Chelating 2-azanorbornyl derivatives as effective nitrogen-nitrogen and nitrogen-chalcogen donating ligands in palladium-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1016/j.tetasy.2008.09.025

New chiral 2-azanorbornane derivatives were prepared and used as (N,S)-, (N,Se)-, and (N,N)-donating ligands in a palladium-catalyzed asymmetric allylic alkylation, giving up to 95% ee and 92% yield.

Full text of DOI:10.1016/j.tetasy.2008.09.025

Tetrahedron: Asymmetry 19 (2008) 2252–2257
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Tetrahedron: Asymmetry
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Chelating 2-azanorbornyl derivatives as effective nitrogen–nitrogen
and nitrogen–chalcogen donating ligands in palladium-catalyzed
asymmetric allylic alkylation
*
_
_
´
Elzbieta Wojaczynska, Jacek Skarzewski
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´
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,S)-, (N,Se)-, and (N,N)-donating
ligands in a palladium-catalyzed asymmetric allylic alkylation, giving up to 95% ee and 92% yield.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 1 August 2008
Accepted 24 September 2008
Available online 22 October 2008
1. Introduction
ketones,6 asymmetric addition of dialkylzinc to imines,7 allylic oxi-
dation of olefins,8 and cyclopropanations.9 Most of these ligands
Over the last few decades, much interest has been focused on
chiral ligands, crucial for the catalytic synthesis of enantiomeric
products.1 Some ligands, successful in various, mechanistically
different, enantioselective reactions were ascribed to the privileged
ligands class.2 Despite the achievements in this field, there still
remains much interest in finding new structures and broadening
the use of those already known. An important feature of the prac-
tically useful ligands is the availability of starting materials for
their synthesis. Usually, these are derived from the chiral pool,
and thus limited to one enantiomer. However, an increasing num-
ber of ligands have recently been prepared using chiral auxiliaries,
often available as both enantiomers.
The highly stereoselective aza-Diels–Alder reaction occurs
between cyclopentadiene and the Schiff bases formed by optically
active 1-phenylethylamine used as an auxiliary. The reaction
serves as an effective method for the preparation of bicyclic chiral
compounds containing nitrogen donor.3 The synthesis of 2-azanor-
bornyl derivative 1 (Fig. 1) and the diverse possibilities of its
modification were extensively explored by Andersson et al.4 Due
to their rigidity and steric effects, these ligands were successful
in transfer hydrogenation reaction,4f,h,5 borane reduction of
contain nitrogen and oxygen as donor atoms. Among others,
(N,N)-coordinating diamine derivatives were used in epoxide rear-
rangements.10 Rare examples of (N,S)-ligands were represented by
thiazolyl-substituted compounds,4c alkyl sulfide derivatives tested
in the transfer hydrogenation of acetophenone,4h and 2-azanorbor-
nylmethanethiol, which catalyzed the enantioselective addition of
diethylzinc to aldehydes.11
A variety of chiral ligands containing chalcogen (S,Se)-donors
have already been studied in asymmetric catalytic reactions,12
some of which are very effective.
The successful chelating ligand should accommodate a catalyt-
ically active metal in a well-defined coordinating surrounding. One
of the strategies applied for the design of new chiral ligand takes
advantage of the stereoelectronic differentiation exerted by the
application of heterodonating ligands. Thus, in the mechanistically
well-understood Tsuji–Trost reaction,13 in addition to the steric
interactions, an attacking nucleophile approaches the Pd-com-
plexed allylic system from the site opposite to the more p-accept-
ing ligand center. Accordingly, in the case of bidentate N(sp3) and
Ph
Nu
Nu
*
N
*
N
N
Ph
CO2Et
Ph
Pd
Ph
W-shaped η3-complex
Figure 2.
Pd
1
X
X
Figure 1.
Ph
M-shaped η3-complex
* Corresponding author. Tel.: +48 71 320 2464; fax: +48 71 328 4064.
E-mail address: jacek.skarzewski@pwr.wroc.pl (J. Skarzewski).
_
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.025

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E. Wojaczynska, J. Skarzewski / Tetrahedron: Asymmetry 19 (2008) 2252–2257
weakly p-accepting chalcogen atoms, the direction trans to chalco-
gen is generally preferred (Fig. 2).13
PhCH2Br
K2CO3
N
Ph
CO2Et
NH
CO2Et
Within the aim of exploring the preparation and use of chiral
organochalcogen compounds, we undertook the synthesis of new
sulfur–nitrogen and selenium–nitrogen mixed donor chelate
ligands, which were tested in the Tsuji–Trost catalytic reaction.14
A facile one-step synthesis applicable for the preparation of 1 on
a multigram scale3a,4g prompted us to use this compound as a read-
ily available starting material for the construction of new chiral
ligands. We believe that broadening the scope of reactions where
the Andersson’s 2-azanorbornyl system can be successfully used,
brings this ligand closer to the privileged class.
3 a
2
H2, Pd/C
LiAlH4
N
1
H2, Pd/C
Ni
Ph
OH
N
Ph
CO2Et
LiAlH4
4a
3b
N
Ph
OH
2. Results and discussion
4b
The Aza-Diels–Alder reaction of cyclopentadiene and an imini-
um ion derived from ethyl glyoxylate and (S)-1-phenylethylamine
led to ester (1S,3R,4R)-1.4g The reduction of the double bond and
amine deprotection was achieved using H2 (7 atm) and a 5% Pd–
C (20 wt %) catalyst, as described in literature leading to compound
2.7a We observed, however, that when this reaction was conducted
in the presence of trace amounts of nickel(II) salts, only the double
bond was hydrogenated and the nitrogen atom remained pro-
tected, yielding 3b as a single product in 90% yield. Amine 2 was
benzylated to give derivative 3a; both esters 3a and 3b were
reduced with LiAlH4 to give the appropriate alcohols 4a and 4b
(Scheme 1). These compounds served as starting materials for
the synthesis of a series of enantiomerically pure ligands contain-
ing (N,S)-, (N,Se)- and (N,N)-donors. In N-benzylated series 4a–6a,
three stereogenic centers are present in the (1S,3R,4R)-bicyclic
fragment, while (S)-1-phenylethyl-substituted derivatives 4b–
12b have an additional stereogenic carbon atom which can serve
as an additional source of asymmetric induction.
Scheme 1.
We introduced a phenylsulfenyl group into 4a and 4b using the
Hata reaction.14,15 Nucleophilic substitution of the hydroxyl group
with diphenyldisulfide yielded the corresponding sulfides 5a (79%)
and 5b (40%). Selenides 6a and 6b were prepared according to the
Grieco protocol16 reacting 4a or 4b with PhSeCN (yields 71% and
24%, respectively). The disulfide derivative 7b was prepared from
4b in a sequence of four reactions: mesylation, followed by reac-
tion with potassium thioacetate, the subsequent reduction of the
resulting thioester with LiAlH4 to the corresponding thiol and oxi-
dation with iodine.11
Swern oxidation of alcohol 4b led to (1S,3R,4R)-2-[(S)-1-phenyl-
ethyl]-2-azabicyclo[2,2,1]heptane-3-carbaldehyde 8b.7b,10a Unfor-
tunately, an analogous reaction of 4a was completely ineffective.
R
N
SPh
5a R = CH2Ph
R
5b R = CHMePh
N
N
Ph
SePh
S)2
PhSSPh
Bu3P
R = CH2Ph
6a
6b R = CHMePh
7 b
1. MsCl
R
N
2. KSC(O)Me
PhSeCN
3. LiAlH4
OH
Bu3P
4. I2, NaOH/MeOH
4a R = CH2Ph
4b
R = CHMePh
Swern oxid.
Ph
N
(S)-PhCHMeNH2
R
S
N
Ph
N
O
9b
H
(R)-PhCHMeNH2
8b R = CHMePh
HS(CH2)3SH
Ph
N
R
N
Ph
HS(CH2)2SH
10b
Ph
S
S
N
Ph
S
S
N
11b
12b
Scheme 2.

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E. Wojaczynska, J. Skarzewski / Tetrahedron: Asymmetry 19 (2008) 2252–2257
2254
H2C(CO2Me)2, BSA (3eq.), AcOK
(3 mol%)
Ph
Ph
Ph
Ph
MeO2C
Pd2(C3H5)2Cl2 (2.5 mol%), Ligand (10 mol%)
CH3CN r.t.
CO2Me
OAc
R1
*
N
Ph
Ligand
R2
Scheme 3.
Even with the use of Dess–Martin reagent the desired aldehyde 8a
could not be obtained.
other hand, the palladium-Se complex can be less stable, which
would decrease the reaction yield.
Aldehyde 8b was then converted into the Schiff base 9b using
reaction with (S)-1-phenylethylamine (yield 56%). The diastereo-
meric imine 10b was also prepared when the amine was replaced
with its (R)-enantiomer. Thus the Schiff bases obtained differed in
configuration at one of five stereogenic centers. Dithioacetals 11b
and 12b were obtained from aldehyde 8b and ethanedithiol or
1,3-propanedithiol with 81% and 32% yield, respectively. All the
performed reactions are shown in Scheme 2.
Compounds 5a and 6a can be also confronted with their meth-
ylated derivatives 5b and 6b. Substitution with methyl group sub-
stantially lowers the yield of the catalytic reaction, although with a
significant increase in enantioselectivity. As ligands 5a/6a and 5b/
6b have identical donor atoms, the difference in their catalytic per-
formance should be due to the increased steric hindrance around
the coordinating nitrogen center for the methyl substituted deriv-
atives 5b and 6b. An additional stereogenic center present in these
ligands provides an additional reason for chiral discrimination.
Disulfide 8b, the only ligand with a C2 symmetry, was ineffec-
tive in the allylic substitution, thus no Pd-complex was formed.
A remarkable difference is seen in the results obtained for the
two Schiff base diastereomers, 9b and 10b. Changing the configu-
ration of only one of the five stereogenic centers from (S) to (R)
leads to lower yield and a dramatic decrease of enantioselectivity.
The two diastereomers create different chiral environments at the
palladium center, which exerts different steric hindrances in the
active complex.
We tested these new chiral azanorbornane derivatives as
ligands in the Pd-catalyzed allylic alkylation (Tsuji–Trost
reaction).13 The results obtained for the model reaction of dimethyl
malonate with rac-1,3-diphenyl-2-propenyl acetate, using 3 mol %
of N,O-bis(trimethylsilyl)acetamide-potassium acetate as a base,
2.5 mol % of [Pd(g
3-C3H5)Cl]2, and 10 mol % chiral ligand in aceto-
nitrile solution (Scheme 3) are shown in Table 1.
As can be seen from Table 1, the product with an (S)-configura-
tion was predominant in the reaction mixture. This stereochemical
preference can be attributed to the general structure of the bicyclic
ligand used. Examination of a simple molecular model often
allowed us to predict the configuration of the Tsuji–Trost reaction
A comparison of the stereochemical outcomes observed for
dithioacetals 11b and 12b shows that much better results were ob-
tained for a six-membered ring derivative. (1S,3R,4R)-2-[(S)-1-
Phenylethyl]-3-(2-dithiane)-2-azabicyclo[2,2,1]heptane 11b proved
to be the best out of all the ligands tested, giving 94% of the
(S)-product with 95% ee. Tentatively, these results can be con-
nected with an increased strain in the five-membered ring of 12b
product. When we took into consideration the key palladium
p-
allyl complex formed on the exo side of bicyclic system, the
substrate could be potentially coordinated in either an ‘M’ or ‘W’
configuration (Fig. 2). However, one of these possibilities
(M-shaped complexes) would bring
a pronounced sterical
hindrance. Thus, the W-shaped complex should be preferred.
Combined with the trans-effect, which directs the nucleophile to
the position opposite to the X donor, it should lead mainly to the
product with an (S)-configuration.
which affects the r-donor/p-acceptor properties of the sulfur
center and the possibility of 11b to adopt a proper conformation
during the coordination to palladium.
3. Conclusions
Table 1
Pd-Catalyzed alkylation of dimethyl malonate with 1,3-diphenyl-2-propenyl acetate
in the presence of N, N-, N, S-, and N, Se-donating ligands
The results obtained for a series of new chiral 2-azanorbornane
derivatives show that they can be used as efficient ligands in the
Tsuji–Trost reaction. Therefore, this work broadens the field of pos-
sible applications of the 2,3-disubstituted 2-azabicyclo[2.2.1]hep-
tanes and serves as an additional proof of the versatility of these
compounds-potential members of the privileged ligands class.2
Ligand L*
R1
R2
Yield of product (%)
Ee (%)
5a
6a
5b
6b
H
H
CH2SPh
CH2SePh
CH2SPh
CH2SePh
(S)-C@NCH(Me)Ph
(R)-C@NCH(Me)Ph
2-Dithiane
2-Dithiolate
95
90
62
55
95
86
94
90
48 (S)
62 (S)
65 (S)
76 (S)
90 (S)
50 (S)
95 (S)
48 (S)
Me
Me
Me
Me
Me
Me
9b
10b
11b
12b
4. Experimental
4.1. General
The observed differences in yield and enantioselectivity
between the ligands can be attributed at the first glance to the
different natures of donor atoms X. The results obtained for
sulfides 5 and selenides 6 show that the selenium derivatives gave
slightly lower yields from their sulfur analogues, but higher stereo-
selectivities were observed for ligands 6. These observations can be
accounted for by the stronger p-accepting properties of the Se do-
nors, as compared to the sulfur atom, which may increase the
enantioselectivity due to a more pronounced trans-effect. On the
Melting points were determined using a Boetius hot-stage
apparatus and are uncorrected. IR spectra were recorded on a Per-
kin Elmer 1600 FTIR spectrophotometer. 1H NMR and 13C NMR
spectra were measured on a Bruker CPX (1H, 300 MHz) or a Bruker
Avance (1H, 500 MHz) spectrometer using TMS as an internal
standard. Optical rotations were measured using an Optical
Activity Ltd. Model AA-5 automatic polarimeter. High resolution
mass spectra were recorded using a microTOF-Q instrument utiliz-
ing electrospray ionization mode. Separations of products by

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E. Wojaczynska, J. Skarzewski / Tetrahedron: Asymmetry 19 (2008) 2252–2257
chromatography were performed on Silica Gel 60 (230–400 mesh)
purchased from Fluka. Thin layer chromatography analyses were
performed using silica gel 60 precoated plates (Merck).
1.60–1.66 (m, 1H), 1.75–1.77 (m, 1H), 1.93–1.98 (m, 1H), 2.11–
2.14 (m, 1H), 2.20–2.28 (m, 2H), 2.43–2.48 (m, 1H), 3.45 (q, 1H,
J = 6.42 Hz), 3.64 (br s, 1H), 6.62–6.63 (m, 2H, ArH), 7.04–7.06
(m, 3H, ArH), 7.28–7.36 (m, 5H, ArH) ppm. 13C NMR (CDCl3): d
22.9, 23.8, 29.1, 35.3, 37.7, 40.7, 59.9, 61.6, 68.9, 125.4, 127.8,
128.4, 128.7, 128.7, 129.0, 132.4, 136.9 ppm. IR (film) 737, 761,
1163, 1304, 1452, 1480, 1583, 2870, 2969, 3059 cmꢁ1. HRMS
(ESI): 324.1653 ([M+H]+); for (C21H26NS)+ M = 324.17862.
4.2. Synthesis of (1S,3R,4R)-2-[(S)-1-phenylethyl]-2-
azabicyclo[2.2.1]hept-5-ene-3-carboxylic acid ethyl ester 1
This compound was prepared according to the literature proce-
dure via the aza-Diels–Alder reaction of cyclopentadiene with an
iminium ion derived from ethyl glyoxylate and (S)-1-phen-
ylethylamine.4g
4.6.2. Preparation of selenides
At first, PhSeCN (0.15 mL, 1.2 mmol) was added by a syringe to a
solution of alcohol 4a or 4b (1 mmol) in dry toluene (15 mL) under
an argon atmosphere. The mixture was cooled to 0 °C in an ice
bath, and tributylphosphine (0.74 mL, 3 mmol) was injected to
the stirred solution. The mixture was kept at room temperature
for 20 h. After evaporation of the solvent, chloroform (10 mL)
was added to the reaction mixture, and then washed with 10%
aqueous NaOH, water and brine. The organic layer was dried over
anhydrous Na2SO4. The solvent was evaporated and product 6a or
6b was purified by column chromatography with hexane-ethyl
acetate (9:1 v/v) as eluent.
4.3. Reduction of Diels–Alder product 1
Ester 1 was hydrogenated in an ethanolic solution using H2
(7 atm) and 5% Pd–C (20 wt %) catalyst as described in the litera-
ture7a to give (1S,3R,4R)-2-azabicyclo[2.2.1]heptane-3-carboxylic
acid ethyl ester 2. (1S,3R,4R)-2-[(S)-1-phenylethyl]-2-azabicy-
clo[2.2.1]heptane-3-carboxylic acid ethyl ester 3b was obtained
by reduction of 1 with H2 (7 atm) and 5% Pd–C in the presence of
traces of nickel(II) salt. The characteristics of 3b was in agreement
with the literature data.7b
4.6.2.1. (1S,3R,4R)-2-Benzyl-3-phenylselenalylmethyl-2-azabic-
4.4. Synthesis of (1S,3R,4R)-2-benzyl-2-azabicyclo[2.2.1]-
heptane-3-carboxylic acid ethyl ester 3a
yclo[2.2.1]heptane 6a.
Yield 71%,
½
a 2D0
ꢀ
¼ ꢁ32:5 (c 0.80,
CH2Cl2), 1H NMR (CDCl3, 300 MHz): d 1.21–1.40 (m, 2H), 1.70–
1.84 (m, 3H), 2.17–2.21 (m, 1H), 2.45–2.48 (m, 1H), 2.57–2.64
(m, 1H), 2.74–2.79 (m, 1H), 3.10–3.15 (m, 2H), 3.35 and 3.49
(ABq, 2* 1H, J = 13.59 Hz), 7.12–7.44 (m, 10H, ArH) ppm. 13C NMR
(CDCl3): d 21.2, 28.8, 35.0, 39.1, 46.8, 50.8, 58.8, 59.2, 125.7,
126.0, 127.1, 127.7, 127.9, 130.9, 133.1, 138.3 ppm. 77Se NMR: d
380.3 ppm. IR (film) 465, 697, 735, 1023, 1071, 1154, 1437, 1453,
Benzylation of compound 2 was performed according to a liter-
ature procedure.5a,7a
4.5. Synthesis of (1S,3R,4R)-2-benzyl-3-hydroxymethyl-2-
azabicyclo[2.2.1]heptane 4a and (1S,3R,4R)-2-[(S)-1-
phenylethyl]-3-hydroxymethyl-2-azabicyclo[2.2.1]heptane 4b
1477, 1579, 1867, 2954, 3062 cmꢁ1
([M+H]+); for (C20H24NSe)+ M = 358.10752.
. HRMS (ESI): 358.1068
These compounds were obtained by reduction of the appropri-
ate esters 3a and 3b, respectively, with LiAlH4 according to the lit-
erature procedure.5a,11
4.6.2.2. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-phenylselenalylmeth-
yl-2-azabicyclo[2.2.1]heptane 6b.
Yield 24%, ½a 2D0
¼ ꢁ80:3 (c
ꢀ
0.66, CH2Cl2). 1H NMR (CDCl3, 300 MHz): d 1.29–1.32 (d, 3H,
J = 6.64 Hz), 1.34–1.43 (m, 3H), 1.54–1.58 (m, 1H), 1.70–1.78 (m,
2H), 2.19–2.24 (m, 1H), 2.49–2.54 (m, 1H), 2.67–2.72 (m, 1H),
3.08–3.11 (m, 1H), 3.37 (q, 1H, J = 6.65 Hz), 3.60 (t, 1H,
J = 4.78 Hz) 7.15–7.61 (m, 10H, ArH) ppm. 13C NMR (CDCl3): d
21.6, 22.6, 30.1, 36.3, 40.3, 48.4, 50.1, 56.4, 62.4, 126.7, 127.1,
4.6. Nucleophilic substitution of hydroxyl group in 4a and 4b
4.6.1. Preparation of sulfides
Tributylphosphine (8 mmol, 1.62 g, 1.97 mL) was added by syr-
inge to a solution of alcohol 4a or 4b (2 mmol) and diphenyldisul-
fide (6 mmol, 1.31 g) in dry toluene (6 mL). The mixture was
transferred to the ampoule, filled with argon and sealed. This reac-
tion mixture was kept at the oil bath at 80 °C for three days.
Diethyl ether (20 mL) was added to the cooled solution, the organic
layer was washed with 10% aqueous NaOH, water and brine, and
dried over anhydrous Na2SO4. The solvent was evaporated and
product 5a or 5b was purified by column chromatography using
hexane–ethyl acetate (9:1 v/v) as eluent.
127.4, 128.3, 128.8, 131.6, 132.8, 134.4.ppm. 77Se NMR:
d
382.7 ppm. IR (film) 692, 738, 1437, 1452, 1476, 1578, 2946,
3057 cmꢁ1. HRMS (ESI): 372.1195 ([M+H]+); for (C21H26NSe)+
M = 372.12316.
4.6.3. Synthesis of bis-3-{(1S,3R,4R)-2-[(S)-1-phenylethyl]-2-aza-
bicyclo[2.2.1]heptane}-methyl disulfide 7b
This compound was prepared from alcohol 4b according to the
literature procedure.11 Mesylation of 4b followed by the reac-
tion with potassium thioacetate and a subsequent reduction of
resulting thioester with LiAlH4 gave (1S,3R,4R)-2-[(S)-1-phenyl-
ethyl]-2-azabicyclo[2,2,1]heptane-3-methanethiol, with the spec-
tral characteristics in agreement with that given in the literature
for its enantiomer.11 Oxidation of this thiol with I2 in methanolic
NaOH solution (20% w/w) gave the appropriate disulfide 7b.
4.6.1.1. (1S,3R,4R)-2-Benzyl-3-phenylsulfanylmethyl-2-azabicy-
clo[2.2.1]heptane 5a.
Yield 79%,
½
a 2D0
ꢀ
¼ ꢁ13:1 (c 1.56,
CH2Cl2), 1H NMR (CDCl3, 300 MHz): d 1.14–1.30 (m, 3H), 1.54–
1.60 (m, 1H), 1.70–1.74 (m, 1H), 1.87–1.91 (m, 1H), 2.13–2.18
(m, 1H), 2.33–2.34 (m, 1H), 2.53–2.71 (m, 2H), 3.18 (s, 1H), 3.58
and 3.66 (ABq, 2* 1H, J = 13.06 Hz), 7.08–7.29 (m, 10H, ArH) ppm.
13C NMR (CDCl3): d 21.3, 28.1, 34.5, 37.3, 40.2, 54.2, 59.4, 67.4,
124.4, 125.9, 127.2, 127.5, 127.8, 128.1, 135.9, 139.2 ppm. IR (film)
698, 737, 1085, 1155, 1321, 1438, 1480, 1583, 2869, 2957,
4.6.4. Bis-3-{(1S,3R,4R)-2-[(S)-1-phenylethyl]-2-azabi-
cyclo[2.2.1]heptane}methyl disulfide 7b
3062 cmꢁ1
.
HRMS (ESI): 310.1653 ([M+H]+); for (C20H24NS)+
Yield 82%, ½a 2D0
ꢀ
¼ ꢁ126:6 (c 0.30, CH2Cl2), 1H NMR (CDCl3,
M = 310.16296.
500 MHz): d 1.19–1.34 (m, 5H), 1.61–1.69 (m, 2H), 2.02–2.06 (m,
1H), 2.34–2.40 (m, 1H), 2.47–2.50 (m, 1H), 2.61–2.66 (m, 1H),
3.25–3.32 (m, 1H), 3.44–3.49 (m, 1H), 7.09–7.25 (m, 5 H, ArH)
ppm. 13C NMR (CDCl3): d 21.5, 21.9, 27.0, 35.0, 38.6, 48.5, 53.8,
55.9, 62.3, 126.7, 127.3, 128.3, 145.4 ppm. IR (film) 545, 701, 768,
4.6.1.2. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-phenylsulfanylmeth-
yl-2-azabicyclo[2.2.1]heptane 5b.
Yield 40%, ½a 2D0
¼ ꢁ5:1 (c
ꢀ
1.47, CH2Cl2), 1H NMR (CDCl3, 500 MHz): d 1.23–1.32 (m, 6H),

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/ Tetrahedron: Asymmetry 19 (2008) 2252–2257
E. Wojaczynska, J. Skarzewski
2256
1135, 1284, 1453, 1491, 2860, 2930, 3024, 3060 cmꢁ1. HRMS (ESI):
493.2712 ([M+H]+); for (C30H41N2S2)+ M = 493.27112.
4.7.2.2. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-(2-dithiolate)-2-aza-
bicyclo[2.2.1]heptane 12b.
Yield 32%, ½a 2D0
¼ þ3:4 (c 0.74,
ꢀ
CH2Cl2), 1H NMR (CDCl3, 300 MHz): d 1.09–1.13 (m, 1H), 1.18–
1.35 (m, 4H), 1.50–1.55 (m, 2H), 1.75–1.85 (m, 1H), 2.20–2.26
(m, 2H), 2.36–2.38 (m, 1H), 2.82–2.90 (m, 2H), 2.95–3.02 (m,
2H), 3.37–3.38 (d, 1H, J = 3.32 Hz), 3.42 (q, 1H, J = 6.56 Hz), 3.58
(br s, 1H), 7.17–7.32 (m, 5 H, ArH) ppm. 13C NMR (CDCl3): d 21.7,
21.9, 29.3, 35.7, 37.2, 38.5, 56.3, 58.1, 60.4, 72.1, 126.9, 127.3,
127.5, 145.3 ppm. IR (film) 701, 768, 1106, 1163, 1304, 1453,
1492, 1674, 1720, 2869, 2922, 2971, 3026, 3061 cmꢁ1. HRMS
(ESI): 306.1309 ([M+H]+); for (C17H24NS2)+ M = 306.13501.
4.7. Oxidation of alcohol 4b and further modifications
Oxidation of 4b under Swern conditions led to (1S,3R,4R)-2-[(S)-
1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carbaldehyde 8b as
described in the literature.7b,10a
4.7.1. Preparation of Schiff base
Aldehyde 8b (0.10 g, 0.43 mmol) and (S)-1-phenylethylamine
(0.054 mL, 0.43 mmol) were dissolved in 5 mL of ethanol, and the
mixture was left over MgSO4 for 24 h. The solvent was evaporated
and the residue was chromatographed on neutral alumina column
(hexane–ethyl acetate (5:1 v/v). Compound 10b was obtained in a
similar manner using (R)-1-phenylethylamine instead of its
enantiomer.
4.8. Catalytic reactions
The Pd-catalyzed allylic substitution reaction of dimethyl mal-
onate with rac-1,3-diphenyl-2-propenyl acetate was performed
using 3 mol % of N,O-bis(trimethylsilyl)acetamide-potassium ace-
tate as a base, 2.5 mol % of [Pd(g
3-C3H5)Cl]2, and 10 mol % of the
4.7.1.1. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-[(S)-1-phenylethylim-
chiral ligand tested in acetonitrile solution. The stereochemical
effect of the catalytic reaction was determined by 1H NMR mea-
surement using Eu(hfc)3 as a chiral shift reagent. The assignment
of absolute configuration was based on the specific rotation
according to the literature data.14
ine]methyl-2-azabicyclo[2.2.1]heptane
9b.
Yield
56%,
½
a 2D0
ꢀ
¼ ꢁ2:5 (c 1.58, CH2Cl2), 1H NMR (CDCl3, 300 MHz):
d
1.20–1.41 (m, 8H), 1.48 (d, 1H, J = 6.55 Hz), 1.54–1.59 (m, 2H),
1.71–1.75 (m, 1H), 1.91–1.96 (m, 1H), 2.24–2.27 (m, 1H), 2.62 (d,
1H, J = 5.38 Hz), 3.46 (q, 1H, J = 6.48 Hz), 3.65 (br s, 1H), 3.80 (q,
1H, J = 6.68 Hz), 6.81–7.40 (m, 10H, ArH) ppm. 13C NMR (CDCl3):
d 21.5, 21.8, 22.7, 28.2, 35.0, 43.1, 57.7, 59.9, 67.4, 70.5, 125.4,
125.7, 126.1, 126.8, 127.0, 127.0, 143.2, 144.1, 166.8 ppm. IR
(film) 699, 759, 1370, 1451, 1662, 1687, 2869, 2966, 3027,
Acknowledgment
We are grateful to the Ministry of Science and Higher Education
for financial support (Grant PBZ-KBN-126/T09/2004).
3062 cmꢁ1
.
HRMS (ESI): 333.2293 ([M+H]+); for (C23H29N2)+
M = 333.2306.
References
4.7.1.2. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-[(R)-1-phenylethyli-
1. (a) New Frontiers in Asymmetric Catalysis; Mikami, K., Lautens, M., Eds.; Wiley-
Interscience: Hoboken, 2007; (b) Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
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Synlett 2000, 1092–1106.
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mine]methyl-2-azabicyclo[2.2.1]heptane 10b.
Yield 39%,
½
a 2D0
ꢀ
¼ þ52:9 (c 0.44, CH2Cl2), 1H NMR (CDCl3, 300 MHz): d 1.16–
1.36 (m, 9H), 1.51–1.54 (m, 2H), 1.63–1.66 (m, 1H), 1.92–1.97
(m, 1H), 2.14–2.18 (m, 1H), 2.63 (d, 1H, J = 5.64 Hz), 3.49 (q, 1H,
J = 6.50 Hz), 3.64 (br s, 1H), 3.74 (q, 1H, J = 6.62 Hz), 7.02–7.30
(m, 10H, ArH) ppm. 13C NMR (CDCl3): d 21.5, 21.8, 22.9, 28.4,
35.1, 43.3, 57.6, 59.9, 67.5, 70.7, 125.3, 125.5, 126.1, 127.2, 127.3,
127.6, 144.2, 144.6, 167.2 ppm. IR (film) 701, 763, 1383, 1451,
1661, 1687, 2869, 2968, 3029, 3061 cmꢁ1. HRMS (ESI): 333.2286
([M+H]+); for (C23H29N2)+ M = 333.2306.
4.7.2. Preparation of dithioacetals
To a stirred solution of aldehyde 8b (80 mg, 0.35 mmol) and
ethanedithiol or 1,3-propanedithiol (0.035 mL, 0.35 mmol) in
5 mL of chloroform 0.1 mL of BF3ꢂEt2O was added by syringe. A
solution was kept over anhydrous sodium sulfate for 24 h. After fil-
tration, the reaction mixture was subsequently washed with water,
aqueous NaOH (5%), water and saturated aqueous NaCl and dried
with Na2SO4. After removal of solvent, the residue was chromato-
graphed on silica column. Elution with chloroform yielded dithio-
acetal 11b or 12b.
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7906.
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4.7.2.1. (1S,3R,4R)-2-[(S)-1-Phenylethyl]-3-(2-dithiane)-2-aza-
bicyclo[2.2.1]heptane 11b.
Yield 81%, ½a 2D0
¼ þ18:4 (c 0.68,
ꢀ
CH2Cl2), 1H NMR (CDCl3, 300 MHz):
d 1.05–1.07 (m, 1H),
1.15–1.28 (m, 5H), 1.48–1.53 (m, 2H), 1.75–1.81 (m, 2H), 1.88–
1.91 (m, 1H), 2.07–2.14 (m, 3H), 2.29–2.30 (m, 1H), 2.40–2.47
(m, 2H), 2.56–2.60 (m, 1H), 3.39 (q, 1H, J = 6.54 Hz), 3.59 (br
s, 1H), 7.17–7.21 (m, 3H, ArH), 7.33–7.36 (m, 2H, ArH) ppm.
13C NMR (CDCl3): d 21.9, 22.6, 26.8, 30.4, 31.5, 31.8, 36.5, 39.9,
54.7, 58.2, 61.4, 72.9, 127.2, 128.0, 128.4, 146.4 ppm. IR
(film) 700, 769, 1163, 1299, 1452, 2826, 2870, 2895, 2969,
3025 cmꢁ1. HRMS (ESI): 320.1553 ([M+H]+); for (C18H26NS2)+
M = 320.15067.

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