New 2-azanorbornyl derivatives: Chiral (N,N)-donating ligands for asymmetric catalysis

Article abstract of DOI:10.1016/j.tetasy.2010.12.011

New chiral 2-azanorbornane derivatives were prepared and used as (N,N)-donating ligands in a copper-catalyzed Henry reaction yielding up to 62% ee.

Full text of DOI:10.1016/j.tetasy.2010.12.011

Tetrahedron: Asymmetry 22 (2011) 161–166
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New 2-azanorbornyl derivatives: chiral (N,N)-donating ligands
for asymmetric catalysis
_
´
Elzbieta Wojaczynska
_
´
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeze Wyspianskiego 27, 50-370 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
New chiral 2-azanorbornane derivatives were prepared and used as (N,N)-donating ligands in a copper-
catalyzed Henry reaction yielding up to 62% ee.
Received 23 November 2010
Accepted 17 December 2010
Available online 2 February 2011
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
enantiopure 2-azanorbornyl derivatives bearing two nitrogen
donors and their application in stereoselective Henry reactions.
Modern asymmetric synthesis makes special use of so-called
privileged catalysts/ligands, chiral inducers that are effective in
numerous, diverse, and industrially useful enantioselective trans-
formations.1 Among them, (N,N)-donor ligands play an important
role due to their relative robustness and ability to be associated
with different metals, which allows performing a wide range of
catalytic reactions to be carried out with excellent enantiocontrol
and with high yield.2 A number of such compounds have been pre-
pared using a 1,2-diphenylethylene-1,2-diamine, 1,2-diaminocy-
clohexane, 2,20-bipiridine, or bis(oxazoline) skeletons. There is
also a wide interest in ligands and catalysts bearing a bicyclic chiral
framework, such as the derivatives of camphor3 or Cinchona alka-
loids.4 A configurationally stable, rigid backbone ensures a proper
localization of donor centers, leading to significant stereodifferen-
tiation in catalytic reactions.
2. Results and discussion
The exo-ester (1S,3R,4R)-1 was obtained as the main product of
the reaction of cyclopentadiene and an iminium ion derived from
ethyl glyoxylate and (S)-1-phenylethylamine.5 A two-step reduc-
tion of compound exo-1 leading to alcohol exo-2 was performed
as described previously.8,10 This derivative served as a starting
material for the synthesis of a series of enantiomerically pure li-
gands with (N,S), (N,Se) donor atoms, and an (N,N)-donating Schiff
base.8 To enlarge the pool of 2-azanorbornyl-derived ligands con-
taining two nitrogen donors, a conversion of alcohol exo-2 to an
azide exo-3 was undertaken. A reaction of compound exo-2 with
diphenylphosphoryl azide led to a desired product, but the yield
was unsatisfactory. Significantly better result was achieved with
HN3/DEAD combination and (1S,3R,4R)-2-[(S)-1-phenylethyl]-3-
azidemethyl-2-azabicyclo[2,2,1]heptane exo-3 was obtained in
88% yield. A subsequent reduction with triphenylphosphine re-
sulted in amine exo-4 (92%, Scheme 1). Both compounds exo-3
and exo-4 opened up the route to the synthesis of (N,N)-donating
ligands containing four stereogenic centers.
The endo-isomer of compound 1, (1S,3S,4R)-1 could be also iso-
lated as the minor product of the Diels–Alder reaction, formed in
10–15% yield. This compound was subsequently converted into
alcohol endo-2, azide endo-3, and amine endo-4 (Scheme 1). Thus,
the influence of the configuration of carbon-3 on the coordination
and catalytic properties of the respective ligands could also be
tested.
A series of imines 5a–5e were obtained via the reaction of
amine exo-4 with aryl aldehydes (Scheme 2). However, compounds
5 were found to be too unstable to be isolated. All attempts at chro-
matographic purification led to their decomposition. Thus, they
were reduced in situ to the corresponding secondary amines exo-
6a–6e bearing different aryl substituents. The endo-isomer of
A
bicyclic system containing
a
2-azanorbornene (2-
azabicyclo[2.2.1]heptene) skeleton has been proven to be an
attractive precursor of chiral ligands useful in asymmetric synthe-
sis. Compound 1 can be prepared on a multigram scale in a
stereoselective aza-Diels–Alder reaction.5 Various possibilities for
the modification of the basic structure and the application of
2-azanorbornyl-derived ligands in asymmetric catalysis have been
extensively explored by Andersson et al.6 and others.7 Over the
course of our studies on the preparation and utilization of chiral
organochalcogen compounds, we obtained a series of 2-azabicy-
clo[2.2.1]heptane derivatives with (N,S), (N,Se), and (N,N) donor
atoms and used them as ligands in a palladium-catalyzed asym-
metric allylic alkylation (Trost–Tsuji reaction), yielding up to 95%
ee.8 The family of these bicyclic ligands containing two nitrogen
donors is relatively small and their use in catalytic reactions was
rather limited.9 This contribution concerns the synthesis of novel
E-mail address: elzbieta.wojaczynska@pwr.wroc.pl
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.12.011

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E. Wojaczynska / Tetrahedron: Asymmetry 22 (2011) 161–166
1. H2, Pd(C), K2CO3
N
Ph
N
Ph
OH
COOEt
2. LiAlH4
CO2Et
OH
OH
CO2Et
exo-1
exo-2
major isomer
+
H
H
1. HIO4
2.
Ph
3.
NH2
1. H2, Pd(C), K2CO3
2. LiAlH4
N
Ph
N
Ph
COOEt
OH
endo-1
(-)-endo-2
minor isomer
Y = 80%
PPh3
N
Ph
N3
N
Ph
NH2
HN3
exo-2
DEAD
(-)-exo-4
(-)-exo-3
Y = 92%
Y = 88%
N
Ph
PPh3
HN3
N
Ph
endo-2
DEAD
N3
NH2
3
(+)-endo -
Y = 85%
4
(-)-endo-
Y = 56%
Scheme 1.
CH2Cl2
Na2SO4
NaBH4
MeOH
N
Ph
N
Ph
N
Ph
+ ArCHO
N
H
Ar
N
Ar
NH2
4
(-)-exo-
5
exo-
exo-6
Y = 50-90%
HCHO
Zn
Ar =
Cl
N
Ph
5a, 6a
5b, 6b
5d, 6d
NMe2
(+)-exo-7
Y = 90%
F
5c, 6c
5e, 6e
N
Ph
N
Ph
1) PhCHO/CH2Cl2/Na2SO4
2) NaBH4/MeOH
Ph
NH2
N
(+)-endo-6a
H
(-)-endo-4
Y = 80%
Scheme 2.
ligand 6a was also prepared starting from endo-4. A set of (N,N)-
donating ligands was completed with tertiary amine exo-7, which
was synthesized by methylation of exo-4 in 90% yield. For this pur-
pose, a reaction of amine exo-4 with formaldehyde in the presence
of zinc was performed.11 All new compounds were characterized
by HRMS, IR, proton, and carbon NMR spectroscopy, and their
structures were further confirmed by 2D NMR spectra (COSY,
NOESY, 1H–13C HMQC, and 1H–13C HMBC). In particular, the NOESY
spectra revealed specific contacts of protons that readily distin-
guished between the exo and endo diastereomers.
We tested the newly obtained chiral azanorbornane derivatives
as ligands in the copper-catalyzed Henry reaction. The Henry (or
nitroaldol) reaction between a nitroalkane and a carbonyl com-
pound serves as a useful tool for the creation of a new carbon–carbon

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E. Wojaczynska / Tetrahedron: Asymmetry 22 (2011) 161–166
bond, and the resulting 2-nitroalcohols are versatile building blocks
and intermediates in organic synthesis, as they can be easily con-
verted into 1,2-aminoalcolhols or amino acids.12 Recently, several
efficient methods have been developed for the enantioselective ver-
sion of this process.13 Despite significant advances in this field, there
are certain shortcomings, such as complex ligand syntheses, high
catalyst loadings, substrate specificity limitations, or the need for
special reaction conditions, which require further research.
A model reaction between benzaldehyde and nitromethane was
chosen for the preliminary ligand testing. Amine exo-6a, which ap-
peared to be the most promising ligand, was then used for the con-
version of various aldehydes. The results are collected in Table 1.
Among the nine ligands tested in the model catalytic reaction,
the highest enantiomeric excess of 61% was noted for amine exo-
6a (Table 1, entry 3), while its endo-isomer and exo-6d led to the
optimal yield of nitroalcohol (95%). Ee values were rather moder-
ate, but not lower than 31%. The effect of the size of the amine sub-
stituent could be illustrated by the exo-4/exo-6a/exo-6d series
(entries 1, 3 and 7), for which an increase in yield was accompa-
nied by the generally maintained ee level. However, a significant
drop in the reaction outcome was observed for exo-6e bearing a
9-anthryl substituent (entry 8); apparently such an attachment
brought about steric hindrance which decreased the effectiveness
of the catalyst.
For all exo ligands, (S)-nitroalcohol was formed as the main
enantiomer, independent of the substituent at the 3-position.
Changing from the exo- to endo-isomer (as observed for com-
pounds 4 and 6a, entries 1–2 and 3–4) resulted in a reversal of
the stereochemical preference together with the lowering of the
ee value and an increase of the chemical yield.
The influence of the reaction conditions on the outcome of the
catalytic reaction was investigated for exo-6a ligand. Changing the
solvent from isopropanol to ethanol led to a decrease in the ee va-
lue (55%) and an increase of yield to 95% (entry 10). The use of
6 mol % instead of 12 mol % of catalyst resulted in a pronounced
decrease of enantiomeric excess (49%, entry 11). When benzalde-
hyde was replaced with other aldehydes (entries 12–16), compa-
rable stereoselectivities (ee = 46–62%) and high yields (up to
95%) were observed. Chiral ligand exo-6a was also tested in a cop-
per-catalyzed diastereoselective reaction of benzaldehyde and
nitroethane. A slight preference for the anti-diastereomer was
noted (de = 26%), which was formed with 49% ee; for the syn-
isomer, the ee was significantly higher (76%) and the overall yield
was 70%.
The results presented clearly indicate that the direction of the
asymmetric induction is dependent primarily on the configuration
of the carbon-3 atom of the chiral ligand. While (3R) (exo) amines
led mainly to (S)-product, their (3S) (endo) counterparts exhibited
the reverse preference. Molecular models of the postulated transi-
tion state reveal the distinct structures of copper(II) complexes
formed by the two diastereomeric ligands (Scheme 3). The N(2)
atom also becomes chiral upon coordination to the metal ion,
and the configuration of this newly formed stereogenic center is
different for the exo- and endo-isomers. As a consequence, the
(S)-1-phenylethyl substituent on N(2) has a different orientation.
According to the generally accepted considerations,13,14 benzalde-
hyde approaches the copper(II) ion in the equatorial plane, and the
coordination trans to N(2) should be preferred due to the presence
of a bulky substituent on N(2). A favorable orientation of the alde-
hyde should also minimize the steric repulsion exerted by the
phenylethyl group. Deprotonated nitromethane binds to the Cu2+
ion at the axial position. However, the accessibility of the metal
center from one side is restricted by the N(2) substituent. In the
case of the exo-isomer, this results in preferential Re attack of the
nitronate (Scheme 3) and the formation of a nitroalcohol with an
(S)-configuration. The opposite enantiomer is expected as the main
product from the reaction catalyzed by the endo-amine as a result
of Si attack.
H
O
CH2NO2
N
H
O
Re-attack
OAc
O
Ph
H
(S)-product
N
HO
exo
Cu
N
H
Me
Ph
H
R
Ph
Ph
AcO
Cu
Me
Ph
R
HO
H
Ph
N
O
Si-attack
H
NH
endo
CH2NO2
(R)-product
H
O
N
H
O
Table 1
Results of the copper-catalyzed Henry reaction
Scheme 3.
OH
*
O
L*
(12% mol.), Cu(OAc)2*nH2O
(CH3)2CHOH
+
CH3NO2
NO2
The analysis reveals the key importance of the 2-phenylethyl
group for the observed asymmetric induction. The minor influence
of the substituent of the secondary amine (R in Scheme 3) is con-
nected to its more remote localization with respect to the metal ion.
R
H
R
Entry
Ligand Lꢀ
exo-4
R
Yield of product (%)
ee
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
48
58
71
95
72
65
95
24
84
95
76
67
95
95
90
95
54% (S)
34% (R)
61% (S)
33% (R)
54% (S)
43% (S)
52% (S)
31% (S)
50% (S)
55% (S)
49% (S)
59% (S)
59% (S)
46% (S)
52% (S)
62% (S)
endo-4
exo-6a
endo-6a
exo-6b
exo-6c
exo-6d
exo-6e
exo-7
3. Conclusions
The use of the new bicyclic (N,N)-donating ligands in a copper-
catalyzed Henry reaction resulted in good to excellent yields and
enantioselectivities of up to 62%. An interesting reversal of the ste-
reochemical outcome was observed for diastereomeric derivatives,
as shown by the exo-4, endo-4 and exo-6a, endo-6a pairs. The pre-
cursors of both forms, esters exo-1 and endo-1, are available from
one Diels–Alder reaction.
The catalytic performance of these ligands may be improved
upon by further structural modification. The conversion of the 3-
substituent containing an amine function could change its donat-
ing properties and allow the introduction of a more pronounced
steric hindrance. Such transformations leading to 2-azanorbornyl
Ph
Ph
Ph
exo-6aa
exo-6ab
exo-6a
exo-6a
exo-6a
exo-6a
exo-6a
Cyclohexyl
4-F-C6H4–
4-Cl-C6H4–
4-Br-C6H4–
1-Naphthyl
a
Reaction conducted in ethanol.
6 mol % of exo-6a used.
b

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E. Wojaczynska / Tetrahedron: Asymmetry 22 (2011) 161–166
164
derivatives bearing two diverse nitrogen donors are currently
underway in our laboratory.
4.4.1. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-azidemethyl-2-
azabicyclo[2,2,1]heptane exo-3
Yield 88%, ½a 2D0
ꢁ
¼ ꢂ71:3 (c 0.60, CH2Cl2), 1H NMR (CDCl3):
d = 1.28–1.48 (m, 3H), 1.33 (d, 3H, J = 6.6 Hz), 1.68–1.82 (m, 2H),
2.12 (d, 1H, J = 11.7 Hz), 2.24 (ABqX, 1H, J1 = 13.2 Hz, J2 = 3.6 Hz),
2.30–2.38 (m, 1H), 2.56 (ABq, 1H, J = 13.2 Hz), 3.23–3.29 (m, 1H),
3.36 (q, 1H, J = 6.6 Hz), 3.58–3.63 (m, 1H), 7.20–7.38 (m, 5H, ArH)
ppm. 13C NMR (CDCl3): d = 21.5, 21.9, 27.2, 34.2, 38.9, 47.8, 56.0,
60.7, 62.5, 127.0, 127.5, 128.4, 145.2 ppm. IR (film): 701, 770,
1264, 1453, 1749, 2097 (N3), 2953, 3026 cmꢂ1. HRMS (ESI):
257.1678 ([M+H]+); for (C15H21N4)+ M = 257.1766.
4. Experimental
4.1. General
IR spectra were recorded on a Perkin–Elmer 1600 FTIR spectro-
photometer. 1H NMR and 13C NMR spectra were measured on a
Bruker Avance DRX (1H, 300 MHz) or a Bruker Avance 600 (1H,
600 MHz) spectrometer using TMS as an internal standard or sol-
vent residual peak as a reference. Optical rotations were measured
using an Optical Activity Ltd. Model AA-5 automatic polarimeter.
High resolution mass spectra were recorded using a microTOF-Q
and WATERS LCT Premier XE instruments utilizing electrospray
ionization mode. Separations of products by chromatography were
performed on Silica Gel 60 (230–400 mesh) purchased from Merck.
Thin layer chromatography was carried out using Silica Gel 60 pre-
coated plates (Merck). HPLC analyses were performed on Chiracel
OD-H or Chiralpak AD-H chiral columns (flow rate of 1.0 mL/min).
4.4.2. (1S,3S,4R)-2-[(S)-1-Phenylethyl]-3-azidemethyl-2-
azabicyclo[2,2,1]heptane endo-3
Yield 85%, ½a 2D0
ꢁ
¼ þ34:5 (c 0.58, CH2Cl2), 1H NMR (CDCl3):
d = 1.15–1.50 (m, 3H), 1.23 (d, 3H, J = 6.6 Hz), 1.52–2.10 (m, 4H),
2.36 (s, 1H), 2.40–2.52 (m, 1H), 2.98–3.12 (m, 2H), 3.40 (br s,
1H), 7.17–7.45 (m, 5H, ArH) ppm. 13C NMR (CDCl3): d = 21.9,
22.0, 27.0, 33.6, 38.8, 47.1, 570, 60.6, 62.0, 126.9, 127.6, 128.3,
145.2 ppm. IR (film): 548, 702, 767, 955, 1029, 1046, 1160, 1263,
1453, 1492, 1748, 2096 (N3), 2810, 2871, 2972, 3026 cmꢂ1. HRMS
(ESI): 257.1757 ([M+H]+); for (C15H21N4)+ m/z = 257.1766.
4.2. Synthesis of (1S,3R,4R)-2-[(S)-1-phenylethyl]-2-
azabicyclo[2,2,1]hept-5-ene-3-carboxylic acid ethyl ester exo-1
and (1S,3S,4R)-2-[(S)-1-phenylethyl]-2-azabicyclo[2,2,1]hept-5-
ene-3-carboxylic acid ethyl ester endo-1
4.5. Reduction of azides16
Azide 3 (0.42 g, 1.6 mmol) was dissolved in 20 mL of methanol.
Triphenylphosphine (0.63 g, 2.4 mmol, 1.5 equiv) was added and
the reaction mixture was heated overnight at reflux. The solvent
was evaporated, and the residue was chromatographed on a silica
column. Elution with chloroform yielded the unreacted phosphine
These compounds were prepared according to the literature
procedure via an aza-Diels–Alder reaction of cyclopentadiene, an
iminium ion derived from ethyl glyoxylate and (S)-1-phenylethyl-
amine.5c The isomers were separated on a silica gel column using
n-hexane–ethyl acetate mixture (9:1 v/v) as eluent (Rf (endo-
1) = 0.21, Rf (exo-1) = 0.08).
and phosphine oxide, while
a chloroform–methanol mixture
(90:10 v/v) eluted the desired product 4.
4.5.1. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-aminemethyl-2-
azabicyclo[2,2,1]heptane exo-4
4.3. Reduction of Diels–Alder products 1
Yield 92%, ½a 2D0
ꢁ
¼ ꢂ17:5 (c 0.40, CH2Cl2). 1H NMR (CDCl3):
Alcohols (1S,3R,4R)-2-[(S)-1-phenylethyl]-3-hydroxymethyl-2-
azabicyclo[2,2,1]heptane exo-2 and (1S,3S,4R)-2-[(S)-1-phenyl-
ethyl]-3-hydroxymethyl-2-azabicyclo[2,2,1]heptane endo-2 were
obtained by reduction of exo-1 and endo-1, respectively, with H2
(1 atm) and 5% of Pd–C in the presence of potassium carbonate10
followed by the reduction of formed esters with LiAlH4 according
to a literature procedure.7a,8,15 The characteristics of exo-2 was
in agreement with the literature data.7a endo-2: Yield 80%,
d = 1.25–1.37 (m, 3H), 1.31 (d, 3H, J = 6.6 Hz), 1.60–1.70 (m, 2H),
1.87 (br s, 2H), 2.03 (d, 1H, J = 10.2 Hz), 2.10–2.20 (m, 1H), 2.24
(d, 2H, J = 2.7 Hz), 2.54–2.62 (m, 1H), 3.34 (q, 1H, J = 6.6 Hz), 3.56
(t, 1H, J = 2.4 Hz), 7.20–7.30 (m, 5H, ArH) ppm. 13C NMR (CDCl3):
d = 21.3, 21.4, 28.0, 33.4, 41.5, 50.9, 52.2, 56.4, 62.6, 126.8, 127.4,
128.3, 145.6 ppm. IR (film): 549, 701, 771, 952, 1134, 1453, 1491,
1599, 2812, 2864, 2947, 3025, 3365 cmꢂ1. HRMS (ESI): 231.1846
([M+H]+); for (C15H23N2)+ m/z = 231.1861.
mp = 45.5–46.5 °C, ½a D20
ꢁ
¼ ꢂ4:5 (c 1.12, CH2Cl2), 1H NMR (CDCl3):
d = 1.05–1.09 (m, 1H), 1.21–1.30 (m, 3H), 1.33 (d, 3H, J = 6.3 Hz),
1.50–1.63 (m, 1H), 1.62–1.82 (m, 1H), 1.85–2.00 (m, 1H), 2.25–
2.30 (m, 1H), 2.35–2.41 (m, 1H), 2.98 (br s, 1H), 3.49–3.57 (m,
2H), 3.67 (q, 1H, J = 6.6 Hz), 7.23–7.32 (m, 5H, ArH) ppm. 13C
NMR (CDCl3): d = 22.8, 24.5, 29.1, 35.7, 43.8, 58.9, 59.8, 65.4,
66.7, 126.9, 127.2, 128.5, 145.2 ppm. IR (film): 701, 766, 1026,
1163, 1306, 1453, 1492, 1747, 2873, 2969, 3244 cmꢂ1. HRMS
(ESI): 232.1690 ([M+H]+); for (C15H22NO)+ m/z = 232.1701.
4.5.2. (1S,3S,4R)-2-[(S)-1-Phenylethyl]-3-aminemethyl-2-
azabicyclo[2,2,1]heptane endo-4
Yield 56%, ½a 2D0
ꢁ
¼ ꢂ19:8 (c 0.61, CH2Cl2), 1H NMR (CDCl3):
d = 1.10–1.40 (m, 4H), 1.23 (d, 3H, J = 6.6 Hz), 1.70–1.80 (m, 1H),
1.85–1.95 (m, 1H), 2.10–2.20 (m, 1H), 2.29 (br s, 2H), 2.38–2.49
(m, 2H), 2.71–2.80 (m, 1H), 2.92–3.10 (m, 1H), 3.35 (q, 1H,
J = 6.6 Hz), 7.21–7.35 (m, 5H, ArH) ppm. 13C NMR (CDCl3):
d = 21.0, 22.1, 27.9, 33.0, 41.6, 50.6, 51.1, 57.6, 61.9, 126.7, 127.5,
128.3, 146.0 ppm. IR (film): 543, 703, 772, 967, 1050, 1180, 1305,
1370, 1453, 1492, 1602, 1741, 2790, 2820, 2873, 2971,
3468 cmꢂ1. HRMS (ESI): 231.1882 ([M+H]+); for (C15H23N2)+ m/
z = 231.1861.
4.4. Preparation of azides
Alcohol 2 (0.46 g, 2 mmol) and triphenylphosphine (0.68 g,
2.6 mmol, 1.3 equiv) were dissolved in 15 mL of dry toluene and
cooled in an ice bath. A 1 M solution of HN3 in benzene (2.6 mL,
2.6 mmol, 1.3 equiv) was then added in one portion under an inert
atmosphere, followed by a 40% solution of DEAD in toluene
(1.37 mL, 3 mmol, 1.5 equiv), which was added dropwise. The reac-
tion mixture was stirred overnight under argon. After evaporation
of the solvent, the residue was chromatographed on a silica column
using n-hexane–ethyl acetate (6:1 v/v), yielding a fraction contain-
ing azide 3.
4.6. Preparation of imines 5 and their reduction to secondary
amines 6
In a typical procedure, amine 4 (0.5 mmol) and the respective
aldehyde (0.5 mmol) dissolved in 8 mL of dichloromethene were
mixed overnight at room temperature over anhydrous Na2SO4.
The filtrate was evaporated and the solid residue was dissolved
in 8 mL of methanol. Sodium borohydride (28.5 mg, 0.75 mmol,

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E. Wojaczynska / Tetrahedron: Asymmetry 22 (2011) 161–166
1.5 equiv) was added in one portion and the solution was stirred
for 2 h and evaporated. Chromatography on silica using chloroform
removed the alcohol (a side-product coming from the reduction of
the unreacted aldehyde), and a chloroform–methanol mixture
(90:10 v/v) eluted amines 6.
1H, J = 7.0 Hz, ArH), 7.33 (t, 2H, J = 7.4 Hz, ArH), 7.36–7.39 (m,
2H, ArH), 7.41–7.48 (m, 3H, ArH), 7.69 (s, 1H, ArH), 7.77–7.82 (m,
3H, ArH) ppm. 13C NMR (CDCl3): d = 21.3, 21.8, 27.8, 33.7, 38.7,
48.0, 51.4, 56.1, 56.3, 62.8, 125.4, 125.9, 126.5, 126.8, 126.9,
127.5, 127.6, 127.7, 127.9, 128.4, 132.6, 133.4, 138.0, 146.1 ppm.
IR (film): 542, 698, 723, 748, 1015, 1091, 1120, 1182, 1455, 1490,
1598, 1660, 2869, 2949, 3057, 3283 cmꢂ1. HRMS (ESI): 371.2499
([M+H]+); for (C26H31N2)+ m/z = 371.2487.
4.6.1. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-(benzylamine)methyl-
2-azabicyclo[2,2,1]heptane exo-6a
Yield 80%, ½a 2D0
ꢁ
¼ þ15:7 (c 0.60, CH2Cl2). 1H NMR (CDCl3):
d = 1.25–1.37 (m, 3H), 1.31 (d, 3H, J = 6.6 Hz), 1.70–1.73 (m, 2H),
1.85 (br s, 1H), 1.97 (d, 1H, J = 11.7 Hz), 2.11 (ABqX, 1H,
J1 = 12.3 Hz, J2 = 2.1 Hz), 2.33–2.35 (m, 2H), 2.52 (ABq, 1H,
J = 12.3 Hz), 3.36 (q, 1H, J = 6.3 Hz), 3.55 (t, 1H, J = 5.7 Hz), 3.61 (s,
2H), 7.22–7.36 (m, 10H, ArH) ppm. 13C NMR (CDCl3): d = 21.5,
21.6, 28.0, 33.9, 38.8, 47.9, 51.4, 56.0, 56.3, 62.8, 126.8, 126.8,
127.5, 128.3, 128.4, 128.4, 140.7, 145.8 ppm. IR (film): 700, 735,
770, 1136, 1371, 1453, 1492, 1602, 1668, 2813, 2863, 2946,
3060 cmꢂ1. HRMS (ESI): 321.2340 ([M+H]+); for (C22H29N2)+ m/
z = 321.2331.
4.6.6. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-[(9-anthryl)
methylamine]methyl-2-azabicyclo[2,2,1]heptane exo-6e
Yield 75%, ½a 2D0
ꢁ
¼ ꢂ22:0 (c 1.10, CH2Cl2). 1H NMR (CDCl3):
d = 1.25–1.40 (m, 6H), 1.73–1.80 (m, 3H), 2.02 (br s, 1H), 2.22 (d,
1H, J = 11.2 Hz), 2.43 (br s, 1H), 2.69 (br s, 1H), 2.78 (d, 1H,
J = 11.9 Hz), 3.43 (br s, 1H), 3.56 (br s, 1H), 4.50 (ABq, 2H,
J = 11.5 Hz), 7.21–7.25 (m, 1H, ArH), 7.34 (t, 2H, J = 7.4 Hz, ArH),
7.39–7.42 (m, 2H, ArH), 7.43–7.48 (m, 2H, ArH), 7.51–7.56 (m,
2H, ArH), 8.00 (d, 2H, J = 8.3 Hz, ArH), 8.28 (d, 2H, J = 8.8 Hz,
ArH), 8.38 (s, 1H, ArH) ppm. 13C NMR (CDCl3): d = 21.2, 21.5,
28.1, 34.1, 39.7, 44.1, 48.0, 56.1, 58.7, 62.8, 124.5, 124.8, 125.9,
126.8, 126.9, 127.5, 128.4, 129.1, 130.3, 131.6, 132.2, 146.0 ppm.
IR (KBr): 695, 732, 1284, 1452, 1678, 2939, 3057, 3404 cmꢂ1. HRMS
(ESI): 421.2546 ([M+H]+); for (C30H33N2)+ m/z = 421.2644.
4.6.2. (1S,3S,4R)-2-[(S)-1-Phenylethyl]-3-(benzylamine)methyl-
2-azabicyclo[2,2,1]heptane endo-6a
Yield 80%, ½a 2D0
ꢁ
¼ þ24:0 (c 1.00, CH2Cl2). 1H NMR (CDCl3):
d = 1.07–1.33 (m, 3H), 1.27 (d, 3H, J = 6.6 Hz), 1.62–1.90 (m, 3H),
2.28–2.42 (m, 3H), 2.53 (br s, 1H), 2.95–3.05 (m, 2H), 3.40 (q, 1H,
J = 6.3 Hz), 3.83 (ABq, 2H, J = 13.2 Hz), 7.19–7.43 (m, 10H, ArH)
ppm. 13C NMR (CDCl3): d = 21.6, 21.9, 27.8, 33.3, 38.1, 47.4, 51.2,
56.3, 57.5, 62.2, 126.8, 126.9, 127.6, 128.3, 128.4, 128.5, 140.8,
145.8 ppm. IR (film): 549, 700, 768, 953, 1028, 1134, 1260, 1452,
1492, 2809, 2863, 2948, 3025, 3060 cmꢂ1. HRMS (ESI): 321.2325
([M+H]+); for (C22H29N2)+ m/z = 321.2331.
4.7. Dimethylation of exo-4
The reaction was performed according to a literature proce-
dure.11 Amine exo-4 (0.2 g, 0.87 mmol), acetic acid (8 equiv), zinc
dust (2 equiv), aqueous 37% formaldehyde (1.5 equiv) and 1 mL
of dioxane were stirred for 30 min at room temperature. Aque-
ous ammonia was added to the filtered reaction mixture and
the resulting solution was extracted with chloroform. The sol-
vent was evaporated, and the residue was chromatographed on
silica using a chloroform–methanol mixture (90:10 v/v) yielding
exo-7.
4.6.3. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-[(4-
chlorophenyl)methylamine]methyl-2-azabicyclo[2,2,1]heptane
exo-6b
Yield 50%, ½a 2D0
ꢁ
¼ ꢂ8:5 (c 1.36, CH2Cl2). 1H NMR (CDCl3):
d = 1.25–1.37 (m, 3H), 1.31 (d, 3H, J = 6.6 Hz), 1.67–1.75 (m, 2H),
1.89 (br s, 1H), 1.95 (d, 1H, J = 11.6 Hz), 2.08 (d, 1H, J = 12.4 Hz),
2.29–2.32 (m, 2H), 2.47 (d, 1H, J = 12.4 Hz), 3.32–3.38 (m, 1H),
3.52–3.55 (m, 1H), 3.56 (s, 2H), 7.17–7.33 (m, 9H, ArH) ppm. 13C
NMR (CDCl3): d = 21.5, 21.5, 27.9, 33.8, 38.7, 47.9, 50.6, 55.9,
56.2, 62.5, 127.3, 128.2, 128.3, 128.4, 128.7, 129.5, 139.4,
145.5 ppm. IR (film): 541, 696, 722, 749, 1119, 1183, 1437, 1668,
2951, 3055, 3391 cmꢂ1. HRMS (ESI): 355.1947 ([M+H]+); for
(C22H28N2Cl)+ m/z = 355.1941.
4.7.1. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-(N,N-dimethylamine)
methyl-2-azabicyclo[2,2,1]heptane exo-7
Yield 85%, ½a 2D0
ꢁ
¼ þ25:0 (c 0.24, CH2Cl2). 1H NMR (CDCl3):
d = 1.18–1.40 (m, 4H), 1.29 (d, 3H, J = 6.6 Hz), 1.50–1.59 (m, 1H),
1.68–1.80 (m, 2H), 1.82–1.92 (m, 1H), 2.12 (s, 6H), 2.38–2.48 (m,
1H), 2.55 (d, 1H, J = 13.2 Hz), 3.18–3.35 (m, 1H), 3.60 (t, 1H,
J = 4.5 Hz), 7.10–7.40 (m, 5H, ArH) ppm. 13C NMR (CDCl3):
d = 20.8, 21.8, 28.3, 33.4, 36.8, 44.2, 46.2, 54.7, 56.6, 62.7, 126.7,
127.4, 128.3, 145.6 ppm. IR (film): 702, 770, 1134, 1278, 1453,
1660, 2766, 2814, 2953, 3060, 3437 cmꢂ1. HRMS (ESI): 259.2171
([M+H]+); for (C17H27N2)+ m/z = 259.2174.
4.6.4. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-[(4-fluorophenyl)
methylamine]methyl-2-azabicyclo[2,2,1]heptane exo-6c
Yield 91%, ½a 2D0
ꢁ
¼ ꢂ16:0 (c 0.75, CH2Cl2). 1H NMR (CDCl3):
4.8. A general procedure for the nitroaldol reaction
d = 1.18–1.45 (m, 3H), 1.31 (d, 3H, J = 6.6 Hz), 1.60–1.92 (m,
4H), 1.91–2.10 (m, 1H), 2.10–2.15 (m, 1H), 2.28–2.40 (m, 2H),
2.48 (d, 1H, J = 12.6 Hz), 3.36 (q, 1H, J = 7.2 Hz), 3.57 (s, 2H),
6.94–7.00 (m, 2H, ArH), 7.19–7.34 (m, 7H, ArH) ppm. 13C NMR
(CDCl3): d = 21.5, 21.5, 27.9, 33.8, 38.8, 48.0, 50.6, 56.0, 56.2,
62.6, 115.1 (d, J = 20.8 Hz), 126.8, 127.4, 128.4, 129.7 (d,
J = 7.6 Hz), 136.4, 146.1, 161.8 (d, J = 238.9 Hz) ppm. IR (film):
542, 699, 722, 828, 1120, 1197, 1220, 1438, 1509, 1602, 2948,
The ligand (0.06 mmol, 12 mol %) and Cu(OAc)2ꢃH2O (10.0 mg,
0.05 mmol, 10 mol %) were dissolved in 1 mL of isopropanol and
stirred for 1 h at room temperature. The appropriate aldehyde
(0.5 mmol, 1 equiv) and nitroalkane (5.0 mmol, 10 equiv) were
added with an additional 1 mL of i-PrOH. The reaction mixture
was cooled to 0 °C. After 3 days, the crude product was isolated
by column chromatography (n-hexane/AcOEt 6:1) to yield b-nitro-
alcohol or the desired b-nitroalcohols as a mixture of diastereo-
mers. Products were analyzed by 1H NMR, and the enantiomeric
excess was determined using chiral HPLC.
3059, 3332 cmꢂ1
.
HRMS (ESI): 339.2267 ([M+H]+); for
(C22H28N2F)+ m/z = 339.2237.
4.6.5. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-[(2-naphthyl)
methylamine]methyl-2-azabicyclo[2,2,1]heptane exo-6d
Yield 54%, ½a 2D0
ꢁ
¼ ꢂ8:3 (c 0.36, CH2Cl2). 1H NMR (CDCl3):
Acknowledgment
d = 1.27–1.43 (m, 3H), 1.33 (d, 3H, J = 6.7 Hz), 1.69–1.77 (m, 3H),
2.10–2.17 (m, 2H), 2.39–2.42 (m, 2H), 2.57–2.61 (m, 1H), 3.43–
3.46 (m, 1H), 3.60 (br s, 1H), 3.79 (ABq, 2H, J = 13.2 Hz), 7.26 (t,
_
Professor Jacek Skarzewski is kindly acknowledged for helpful
discussions.

´
166
E. Wojaczynska / Tetrahedron: Asymmetry 22 (2011) 161–166
67, 1567–1573; (e) Magnus, A.; Bertilsson, S. K.; Andersson, P. G. Chem. Soc. Rev.
2002, 31, 223–229.
References
10. Alonso, D. A.; Bertilsson, S. K.; Johnsson, S. Y.; Nordin, S. J. M.; Södergren, M. J.;
Andersson, P. G. J. Org. Chem. 1999, 64, 2276–2280.
11. da Silva, R. A.; Estevam, I. H. S.; Bieber, L. W. Tetrahedron Lett. 2007, 48, 7680–
7682.
12. (a) Henry, L. Bull. Chim. Soc. Fr. 1895, 13, 999–1003; (b) Luzzio, F. A. Tetrahedron
2001, 57, 915–945.
1. Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691–1693.
2. (a) Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 97, 3161–3195; (b) Lucet, D.;
Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580–2627; (c)
Caputo, C. N.; Jones, N. D. Dalton Trans. 2007, 4627–4640; (d) Marqués-López,
E.; Merino, P.; Tejero, T.; Herrera, R. P. Eur. J. Org. Chem. 2009, 2401–2420.
3. (a) Chelucci, G. Chem. Soc. Rev. 2006, 35, 1230–1243; (b) Langlois, Y.;
Kouklovsky, C. Synlett 2009, 3065–3081; (c) Gayet, A.; Bolea, C.; Andersson,
P. G. Org. Biomol. Chem. 2004, 2, 1887–1893.
13. For reviews, see: (a) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C. Tetrahedron:
Asymmetry 2006, 17, 3315–3326; (b) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org.
Chem. 2007, 2561–2574; For some recent examples, see: (c) Kowalczyk, R.;
4. (a) He, W.; Zhang, B.-L.; Jiang, R.; Liu, P.; Sun, X.-L.; Zhang, S.-Y. Tetrahedron Lett.
2006, 47, 5367–5370; (b) Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem. Soc.
2008, 13, 6070–6071; (c) Lu, X.; Deng, L. Angew. Chem., Int. Ed. 2008, 47, 7710–
_
_
Sidorowicz, Ł.; Skarzewski, J. Tetrahedron: Asymmetry 2008, 19, 2310–2315; (d)
_
Kowalczyk, R.; Kwiatkowski, P.; Skarzewski, J.; Jurczak, J. J. Org. Chem. 2009, 74,
753–756; (e) Breuning, M.; Hein, D.; Steiner, M.; Gessner, V. H.; Strohmann, C.
Chem. Eur. J. 2009, 15, 12764–12769; (f) Selvakumar, S.; Sivasankaran, D.; Singh,
V. K. Org. Biomol. Chem. 2009, 7, 3156–3162; (g) Bandini, M.; Cabiddu, S.;
Cadoni, E.; Olivelli, P.; Sinisi, R.; Umani-Ronchi, A.; Usai, M. Chirality 2009, 21,
239–244; (h) Steurer, M.; Bolm, C. J. Org. Chem. 2010, 75, 3301–3310; (i) Wang,
Q.; Shantz, D. F. J. Catal. 2010, 271, 170–177; (j) Yang, W.; Liu, H.; Du, D.-M. Org.
Biomol. Chem. 2010, 8, 2956–2960; (k) Ingalsbe, M. L.; St. Denis, J. D.; Gleason, J.
L.; Savage, G. P.; Priefer, R. Synthesis 2010, 98–102; (l) Noole, A.; Lippur, K.;
Metsala, A.; Lopp, M.; Kanger, T. J. Org. Chem. 2010, 75, 1313–1316; (m) Weng, J.;
Li, Y.-B.; Li, F.-Q.; Liu, C.; Chan, A. S. C.; Lu, G. J. Org. Chem. 2010, 75, 3125–3128.
14. (a) Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67,
4875–4881; (b) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692–12693.
´
7713; (d) Zielinska-Błajet, M.; Skarzewski, J. Tetrahedron: Asymmetry 2009, 20,
1992–1998; (e) Wojaczyn´ ska, E.; Zielin´ ska-Błajet, M.; Turowska-Tyrk, I.;
_
Skarzewski, J. Tetrahedron: Asymmetry 2010, 21, 853–858.
5. (a) Bailey, P. D.; Wilson, R. D.; Brown, G. R. Tetrahedron Lett. 1989, 30, 6781–
6784; (b) Nakano, H.; Kumagai, N.; Kabuto, C.; Matsuzaki, H.; Hongo, H.
Tetrahedron: Asymmetry 1995, 6, 1233–1236; (c) Ekegren, J. K.; Modin, S. A.;
Alonso, D. A.; Andersson, P. G. Tetrahedron: Asymmetry 2002, 13, 447–449.
6. Brandt, P.; Andersson, P. G. Synlett 2000, 1092–1106.
7. (a) Nakano, H.; Kumagai, N.; Matsuzaki, H.; Kabuto, C.; Hongo, H. Tetrahedron:
Asymmetry 1997, 8, 1391–1401; (b) Lu, J.; Xu, Y.-H.; Loh, T.-P. Tetrahedron Lett.
2008, 49, 6007–6008.
_
8. Wojaczyn´ ska, E.; Skarzewski, J. Tetrahedron: Asymmetry 2008, 19, 2252–2257.
9. (a) Södergren, M. J.; Andersson, P. G. J. Am. Chem. Soc. 1998, 120, 10760–10761;
(b) Södergren, M. J.; Bertilsson, S. K.; Andersson, P. G. J. Am. Chem. Soc. 2000,
122, 6610–6618; (c) Modin, S. A.; Andersson, P. G. J. Org. Chem. 2000, 65, 6736–
6738; (d) Bertilsson, S. K.; Södergren, M. J.; Andersson, P. G. J. Org. Chem. 2002,
15. Alonso, D. A.; Guijarro, D.; Pinho, P.; Temme, O.; Andersson, P. G. J. Org. Chem.
1998, 63, 2749–2751.
16. Pal, B.; Jaisankar, P.; Giri, V. S. Synth. Commun. 2004, 34, 1317–1323.