, 1737.
5. (a) Kober, R.; Papadopoulos, K.; Miltz, W.; Enders, D.;
Steglich, W.; Reuter, H.; Puff, H. Tetrahedron 1985, 42, 1963.
´
2002, 124, 1866. (d) Cordova, A.; Barbas, C. F., III
¨
(b) Enders, D.; Oberborsch, S.; Adam, J. Synlett 2000, 644.
(c) Seebach, D.; Hoffmann, M. Eur. J. Org. Chem. 1998, 1337.
(d) Aoyagi, Y.; Jain, R. P.; Williams, R. M. J. Am. Chem. Soc.
Tetrahedron Lett. 2002, 43, 7749. (e) Chowdari, N. S.; Suri,
J. T.; Barbas, C. F., III. Org. Lett. 2004, 6, 2507. (f) Cobb,
A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558. (g) Itoh,
T.; Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org.
Lett. 2003, 5, 4301. (h) Mu¨nch, A.; Wendt, B.; Christmann, M.
Synlett 2004, 2751. (i) Zhuang, W.; Saaby, S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2004, 43, 4476. (j) Ibrahem, I.;
¨
2001, 123, 3472 and references therein. (e) Schollkopf, U. In
Boschke, F. L., Ed.; Topics in current chemistry; Springer:
Berlin, 1983; Vol. 109, pp 45–85. (f) Evans, D. A.; Urpi, F.;
Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am. Chem. Soc.
1990, 112, 8215. (g) Palomo, C.; Oiarbide, M.; Landa, A.;
Gonzales-Rego, M. C.; Garcia, J. M.; Gonzales, A.; Odriozola,
J. M.; Martin-Pastor, M.; Linden, A. J. Am. Chem. Soc. 2002,
124, 8637 and references therein.
´
Cordova, A. Tetrahedron Lett. 2005, 46, 2839.
´
17. (a) Cordova, A. Amine-catalyzed direct asymmetric Mannich-
type reactions: enantioselective synthesis of amino acid and
amino alcohol derivatives, 225th ACS National Meeting
´
March , New Orleans, LA, 2003. (b) Cordova, A. Synlett
6. (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
(b) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc.
1997, 119, 7153. (c) Kobayashi, S.; Hamada, T.; Manabe, K.
J. Am. Chem. Soc. 2002, 124, 5640. (d) Ishitani, H.; Ueno, M.;
Kobayashi, S. Org. Lett. 2002, 4, 143. (e) Ishitani, H.; Ueno,
S.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180.
7. (a) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc.
1998, 120, 2474. (b) Fujii, A.; Hagiwara, E.; Sodeoka, M.
J. Am. Chem. Soc. 1999, 121, 545. (c) Hamashima, Y.; Yagi,
K.; Tamas, H.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
14530. (d) Hamashima, Y.; Hotta, M.; Sodeoka, M. J. Am.
Chem. Soc. 2002, 124, 11240.
´
2003, 1651. (c) Cordova, A. Chem. Eur. J. 2004, 10, 1987.
(d) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.;
Shoji, M.; Sakai, K. Angew. Chem., Int. Ed. 2003, 42, 3677.
18. Wenzel, E. N.; Jacobsen, E. N. J. Am. chem. Soc. 2002, 124,
12964.
19. Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
20. Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566.
21. Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2005, 44, 2896.
´
22. (a) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.; Cordova,
´
A. Angew. Chem., Int. Ed. 2005, 44, 1343. (b) Cordova, A.;
´
Casas, J.; Ibrahem, I.; Sunden, H.; Engqvist, M.; Reyes, E.
´
Chem. Eur. J., 2005, in press. (c) Cordova, A.; Engqvist, M.;
´
Ibrahem, I.; Casas, J.; Sunden, H. Chem. Commun. 2005, 2047.
8. (a) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am.
Chem. Soc. 1998, 120, 4548. (b) Ferraris, D.; Young, B.; Cox,
C.; Drury, W. J., III,; Dudding, T.; Lectka, T. J. Org. Chem.
1998, 63, 6090. (c) Ferraris, D.; Young, B.; Cox, C.; Dudding,
T.; Drury, W. J., III,; Ryzhkov, L.; Taggi, T.; Lectka, T. J. Am.
Chem. Soc. 2002, 124, 67.
´
(d) Sunden, H.; Dahlin, N.; Ibrahem, I.; Adolfsson, H.;
´
´
Cordova, A. Tetrahedron Lett. 2005, 46, 3385. (e) Cordova, A.
´
Tetrahedron Lett. 2004, 45, 3949. (f) Casas, J.; Sunden, H.;
9. Josephsohn, W. S.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2004, 126, 3734.
´
´
Cordova, A. Tetrahedron Lett. 2004, 45, 6117. (g) Cordova,
´
A.; Sunden, H.; Engqvist, M.; Ibrahem, I.; Casas, J. J. Am.
10. Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron Lett. 1999,
40, 307.
´
Chem. Soc. 2004, 126, 8914. (h) Sunden, H.; Engqvist, M.;
´
Casas, J.; Ibrahem, I.; Cordova, A. Angew. Chem., Int. Ed.
11. (a) Matsunaga, S.; Kumagai, N.; Harada, N.; Harada, S.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 4712. (b) Yoshida,
T.; Morimoto, H.; Kumagai, N.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2005, 44, 3470.
´ ´
2004, 43, 6532. (i) Bøgevig, A.; Sunden, H.; Cordova, A.
´
Angew. Chem., Int. Ed. 2004, 43, 1109. (j) Cordova, A.;
´
Sunden, H.; Bøgevig, A.; Johansson, M.; Himo, F. Chem. Eur.
J. 2004, 10, 3673 and references therein.
12. Trost, B. M.; Terrell, L. M. J. Am. Chem. Soc. 2003, 125, 338.
13. (a) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2001, 40, 2995. (b) Marigo, M.; Kjaersgaard, A.; Juhl,
K.; Gathergood, N.; Jørgensen, K. A. Chem. Eur. J. 2003, 9,
2395. (c) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen,
K. A. J. Org. Chem. 2003, 68, 2583.
´
23. Ibrahem, I.; Casas, J.; Cordova, A. Angew. Chem., Int. Ed.
2004, 43, 6528.
´ ´
24. Sunden, H.; Ibrahem, I.; Eriksson, L.; Cordova, A. Angew.
Chem., Int. Ed. 2005, 44, 4877.
25. For the first use of dihydroxyacetone phosphate mimic 1c in
amino acid-catalyzed direct catalytic Mannich reactions see:
14. Reviews see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2001, 40, 3726. (b) List, B. Tetrahedron 2002, 58, 5573.
(c) Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42, 975.
(d) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 116,
´
Ibrahem, I.; Cordova, A. Tetrahedron Lett. 2005, 46, 3363.
After our report these two excellent reports appeared:
Westermann, B.; Neuhaus, C. Angew. Chem., Int. Ed. 2005,
44, 4077. Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G.
Angew. Chem., Int. Ed. 2005, 44, 4079.
´
5248. (e) Cordova, A. Acc. Chem. Res. 2004, 37, 102.
¨
(f) Berkessel, A., Groger, H., Eds.; Wiley-VCH: Weinheim,
¨
26. Kaman, J.; Forro, E.; Fu¨lop, F. Tetrahedron: Asymmetry 2001,
12, 1881.
2005.
15. (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (b) List, B.;