Aza-Diels-Alder reaction catalyzed by novel chiral metalocomplex Bronsted acids

Article abstract of DOI:10.1016/j.tetasy.2013.01.011

A series of Co(III) anionic complexes of Schiff bases obtained from salicylaldehydes and enantiomerically pure amino acids has been synthesized. The outersphere counterion was exchanged by H⁺ and the novel chiral Bronsted acids were used to induce asymmetry into an aza-Diels-Alder reaction. The influence of the temperature, solvent polarity, and structural modification of the chiral anions on the enantioselectivity of the process has also been investigated.

Full text of DOI:10.1016/j.tetasy.2013.01.011

Tetrahedron: Asymmetry 24 (2013) 178–183
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Aza-Diels–Alder reaction catalyzed by novel chiral metalocomplex
Brønsted acids
Victor I. Maleev a, , Tat’yana V. Skrupskaya a, Lidia V. Yashkina a, Anna F. Mkrtchyan b, Ashot S. Saghyan b,
⇑
Michayl M. Il’in a, Denis A. Chusov a
a A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilova Str. 28, 119991 Moscow, Russian Federation
b Research Institute of Biotechnology, National Academy of Sciences of the Republic of Armenia, Gyurjyana Str. 14, 375056 Yerevan, Armenia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 November 2012
Accepted 4 January 2013
A series of Co(III) anionic complexes of Schiff bases obtained from salicylaldehydes and enantiomerically
pure amino acids has been synthesized. The outersphere counterion was exchanged by H+ and the novel
chiral Brønsted acids were used to induce asymmetry into an aza-Diels–Alder reaction. The influence of
the temperature, solvent polarity, and structural modification of the chiral anions on the enantioselectivity
of the process has also been investigated.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
1 eq.(S)-amino
acid (H2N-CHR-
COOH), 0.5 eq.
Na3[Co(CO3)3],
In the fast growing field of asymmetric organic catalysis,
designing chiral organic anions as stereoinductors in reactions that
proceed via cationic transition states is a recent fashionable trend.1
At the same time asymmetric catalysis with chiral metalocomplex
anions as stereoinductors still remains relatively unexplored. Re-
cently, we reported on a set of stereochemically inert Co(iii) based
octahedral metalocomplex anions with alkali metal counter-cat-
ions (the preparation pathway is presented in Scheme 1) to serve
as asymmetric catalysts in C–C bond formating reactions.2 Herein
we report on the design and catalytic performance of a novel fam-
ily of Brønsted acids derived from chiral anionic metalocomplexes
by ion exchange of the alkali metal cations for protons.
R
R
O
O
O
CHO
HO
M
N
N
Co
O
EtOH, 3h reflux,
chromatography,
ion exchange
(Na+
M+)
Scheme 1. Complex preparation.
O
O
O
O
R
R
R
R
2. Results and discussion
M
O
O
Co
O
O
O
H
ionexchange
N
N
N
N
resin in H+
form
Co
Novel chiral metalocomplex Brønsted acids were prepared from
previously synthesized complexes2 by ion exchange (alkali metal
ions by protons) as shown in Scheme 2.
O
O
O
In addition to the central chirality of the amino acid moieties,
the intrinsic properties of these complexes include their meridi-
anal chirality, with the complexes existing in two enantiomeric
(R = iPr);
(R = iBu);
1
2
3
4
5
(R = (R)-CH(OH)Me); (R = CH2-Ind)
(R = H);
K
and D-configurations, as shown in Chart 1 (using a glycine com-
Scheme 2. Preparation of novel chiral metalocomplex Brønsted acids.
plex as an illustration).
As a benchmark reaction for testing the novel chiral Brønsted
acids, we chose the acid catalyzed asymmetric aza-Diels–Alder
reaction3 (see Scheme 3).
Aza-Diels–Alder reactions are becoming a mainstay of hetero-
cycle and natural product synthesis4 and are among the most
powerful C–C bond-forming reactions for the preparation of nitro-
gen-containing compounds such as piperidines and quinolidine
derivatives.5 Products of aza-Diels–Alder reactions can be used
⇑
Corresponding author. Fax: +7 499 135 6356.
E-mail address: vim@ineos.ac.ru (V.I. Maleev).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.01.011

V. I. Maleev et al. / Tetrahedron: Asymmetry 24 (2013) 178–183
179
Table 2
Catalysis of aza-Diels–Alder reaction 7 with 6a by different chiral metalocomplex
Brønsted acids (Scheme 3)a
O
O
Catalyst
-1b
(S,S)-2
(S,S)-2
(S,S)-3
Yield (%)
8a/9a
8a ee%
9a ee%
O
O
D
K
D
K
12
58
93
82
80
8
3/1
6/1
4/1
5/1
3/1
2/1
nd
+34
ꢀ37
+50
ꢀ6
14
nd
nd
33
27
0
O
O
N
Co
N
N
Co
N
D
D
(S,S)-3
+63
+17
nd
O
O
O
O
(S,S)-4c
K(S,S)-5
5
3
nd
nd
O
O
D
(S,S)-5
nd
nd
Δ-stereoisomer
stereoisomer
a
Reaction conditions: 7 (1 mmol), 6a (1 mmol), argon atmosphere, 48 h, catalyst
(0.05 mmol), CCl4 (3 ml). Signs ‘ꢀ‘ and ‘+’ indicate opposite configurations of the
Chart 1. Illustration of the axial chirality of cobaltate anions with using complex 1
as the simplest model. C2 axes are directed from observer cross Co atom.
reaction product and correspond to the specific rotation signs.
b
Enantiomers of 1 were resolved according to a literature procedure.16
K
-4 is only 1H NMR detectable minor isomer and was not used to
c
Complex
catalyze.
for the preparation of precursors to all of the known naturally
occurring prosopis piperidine alkaloids via a Schmidt rearrange-
ment,6 and Baeyer–Villiger oxidation.7 There are already several
diastereoselective aza-Diels–Alder reactions.8,9 The inter- and
intramolecular aza-Diels–Alder reactions of imines with electron-
rich dienophiles have been catalyzed by Lewis acids such as BF3
OEt2,10 InCl3,11 BiCl3,12 transition metal carbonyls, and lanthanide
triflates13 as well as Brønsted acids such as TFA and p-TsOH.14
Kobayashi et al. and Jørgensen et al. have successfully used chiral
Lewis acid complexes as catalysts for these transformations.15
However, some of these catalysts suffer from disadvantages
such as a strong acidic nature, nucleophilic character, high cost,
long reaction times, and low yields. Moreover, many Lewis acids
either decompose or become deactivated because of the presence
of water during imine formation.
in Table 1. The configuration of the major endo-stereoisomer
(designated as ‘+’ and having a greater HPLC retention time) was
assigned as (1S,3R,4S) in the case of
of X-ray data (vide infra). As shown in Table 1 only three solvents,
THF, toluene, and CCl4, provided the product in reasonable yield
and ee in excess of 30%. We chose CCl4 for further studies because
the best endo/exo ratios of the product were observed in this
solvent.
D(S,S)-2 catalysis on the basis
Having established the optimal catalytic conditions, we then
determined the optimal catalyst structure. We tested the catalytic
activity of all of the complexes shown in Scheme 2 in both
-stereoisomeric forms under the optimal conditions and the
results are presented in Table 2.
K- and
D
As shown in Table 2, the catalysts differ in their efficiencies.
Catalysts 4 and 5, derived from threonine and tryptophan respec-
In the aza-Diels–Alder reactions, it is necessary to activate the
imine double bond. This is due to the low electrophilicity of the
imines as compared with the corresponding carbonyl compounds.
We expected that activation of the Schiff bases could be achieved
by protonation of the imino nitrogen with the new metalocomplex
Brønsted acids, with the chiral anions formed providing the asym-
metric induction in the stereodetermining step.
tively, had negligible activities in both
K- and D-forms, possibly be-
cause of the basicities of their side groups. The glycine complex 1
also had low efficiency. Compounds 2 and 3 were the most active
catalysts with the D(S,S)-3 isomers furnishing the best enantiomeric
purity of the major endo-adduct (63%). The enantiomeric outcome of
the reaction was critically dependent on the configuration of the
The reaction of cyclohexenone 7 with 6a (Scheme 3) was carried
complex with
K(S,S)-3 yielding the adduct with low ee and opposite
out in several solvents catalyzed by either
K(S,S)-2 or D(S,S)-2 at
sense of chirality (6%).
an ambient temperature for 48 h. The results are summarized
H
R2
R1
H
R1
R2
H
H
H
O
1-5 mol% cat*
R1 +
N
N
O
O
+
solvent, 48h, RT
R2
N
H
H
6a-j
7
endo-8a-j
exo-9a-j
Scheme 3. Benchmark aza-Diels–Alder reaction (a, R1 = Ph, R2 = Ph; b, R1 = o-Cl-Ph, R2 = Ph; c, R1 = m-Cl-Ph, R2 = Ph; d, R1 = p-F-Ph, R2 = Ph; e, R1 = p-Me-Ph, R2 = Ph; f, R1
p-MeO-Ph, R2 = Ph; g, R1 = m-MeO-Ph, R2 = Ph; h, R1 = Ph, R2 = p-Cl-Ph; i, R1 = Ph, R2 = p-Me-Ph; j, R1 = Ph, R2 = p-MeO-Ph).
=
Table 1
Catalysis of aza-Diels–Alder reaction 7 with 6a (Scheme 3) by
K(S,S)-2 and D
(S,S)-2 in different solventsa
Solvents
Hexane
CCl4
Dioxane
Toluene
Et2O
THF
DCM
EtOH
MeCN
Catalyst (S,S)-2 configuration
K
D
K
D
K
D
K
D
K
D
K
D
K
D
K
D
K
D
Yield (%)
endo/exo
ee(endo) (%)
ee(exo), (%)
72
3/1
ꢀ8
6
36
3/2
+6
0
58
6/1
93
76
92
1/2
+24
0
65
84
7/3
0
72
5/1
ꢀ8
6
81
2/1
+10
0
99
99
52
78
3/2
0
99
1/2
ꢀ6
2
99
1/2
+3
83
2/1
ꢀ2
0
82
3/2
+6
0
4/1
+50
nd
3/7
ꢀ14
10
5/1
ꢀ42
nd
2/1
ꢀ2
38
1/1
+18
3/2
ꢀ8
18
ꢀ37
b
b
nd
12b
2
0
6
a
Reaction conditions: 7 (1 mmol), 6a (1 mmol), argon atmosphere, 48 h, catalyst
K(S,S)- or D(S,S)-2 (0.05 mmol), solvent (3 ml). The enantiomeric purity was determined
i
by chiral HPLC analysis (Chiralpak IB-3 chiral stationary phase, PrOH/hexane (1:9), 254 nm). Signs ‘ꢀ‘ and ‘+’ indicate opposite configurations of the reaction product and
correspond to the specific rotation.
b
Opposite configuration of the enantiomer.

180
V. I. Maleev et al. / Tetrahedron: Asymmetry 24 (2013) 178–183
Table 3
The assignment of the (1S,3R,4S)-absolute configuration of 8a
with a greater HPLC retention time (see Fig. 1) was accomplished
by the anomalous scattering of oxygen and nitrogen atoms (Cu
Catalysis of aza-Diels–Alder reaction 7 with 6a by
D(S,S)-3 (from 1 to 10 mol %) with
various amounts of CCl4 solvent (Scheme 3)a
Entry Catalyst
(%)
Solvent
(ml)
Yield
(%)
8a:9a 8a eeb
(%)
9a ee
(%)
Ka radiation) within the X-ray diffraction investigation.
1
2
3
4
5
6
7
8
9
10
5
2
1
2
2
2
2
2
2
1
1
1
1
5
2.5
1
0.65
0.5
0.25
72 73:27
80 75:25
67 72:28
35 70:30
25 62:38
45 77:23
67 72:28
80 70:30
65 70:30
80 76:24
56
53
56
53
59
45
56
63
51
37
38
33
32
21
32
15
32
27
20
10
10
a
Reaction conditions: 7 (1 mmol), 6a (1 mmol), argon atmosphere, 48 h, catalyst
D
(S,S)-3 (0.01–0.1 mmol), CCl4 (0.25–5 ml).
Configuration of the product was (1S,3R,4S).
b
Catalyst
D(S,S)-3 was tested by varying the substrate/catalyst
ratios and catalyst concentrations. As shown in Table 3, there
was no change in the enantiomeric excess of the main product
when decreasing the catalyst loading from 10 to 1 mol % (Table 3,
entries 1–4). However, the best yield and ee were achieved at
2 mol % of the catalyst (Table 3, entry 8). We also checked the influ-
ence of the dilution of the reaction mixture on the catalysis efficacy
(Table 3, entries 5–10). A dilution led to a decrease of the chemical
yield but the best ee of the product was achieved at 0.65 ml (1.5 M
of the starting material) of carbon tetrachloride (Table 3, entry 8).
After choosing the optimal reaction condition, we proceeded to
explore the substrate scope and limitations of the present protocol.
Our results are presented in Table 4. The yield of the products was
in the range of 72–85%. However, the introduction of chloro-sub-
stituents in the aldehyde aromatic rings decreased the yield to
38–52% (Table 4, entries 2–3). A stronger electron donating group
such as p-methoxyaniline decreased the yield to 66% (Table 4, en-
try 10). The ratio between the exo- and endo-isomer was almost the
same in most cases. Only ortho-substituents reduced the ratio to
60:40 (Table 4, entry 2), probably, because of steric effects. On
the other hand, weak electron withdrawing groups, such as
p-chloro, increased the ratio to 80:20 (Table 4, entry 8). The enan-
tiomeric excesses of the exo-products were always low (20–25%).
In the case of an unsubstituted substrate, the ee of the exo-isomer
became 27% (Table 4, entry 1). The introduction of chloro-
substituents at the ortho-position of R1 led to a racemic product
(Table 4, entry 2). Some products were crystalline and were recrys-
tallized after separation by column chromatography. In these cases
the enantiomeric purity of the product was very high, with up to
98% being obtained (Table 4, entries 1, 6, 10 in brackets).
Figure 1. Structure of 8a with a greater HPLC retention time, as determined by
X-ray analysis.
3. Conclusion
A novel family of simple chiral Brønsted acid catalysts has been
developed. Their ease of preparation and assembly, the possibility
of almost infinite variations of their structures, the introduction of
different functional groups into their side chains, and the variation
charge/nature of the outersphere cations make them interesting
systems for future exploration as catalysts in a wide range of
Brønsted or Lewis acid catalyzed reactions.
4. Experimental
1H NMR spectra were recorded on a Bruker Avance 300
(300 MHz) spectrometer. Chemical shifts were measured in the d
scale relative to the signal of residual protons of the deuterated sol-
vent. Optical rotations were measured on a Perkin–Elmer 341
polarimeter in a temperature maintained cell (l = 5 cm) at 25 °C.
The solvent and the sample concentration in grams per 100 mL
were indicated for all compounds. Elemental analyses of all of
the synthesized compounds were performed at the Laboratory
of Elemental Analysis of the A.N. Nesmeyanov Institute of Orga-
noelement Compounds (Russian Academy of Sciences). Silica gel
Kieselgel 60 (Merck), Al2O3 (Chemapol), and Sephadex LH-20
(Supelco) were used. Solvents were purified according to standard
procedures. Sodium tricarbonatocobaltate(III) Na3[Co(CO3)3] was
synthesized by the described procedure17 as a dark green powder,
mp >300 °C. The enantiomeric purities of the endo- and exo-
products were determined by HPLC on a Chiralpak IB-3 column
eluted with a mixture of hexane/iPrOH (90:10 or 99:1) 1 mL/min
and detected at 254 nm.
Table 4
The scope of substrates in aza-Diels–Alder reaction 7 with 6a–j, (Scheme 3) catalyzed
by
D
-3 (from 1 to 10 mol)a
Entry
R1
R2
Yield (%) 8:9
8 eeb (%) 9 ee (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
85 75:25 63 (98)
27
nd
nd
20
nd
nd
22
20
25
nd
o-Cl-Ph
m-Cl-Ph
p-F-Ph
p-Me-Ph
p-MeO-Ph
38 60:40
0
52 74:26 50 (71)
72 80:20 77 (81)
72 72:28
75 75:25 39 (94)
83 74:26 46
80 80:20 58 (76)
95 73:27 16
66 75:25 39 (94)
56
m-MeO-Ph Ph
4.1. X-ray analysis
Ph
Ph
Ph
p-Cl-Ph
p-Me-Ph
p-MeO-Ph
Single crystals of the (1S,3R,4S)-8a with greater HPLC retention
time suitable for X-ray diffraction were obtained by crystallization
from CHCl3. Crystals of (1R,3S,4R)-8a (C19H19NO, M = 277.35)
are orthorhombic, space group P2(1)2(1)2(1), at 100 K: a =
9.9218(1) Å, b = 11.2198(2) Å, c = 12.9943(3) Å, V = 1446.53(4) Å3,
10
a
Reaction conditions:
7 (1 mmol), 6a–j (1 mmol), argon atmosphere, 48 h,
catalyst (0.05 mmol), CCl4 (3 ml). The yield was detected by NMR as the sum of the
exo- and endo-products. The endo-/exo-ratio was detected by NMR of crude mixture.
Product ee was determined by chiral HPLC analysis.
Z = 4 (Z0 = 1), dcalcd = 1.274 g cmꢀ3
,
l(Cu K
a
) = 0.608 cmꢀ1, F(000) =
b
Configuration of the product was (1S,3R,4S); in the brackets are presented the
product ee after one crystallization.
592. Intensities of 18,481 reflections were measured with a

V. I. Maleev et al. / Tetrahedron: Asymmetry 24 (2013) 178–183
181
BrukerAPEX II Duo CCD diffractometer [k(Cu K
a
) = 1.54178 Å,
x
-
(m, 1H), 2.49 (m, 1H), 2.74 (m, 1H), 2.8 (m, 1H), 4.56 (br s, 1H), 4.66
(d, 1H, J = 2.2), 6.65 (d, 2H, J = 8.18), 6.74 (t, 1H, J = 7.28), 7.18 (m,
2H), 7.29 (m, 4H). tR (min) = 3.06 ((1R,3S,4R)-isomer) and 3.59
((1S,3R,4S)-isomer). Product (1S,3R,4S)-8a was crystallized with
scans, 2h < 134.4°] and 2535 independent reflections [Rint = 0.0203]
were used in further refinement. The structure was solved by di-
rect methods and refined by the full-matrix least-squares tech-
nique against F2 in the anisotropic-isotropic approximation. For
(1S,3R,4S)-8a, the refinement converged to wR2 = 0.0711 and
GOF = 1.050 for all independent reflections (R1 = 0.0257 was calcu-
ee 98% and isolated yield 30%, ½a D25
¼ þ74:6 (c 0.1, CHCl3).
ꢃ
4.4.2. exo-2,3-Diphenyl-2-azabicyclo[2.2.2]octan-5-one
1H NMR (CDCl3, J/Hz): 1.68 (m, 2H), 1.92 (m, 1H), 2.27 (m, 1H),
2.42 (m, 1H), 2.75 (m, 2H), 4.56 (br s, 1H), 4.78 (d, 1H, J = 1.94), 6.6
(d, 2H, J = 8.57), 6.71 (t, 1H, J = 7.28), 7.15 (m, 2H), 7.4 (m, 4H). tR
(min) = 4.16 and 4.68.
lated against F for 2532 observed reflections with I > 2r(I)). The
absolute configuration was established by the Bijvoet pairs analy-
sis; for the (1S,3R,4S)-configuration, the Flack parameter was
0.1(1).18 All calculations were performed using SHELXTL PLUS 5.0.19
4.2. Synthesis of sodium bis[N-salicylideneaminoacidato]-
cobaltates 1–5 (general procedure)
4.4.3. endo-3-(4-Methoxyphenyl)-2-phenyl-2-azabicyclo[2.2.2]
octan-5-one
Salicylaldehyde (or substituted salicylaldehyde) (10 mmol) was
added to a stirred mixture of Na3[Co(CO3)3ꢁ3H2O] (5 mmol) and
(S)-amino acid (10 mmol) in EtOH (25 mL). The reaction mixture
was refluxed for 3 h after which the precipitate was filtered off.
The solvent was removed in vacuo, and the residue was washed
with diethyl ether and dissolved in EtOH. The isomers were
separated by column chromatography (Al2O3, EtOH as eluent).
N
O
OMe
The
K- or D-isomers were additionally purified by gel chromatog-
raphy on Sephadex LH-20 (EtOH/benzene, 1:3). Analytical data of
1H NMR (CDCl3, J/Hz): 1.50–2.80 (m, 7H), 3.77 (s, 3H), 4.54 (br m,
1H), 4.61 (br m, 1H), 6.67 (d, 2H, J = 8.4), 6.84 (d, 2H, J = 8.4),
7.10–7.25 (m, 5H). tR (min) = 5.71 and 6.14. Product with greater
the complexes are presented in our previous work.2
HPLC retention time was crystallized with ee 94%, ½a D25
¼ þ36:4
ꢃ
4.3. Preparation of the acidic form of the cobaltate complexes
(c 0.11, CHCl3).
At first, their sodium salts (0.1 mmol) were dissolved in a 50%
aqueous EtOH (10 mL) and passed through a column (100 ꢂ
20 mm) filled with an ion-exchange resin DOWEX-50Wꢂ8 in H+-
form. After removing the solvents in vacuo and drying over
P2O5, the complexes were used as catalysts without additional
purification.
4.4.4. endo-2-(4-Methoxyphenyl)-3-phenyl-2-azabicyclo[2.2.2]
octan-5-one
OMe
4.4. Asymmetric aza-Diels–Alder reaction (general procedure)
N
A vacuumized Shlenk bulb was heated with a heatgun and
cooled in a dry argon flow to an ambient temperature. A catalyst
(0.01 mmol), cyclohexen-2-one (0.02 mL, 0.2 mmol), and 0.65 ml
of CCl4 were injected into the bulb under Ar. To the resulting solu-
tion after 2 min of stirring, a Schiff base (0.2 mmol) was added. The
reaction mixture was stirred for 48 h at an ambient temperature
under Ar. Then the reaction mixture was passed through a SiO2
layer (Ø 5 ꢂ 30 mm) in AcOEt to remove the catalyst. The chemical
yield and diastereomer ratio were determined by 1H NMR spec-
trometry. Product purification and diastereomer separation were
made by preparative TLC or column chromatography on SiO2
(hexane/AcOEt/Et3N 40:10:1 or PE/AcOEt 4:1). Some of the prod-
ucts were crystallized from PE/AcOEt in order to improve the
enantiomeric purity and determine optical rotations and perform
X-ray structure determination. Assignment of the diastereomeric
products to the endo- or exo-form was made using 1H NMR
spectrometry in accordance with the literature data.20
O
1H NMR (CDCl3, J/Hz): 1.66–1.81 (m, 1H), 1.95–2.35 (m, 3H), 2.46
(dd, 2H, J = 18.8, 2.5), 2.70–2.85 (m, 2H), 3.72 (s, 3H), 4.44 (br m,
1H), 4.58 (d, 1H, J = 2.3), 6.62 (d, 2H, J = 9.1), 6.76 (d, 2H, J = 9.1),
7.15–7.35 (m, 5H). tR (min) = 4.80 and 5.10 min.
4.4.5. exo-2-(4-Methoxyphenyl)-3-phenyl-2-azabicyclo[2.2.2]
octan-5-one
1H NMR (CDCl3, J/Hz): 1.50–2.50 (m, 5H), 2.60–2.85 (m, 2H),
3.70 (s, 3H), 4.44 (br m, 1H), 4.70 (br m, 1H), 6.55 (d, 2H, J = 9.1),
6.74 (d, 2H, J = 9.1), 7.30–7.50 (m, 5H).
4.4.6. endo-2-(4-Chlorophenyl)-3-phenyl-2-azabicyclo[2.2.2]
octan-5-one
ClH
4.4.1. endo-2,3-Diphenyl-2-azabicyclo[2.2.2]octan-5-one
N
O
N
O
1H NMR (CDCl3, J/Hz): 1.50–2.50 (m, 5H), 2.70–2.85 (m, 2H), 4.49
(br m, 1H), 4.61 (d, 1H, J = 2.5), 6.57 (d, 2H, J = 8.7), 7.11 (d, 2H,
J = 8.7), 7.20–7.35 (m, 5H). tR (min) = 4.53 and 4.93. Product with
1H NMR (CDCl3, J/Hz): 1.75 (m, 1H), 2.05 (m, 1H), 2.12 (m, 1H), 2.28

182
V. I. Maleev et al. / Tetrahedron: Asymmetry 24 (2013) 178–183
greater HPLC retention time was crystallized ee 76%, ½a D25
ꢃ
¼ þ53:6
J = 7.2), 7.12–7.33 (m, 6H). tR (min) = 3.75 and 4.55. For the exo-
product 4.52 (br m, 1H), 4.74 (br m, 1H).
(c 0.17, CHCl3).
4.4.7. endo-3-(2-Chlorophenyl)-2-phenyl-2-azabicyclo[2.2.2]
4.4.11. endo-3-(3-Methoxyphenyl)-2-phenyl-2-azabicyclo-
octan-5-one
[2.2.2]octan-5-one
N
N
O
O
Cl
1H NMR (CDCl3, J/Hz): 1.60–2.85 (m, 7H), 4.60 (m, 1H), 5.01 (m,
1H), 6.59 (m, 2H), 6.81 (m, 1H), 7.10–7.55 (m, 6H). tR
(min) = 3.27 and 4.71.
OMe
1H NMR (CDCl3, J/Hz): 1.65–1.85 (m, 1H), 1.95–2.35 (m, 3H), 2.40–
2.55 (m, 1H), 2.65–2.90 (m, 2H), 3.76 (s, 3H), 4.54 (br m, 1H), 4.62
(br m, 1H), 6.60–6.95 (m, 5H), 7.10–7.30 (m, 4H). tR (min) = 5.06
and 5.66.
4.4.8. endo-3-(3-Chlorophenyl)-2-phenyl-2-azabicyclo[2.2.2]-
octan-5-one
4.4.12. endo-3-Phenyl-2-(p-tolyl)-2-azabicyclo[2.2.2]octan-
5-one
Me
N
O
N
O
Cl
1H NMR (CDCl3, J/Hz): 1.65–1.85 (m, 1H), 1.95–2.35 (m, 3H), 2.48
(dd, 1H, J = 19.0, 2.3), 2.65–2.85 (m, 2H), 4.55 (br m, 1H), 4.63 (br
m, 1H), 6.64 (d, 2H, J = 8.2), 6.77 (t, 1H, J = 7.2), 7.13–7.33 (m,
6H). tR (min) = 4.38 and 5.24. Product with greater HPLC retention
1H NMR (CDCl3, J/Hz): 1.60–1.85 (m, 1H), 1.95–2.37 (m, 6H (includ-
ing 2.22 (s, 3H)), 2.40–2.52 (m, 1H), 2.70–2.82 (m, 2H), 4.52 (br m,
1H), 4.62 (d, 1H, J = 2.7), 6.58 (d, 2H, J = 8.4), 6.99 (d, 2H, J = 8.4),
7.20–7.45 (m, 5H). tR (min) = 5.50 and 6.20. For the exo-product
4.52 (br m, 1H), 4.74 (br m, 1H). tR (min) = 3.46 and 4.48.
time was crystallized ee 71%, ½a D25
¼ þ50:8 (c 0.33, CHCl3).
ꢃ
4.4.9. endo-3-(4-Fluorophenyl)-2-phenyl-2-azabicyclo[2.2.2]-
octan-5-one
5. Crystallographic data
CCDC 885213 contains the supplementary crystallographic data
for (1R,3S,4R)-8a. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge, CB21EZ, UK; or deposit@
ccdc.cam.ac.uk).
N
O
Acknowledgments
F
1H NMR (CDCl3, J/Hz): 1.65–1.85 (m, 1H), 1.95–2.35 (m, 3H),
2.40–2.55 (m, 1H), 2.65–2.85 (m, 2H), 4.55 (br m, 1H), 4.64 (br
m, 1H), 6.65 (d, 2H, J = 8.3), 6.76 (t, 1H, J = 7.5), 7.00 (dd, 2H,
J = 8.6, 8.6), 7.19 (dd, 2H, J = 7.5, 8.3), 7.23–7.33 (m, 2H). tR
(min) = 4.84 and 5.60. For exo-isomer tR (min) = 3.64 and 4.36.
This work was financially supported by the RFBR grant
09-03-00730 and P-8 Program of Basic Research of Presidium
RAS. We gratefully thank Professor Yuri N. Belokon for valuable
discussions and recommendations during article preparation and
Ivan Ananyev and Professor Konstantin A. Lyssenko for the X-ray
diffraction investigation.
4.4.10. endo-2-Phenyl-3-(p-tolyl)-2-azabicyclo-[2.2.2]octan-5-
one
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