Preparation of planar chiral amino phenols based on the [2.2]paracyclophane backbone

Article abstract of DOI:10.1016/S0957-4166(01)00497-9

The synthesis of various planar and central chiral secondary and tertiary amino phenols based on the [2.2]paracyclophane backbone is described. Planar chiral tertiary amino phenols are prepared by reductive amination of 5-formyl-4-hydroxy[2.2]paracyclopha

Full text of DOI:10.1016/S0957-4166(01)00497-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2845–2850
Preparation of planar chiral amino phenols based on the
[2.2]paracyclophane backbone
Stefan Dahmena and Stefan Bra¨seb,*
aInstitut fu¨r Organische Chemie der Rheinisch-Westfa¨lischen Technischen Hochschule Aachen, Professor-Pirlet-Straße 1,
D-52074 Aachen, Germany
bKekule´-Institut fu¨r Organische Chemie und Biochemie der Rheinischen Friedrich-Wilhelms-Universita¨t Bonn,
Gerhard-Domagk-Straße 1, D-53121 Bonn, Germany
Received 17 October 2001; accepted 2 November 2001
Abstract—The synthesis of various planar and central chiral secondary and tertiary amino phenols based on the
[2.2]paracyclophane backbone is described. Planar chiral tertiary amino phenols are prepared by reductive amination of
5-formyl-4-hydroxy[2.2]paracyclophane (FHPC) with secondary amines. The reduction of imine and ketimine precursors, as well
as the 1,2-addition to these compounds is also described. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
ketimine precursors, by 1,2-addition or by reductive
amination. Herein, we report on the results of that
study.
The element of planar chirality plays an important role
in many modern ligand systems.1–3 However, the major-
ity of planar chiral ligands is based on ferrocene
derivatives2 or arene transition metal complexes.3 So
far, only limited attention has been paid to planar
chiral ligands derived from [2.2]paracyclophane.4
2. Results and discussion
One of the three key intermediates of our strategy is the
5-formyl-4-hydroxy[2.2]paracyclophane
4
(FHPC),
Amino alcohol ligands are among the most versatile
precursors for catalysts and can be applied in a variety
of catalytic asymmetric reactions.5 While the number of
simple central chiral amino alcohols is very high
because of their availability from natural sources or
asymmetric synthesis (e.g. approximately 500 amino
alcohols or amino alcohol derivatives have recently
been review by Pu and Yu6 as ligands in diethyl zinc
additions to aldehydes), examples of more complex
molecules such as planar chiral ferrocenes or axial
chiral binaphthalenes are much fewer. The field of
amino alcohol ligands based on the [2.2]paracyclophane
backbone is more or less undeveloped.
which can be regarded as a planar chiral analogue of
salicylaldehyde. The compound was first prepared by
Rozenberg, Belokon et al.7 followed by a number of
reports on alternative routes to the racemic as well as
the enantiomerically pure compound.8
The synthesis of FHPC was carried out according to
Scheme 1 in a multi-stage reaction: bromination of the
unsubstituted [2.2]paracyclophane 1, lithium–halogen
exchange with n-BuLi, quenching of the organometallic
intermediate with trimethyl borate, and oxidative work-
up furnished the hydroxy[2.2]paracyclophane 3.7b,9 The
ortho-formylation of 3 catalyzed by SnCl4 and Bu3N
according to the procedure of Belokon, Rozenberg et
al.7b to give 4 only proceeds to 20–30% conversion.
Although various Lewis acids were screened and the
ratio of Lewis acid to amine was varied, we could not
find better conditions.
As part of an ongoing study of [2.2]paracyclophane
ligands in asymmetric catalysis, we have synthesized a
variety of different secondary and tertiary amino phe-
nols as potential ligands, either by reduction of imine or
We therefore chose to use the method of Hopf and
Barrett,8a which proceeds via the formation of a
* Corresponding author. Tel.: +49 228 732653; fax: +49 228 739608;
e-mail: braese@uni-bonn.de
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00497-9

2846
S. Dahmen, S. Bra¨se / Tetrahedron: Asymmetry 12 (2001) 2845–2850
i
ii-iv
v-viii
55%
ix
+
98%
88%
N
N
O
Br
OH
OH
OH
HO
(Sp,S)-5
1
(Rp,S)-5
2
3
4
FHPC
x
xi
R
R
R
+
quant.
O
N
N
OH
OH
HO
6 (R = Me) AHPC
7 (R = Ph)
(Rp,S)-8 (R = Me)
(Rp,S)-9 (R = Ph)
(Sp,S)-8 (R = Me)
(Sp,S)-9 (R = Ph)
Scheme 1. Preparation of racemic and enantiomerically pure FHPC 4, AHPC 6 and 5-benzoyl-4-hydroxy[2.2]paracyclophane 7.
In the resolution step, only the condensation with (S)-phenylethylamine is shown for clarity. (i) Br2, Fe, CH2Cl2, reflux, 20 h; (ii)
n-BuLi, THF, −50°C, 3 h; (iii) B(OCH3)3; (iv) H2O2, KOH; (v) diethylcarbamoyl chloride, DMAP, toluene, reflux, 16 h; (vi)
s-BuLi, TMEDA, THF, −78°C, 3 h; (vii) DMF, −78°C to rt, 12 h; (viii) HCl (aq.); (ix) (S)-phenylethylamine, toluene, reflux, 40
h; (x) TiCl4, RCOCl, CH2Cl2, 0°C to rt, 2 h; (xi) (S)-phenylethylamine, Bu2SnCl2 (R=Me) or TiCl4 (R=Ph), toluene, reflux,
16–40 h.7,9,10
diethylcarbamate. ortho-Deprotonation of the latter
with s-BuLi/TMEDA and subsequent reaction with
DMF, delivered, after acidic work-up, the desired
racemic FHPC ( )-4 (Scheme 1).
Although the latter is a diastereomer of (Rp,S)-8 with
opposite configuration of the planar chiral backbone,
the outcome of the reaction should be determined by
the backbone thus giving the (S)-configured product
with respect to the newly formed stereocenter.
The other key intermediates were the 5-acetyl-4-
hydroxy[2.2]paracyclophane
6
and
5-benzoyl-4-
hydroxy[2.2]paracyclophane 7, which were synthesized
by ortho-selective Friedel–Crafts acylation of phenol
3.10 The resolution of ( )-4,7 ( )-6 and ( )-710 was
conducted according to literature procedures via their
imines 5 or ketimines 8 and 9 with (S)- or (R)-
phenylethylamine, respectively (Scheme 1). Enantiomer-
ically pure 4 and 6 were obtained by hydrolysis of the
corresponding imines and ketimines.
i
(Sp,R)-5
65%
NH
HO
(Sp,R)-10
i
(Sp,S)-5
2.1. Reduction of imines and ketimines
84%
NH
HO
The reduction of imines based on 4 was carried out
under standard conditions with sodium borohydride in
methanol at room temperature. The reaction proceeded
smoothly affording the secondary amino phenols 10 in
good yields (65–84%) (Scheme 2).
(Sp,S)-10
Scheme 2. Reduction of diastereomeric imines 5. (i) NaBH4,
MeOH, rt, 12 h.
However, reduction of the ketimines was much slower
(Scheme 3). The addition of acetic acid to the reaction
mixture improved the formation of the product amino
phenols. Ketimine (Rp,S)-8 bearing a methyl sub-
stituent in the side chain was transformed to the
product (Rp,R,S)-11 with complete stereoselectivity
regarding the newly formed stereogenic center (>98%
d.e.). This corresponds to attack of borohydride from
the unhindered ‘bottom side’ of the paracyclophane
while the paracyclophane backbone efficiently shields
the other side of the imine double bond. To test the
dependency of the selectivity of the reduction on the
size of the substituents in the side chain, ketimine
(Sp,S)-9 was also subjected to these reaction conditions.
As expected, the larger phenyl ring of (Sp,S)-9 interacts
with the attacking borohydride much more strongly
than the small methyl group leading to a diminished
stereoselectivity of 78% d.e. (Scheme 3).
2.2. 1,2-Addition to imines and ketimines
A further reaction yielding secondary amino phenols is
the 1,2-addition to imines. As the stereochemical con-
siderations are the same as for the borohydride reduc-
tion (Scheme 3), the attack of the nucleophile again
occurs from the unhindered side of the paracyclophane.

S. Dahmen, S. Bra¨se / Tetrahedron: Asymmetry 12 (2001) 2845–2850
2847
2.3. Reductive amination
i
(Rp,S)-8
Reductive amination is a powerful method for the
selective formation of secondary and tertiary amines.
As secondary amino phenols could be obtained by
reduction of the imine precursors in an acceptable
fashion, the direct reductive amination of FHPC with
secondary amines was examined.
>98% de
70%
HN
OH
(Rp,R,S)-11
Ph
i
(Sp,S)-9
The reaction proceeded smoothly in the presence of 5
equiv. of amine and 2 equiv. of HCl with Na(CN)BH3
as reductant. The presence of HCl was necessary to
form the iminium cation intermediate, which is the
species that is selectively reduced by cyanoborohydride.
78% de
98%
NH
HO
(Sp,S,S)-12
Compound (Sp)-14 is a stable amino phenol, which was
obtained as a white solid after chromatography on
silica (Scheme 5). The less hindered amino phenols
(Rp)-15 and (Rp)-16 however, are unusually acid sensi-
tive and decompose on silica. Analytically pure samples
could be obtained by chromatography on neutral alu-
minum oxide. The decomposition products obtained
indicate, that upon protonation of the tertiary amine
moiety, elimination and subsequent reactions of the
paracyclophanyl methyl cation take place.
R
N
HO
BH4
favoured
Scheme 3. Reduction of ketimines 8 and 9. (i) NaBH4,
AcOH, MeOH, rt, 5–12 h. The [2.2]paracyclophane backbone
shields the upper side of the imine double bond.
i
(Sp)-4
82%
Thus, the resulting amino phenol product (Sp,R,S)-11
(Scheme 4) has the opposite configuration at the newly
formed stereogenic center compared to the products
obtained from the reduction of ketimines (Scheme 3).
These methods are therefore complementary for the
introduction of chirality in the paracyclophane side
chain.11
N
HO
(Sp)-14
i
(Rp)-4
However, the ketimine double bond was resistant to
addition reactions ((Sp,S)-8 in Scheme 4). Even in the
presence of several equivalents of methyl lithium at
room temperature, no reaction was observed and the
starting material was recovered quantitatively after
work-up.
35%
N
OH
(Rp)-15
i
(Rp)-4
48%
N
OH
i
(Sp,S)-5
>98% de
84%
(Rp)-16
NH
HO
Scheme 5. Reductive amination. (i) Amine (5 equiv.), conc.
HCl (2 equiv.), Na(CN)BH3 (2 equiv.), MeOH, rt, 5–12 h.
(Sp,R,S)-11
i
3. Conclusion
(Sp,S)-8
NH
HO
In conclusion, we have demonstrated the formation of
secondary and tertiary amino phenols based on the
[2.2]paracyclophane backbone. Secondary amino phe-
nols were synthesized by reduction of imines or 1,2-
addition. Tertiary amino phenols could be obtained by
reductive amination of FHPC 4 with secondary amines.
(Sp,S)-13
Scheme 4. 1,2-Addition to imines and ketimines. (i) MeLi,
THF, −78°C to rt, 12 h.

2848
S. Dahmen, S. Bra¨se / Tetrahedron: Asymmetry 12 (2001) 2845–2850
The tertiary amino phenol products 14–16 are espe-
cially interesting as chiral catalytic ligands for e.g. the
addition of diethylzinc to aldehydes12 and transfer
hydrogenation reactions. The application of the amino
phenols described herein as catalyst precursors is under
examination and the results will be reported soon.
125.98 (t), 126.43 (t), 126.93 (t), 127.25 (t), 128.55 (t),
132.24 (t), 132.81 (t), 132.88 (t), 137.35 (q), 138.97 (q),
139.68 (q), 143.42 (q), 156.38 (q, C-4) ppm; IR (KBr):
w=3305 (OH), 1598, 1430 cm−1; MS (70 eV, EI), m/z
(%): 357 (100) [M+], 253 (24), 236 (25), 148 (26); 104
(72); HRMS C25H27NO calcd: 357.2093, found:
357.2092.
4. Experimental
4.1. General
4.2.2. (Sp,S)-5-[(1%-Phenylethylamino)methyl]-4-hydroxy-
[2.2]paracyclophane (Sp,S)-10. The reaction was carried
out as described for (Sp,R)-10 starting from (Sp,S)-5-
[(1%-phenylethylimino)methyl]-4-hydroxy[2.2]paracyclo-
phane (Sp,S)-5 (100 mg, 0.29 mmol). After chromatog-
raphy on silica (1.7×20 cm, dichloromethane), the title
compound was obtained as an oil (87 mg, 84%); Rf=
0.32 (pentane/ether=1:1); [h]2D0=−131 (c 0.5, CHCl3);
1H NMR (400 MHz, CDCl3): l 1.38 (d, J=6.8 Hz, 3H,
CH3), 2.44–2.66 (m, 3H), 2.71–2.85 (m, 1H), 2.91–3.10
(m, 3H), 3.19 (d, J=14.0 Hz, 1H, pcCHHN), 3.28–3.37
(m, 1H), 3.54 (d, J=14.0 Hz, 1H, pcCHHN), 3.66 (q,
J=6.6 Hz, 1H, NCH(CH3)Ph), 6.09 (d, J=7.7 Hz,
1H), 6.21 (d, J=8.0 Hz, 1H), 6.39 (d, 7.7 Hz, 1H), 6.43
(s, br, 2H), 6.67 (d, br, J=8.0 Hz, 1H), 7.29–7.46 (m,
5H, HAr) ppm; 13C NMR (100 MHz, CDCl3): l 23.55
(p, NCH(CH3)Ph), 29.74 (s), 32.51 (s), 33.80 (s), 33.87
(s, C-1, C-2, C-9, C-10), 46.99 (s, pcCH2N), 57.41 (t,
NCH(CH3)Ph), 122.16 (q), 124.04 (t), 125.70 (q),
126.09 (t), 126.67 (t), 126.95 (t), 127.49 (t), 128.59 (t),
132.08 (t), 132.55 (t), 132.76 (t), 137.11 (q), 139.25 (q),
139.54 (q), 143.00 (q), 156.46 (q, C-4) ppm; IR (KBr):
w=3306 (OH), 1598, 1566, 1420 cm−1; MS (70 eV, EI),
m/z (%): 357 (100) [M+], 253 (24), 236 (25), 148 (269;
104 (72); HRMS C25H27NO calcd: 357.2093, found:
357.2092.
All chemicals and solvents were used as received unless
otherwise stated. THF (Na, benzophenone), toluene
(Na, benzophenone), CH2Cl2 (CaH2), methanol (Mg)
were distilled under argon from the drying agent indi-
1
cated. H and 13C NMR spectra were recorded with a
Varian VXR 300 (300/75 MHz), Varian Unity 500
(500/125 MHz), Varian Inova (400/100 MHz) or Gem-
ini 300 S (300/75 MHz) instrument. Abbreviations for
1H NMR: s=singlet, d=doublet, t=triplet, m=multi-
plet, pc=paracyclophane backbone; abbreviations for
13C NMR: p=primary, s=secondary, t=tertiary, q=
quaternary carbon atom as determined by ATP and
DEPT experiments. Preparative liquid chromatography
was performed on straight phase silica gel (Merck 60,
230–400 mesh, 0.040–0.063 mm) or on neutral alu-
minum oxide (Merck, 60 PF254 Type E), with the eluent
indicated. IR spectra were recorded on a Perkin–Elmer
FT-IR 1750. Mass spectra were recorded on a Finnigan
SSQ 7000 and HRMS on a Finnigan MAT 95, respec-
tively. Optical rotations were measured with a Perkin–
Elmer P 241 polarimeter in a 10 cm cell with the solvent
indicated. FHPC 4, AHPC
6 and 5-benzoyl-4-
hydroxy[2.2]paracyclophane 7 were synthesized and
resolved using literature procedures.7,9,10
4.2.3.
(Rp,R,S)-5-[1%-(1¦-Phenylethylamino)ethyl]-4-
4.2. Reduction of imines and ketimines
hydroxy[2.2]paracyclophane 11. To a solution of (Rp,S)-
[1%-(1¦-phenylethylamino)ethyl]-4-hydroxy[2.2]paracyclo-
phane (Rp,S)-8 (100 mg, 0.27 mmol) in methanol/
dichloromethane (2:1, 30 mL) was added NaBH4 (38
mg, 1 mmol) at rt and dropwise conc. acetic acid (0.1
mL). The mixture was stirred for 5 h. After quenching
with water, the mixture was extracted with
dichloromethane and the combined organic layers were
dried over MgSO4. Chromatography on silica (1.7×20
cm, dichloromethane) afforded the title compound as a
white solid (70 mg, 70%): Rf=0.32 (pentane/ether=
4.2.1. (Sp,R)-5-[(1%-Phenylethylamino)methyl]-4-hydroxy-
[2.2]paracyclophane (Sp,R)-10. To a solution of (Sp,R)-5
- [(1% - phenylethylimino)methyl] - 4 - hydroxy[2.2]para-
cyclophane (Sp,R)-5 (100 mg, 0.29 mmol) in methanol
(4 mL) was added NaBH4 (38 mg, 1 mmol) at rt and
the mixture was stirred for 12 h. After quenching with
water, the mixture was extracted with dichloromethane
and the combined organic layers were dried over
MgSO4. Chromatography on silica (1.7×20 cm,
dichloromethane) afforded the title compound as a
white solid (65 mg, 65%): Rf=0.32 (pentane/ether=
1
1:1); [h]2D0=+86 (c 1.0, CHCl3); H NMR (400 MHz,
CDCl3): l 1.03 (d, J=6.6 Hz, 3H, NCH(CH3)Ph), 1.59
(d, J=6.9 Hz, 3H, pcCH(CH3)N), 2.53–2.62 (m, 1H),
2.69–2.78 (m, 1H), 2.82–2.91 (m, 1H), 3.00–3.20 (m,
4H), 3.38–3.45 (m, 1H), 4.04 (q, J=6.6 Hz, 1H,
NCH(CH3)Ph), 4.14 (q, br, J=6.3 Hz, 1H,
pcCH(CH3)N), 6.07 (d, J=7.7 Hz, 1H), 6.28 (d, J=7.4
Hz, 1H), 6.50 (m, 2H), 6.64 (dd, J=7.7 Hz, 1.6 Hz,
1H), 6.91 (dd, J=8.0 Hz, 1.9 Hz, 1H), 7.31–7.46 (m,
5H, HAr) ppm; 13C NMR (100 MHz, CDCl3): l 23.75
(p, NCH(CH3)Ph and pcCH(CH3)N), 30.06 (s), 32.64
(s), 34.08 (s), 34.70 (s, C-1, C-2, C-9, C-10), 53.99 (s,
pcCH2N), 56.39 (t, NCH(CH3)Ph), 125.92 (t), 126.14
(t), 127.46 (t), 127.51 (t), 127.82 (q), 128.94 (t), 129.68
1
1:1); [h]2D0=−146 (c 1.2, CHCl3); H NMR (400 MHz,
CDCl3): l 1.46 (d, J=6.6 Hz, 3H, CH3), 2.51–2.66 (m,
3H), 2.78–2.87 (m, 1H), 2.94–3.10 (m, 3H), 3.23 (d,
J=13.2 Hz, 1H, pcCHHN), 3.29–3.37 (m, 1H), 3.58 (d,
J=13.2 Hz, 1H, pcCHHN), 3.83 (q, J=6.6 Hz, 1H,
NCH(CH3)Ph), 6.07 (d, J=7.7 Hz, 1H), 6.37 (d, J=7.7
Hz, 1H), 6.44–6.51 (m, 3H), 6.57 (dd, J=7.7 Hz, 1.6
Hz, 1H), 6.85 (dd, J=8.0 Hz, 1.7 Hz, 1H), 7.18–7.35
(m, 5H, HAr) ppm; 13C NMR (100 MHz, CDCl3): l
22.87 (p, NCH(CH3)Ph), 29.70 (s), 32.56 (s), 33.94 (s),
34.07 (s, C-1, C-2, C-9, C-10), 47.13 (s, pcCH2N), 57.67
(t, NCH(CH3)Ph), 122.75 (q), 124.09 (t), 125.73 (q),

S. Dahmen, S. Bra¨se / Tetrahedron: Asymmetry 12 (2001) 2845–2850
2849
(t), 132.74 (t), 133.96 (t), 134.02 (t), 137.26 (q), 138.35
(q), 140.60 (q), 144.43 (q), 155.71 (q, C-4) ppm; IR
(KBr): w=3309 (OH), 1593, 1566, 1430 cm−1; MS (70
eV, EI), m/z (%): 371 (100) [M+], 145 (96), 104 (97);
HRMS C26H29NO calcd: 371.2249, found: 371.2250.
127.11 (t), 127.57 (t), 127.68 (q), 128.79 (t), 129.16 (t),
132.43 (t), 133.77 (t), 134.11 (t), 136.92 (q), 138.22 (q),
140.21 (q), 142.86 (q), 155.34 (q, C-4) ppm; IR (KBr):
w=3309 (OH), 1593, 1565, 1430 cm−1; MS (70 eV, EI),
m/z (%): 371 (94) [M+], 145 (100), 105 (31), 104 (99);
HRMS C26H29NO calcd: 371.2249, found: 371.2249.
4.2.4. (Sp,S,S)-5-[Phenyl-(1%-phenylethylamino)methyl]-4-
hydroxy[2.2]paracyclophane 12. To a solution of (Sp,S)-
5-[phenyl-(1%-phenylethylimino)methyl]-4-hydroxy[2.2]-
paracyclophane (Sp,S)-9 (100 mg, 0.23 mmol) in etha-
nol (10 mL) was added at rt NaBH4 (38 mg, 1 mmol)
and the mixture was stirred for 2 h. After quenching
with water, the mixture was extracted with dichloro-
methane and the combined organic layers were dried
over MgSO4. After removal of the solvent, the title
compound was obtained as a yellow oil (98 mg,
4.4. Reductive amination
4.4.1.
(Sp)-5-[(Dibenzylamino)methyl]-4-hydroxy[2.2]-
paracyclophane (Sp)-14. To a solution of (Sp)-5-formyl-
4-hydroxy[2.2]paracyclophane (Sp)-4 (72 mg, 0.28
mmol) in methanol (10 mL) was added dibenzylamine
(274 mg, 1.4 mmol) and 5 M HCl (100 mL) at rt. After
stirring for 0.5 h, Na(CN)BH3 (21 mg, 0.33 mmol) was
added and the mixture was stirred for a further 2 h. The
mixture was quenched with water, neutralized with
NaHCO3 solution and extracted several times with
dichloromethane. After chromatography on silica (1.7×
20 cm, dichloromethane), the title compound was
obtained as a white solid (100 mg, 82%): Rf=0.58
1
98%): major diastereomer (d.e.=78%); H NMR (400
MHz, CDCl3): l 1.63 (d, J=6.6 Hz, 3H, CH3), 2.41–
2.51 (m, 1H), 2.54–2.64 (m, 1H), 2.73–2.92 (m, 2H),
3.00–3.23 (m, 3H), 3.39–3.47 (m, 1H, C-1, C-2, C-9,
C-10), 4.00 (q, br, J=6.6 Hz, 1H, NCH(CH3)Ph), 4.86
(s, 1H, pcCH(Ph)N), 5.97 (d, J=7.4 Hz, 1H), 6.30 (d,
J=7.7 Hz, 1H), 6.52 (dd, J=8.0 Hz, 1.6 Hz, 1H), 6.61
(dd, J=7.7 Hz, 1.9 Hz, 1H), 6.78 (dd, J=7.7 Hz, 1.9
Hz, 1H), 6.97–7.02 (m, 2H, HAr), 7.04 (dd, J=7.7 Hz,
1.6 Hz, 1H, Hpc), 7.12–7.40 (m, 8H, HAr) ppm; 13C
NMR (100 MHz, CDCl3): l 22.25 (p, NCH(CH3)Ph),
29.99 (s), 33.69 (s), 34.02 (s), 34.17 (s, C-1, C-2, C-9,
C-10), 55.20 (t, NCH(CH3)Ph), 62.89 (t, pcCH(Ph)N),
123.66 (q), 125.79 (t), 126.26 (t), 126.31 (t), 127.08 (t),
127.19 (t), 127.36 (t), 127.43 (t), 127.65 (q), 128.50 (t),
128.65 (t), 128.68 (t), 132.30 (t), 133.68 (t), 138.04 (q),
138.65 (t), 140.25 (q), 143.16 (q), 143.50 (q), 156.75 (q,
C-4) ppm.
1
(dichloromethane); [h]2D0=−93 (c 1.0, CHCl3); H NMR
(400 MHz, CDCl3): l 2.43–2.58 (m, 2H, Hpc), 2.61–2.70
(m, 1H, Hpc), 2.91–3.01 (m, 3H, Hpc), 3.10 (d, J=13.2
Hz, 2H, NCH2Ph), 3.18 (d, J=14.6 Hz, 1H, NCH2pc),
3.28–3.36 (m, 1H, Hpc), 3.39 (d, J=14.3 Hz, 1H,
NCH2pc), 3.95 (d, J=12.9 Hz, 2H, NCH2Ph), 5.84 (d,
J=8.0 Hz, 1H, Hpc), 6.11 (d, J=7.7 Hz, 1H, Hpc), 6.33
(d, br, J=7.7 Hz, 1H, Hpc), 6.40 (d, J=7.7 Hz, 1H,
Hpc), 6.41 (m, br, 2H, Hpc), 7.27–7.42 (m, 10H, HAr)
ppm; 13C NMR (100 MHz, CDCl3): l 30.35, 33.10,
34.14, 34.18 (C-1, C-2, C-9, C-10), 53.87 (C-17), 58.82
(C-18), 121.21 (q), 124.61 (t), 125.92 (q), 126.14 (t),
127.43 (t, all C-Arpc), 128.01 (t), 128.86 (t), 130.00 (t, all
C-Ar), 132.40 (t), 132.87 (t), 133.04 (t, all C-Arpc),
137.06 (q), 137.16 (q), 139.78 (q), 140.01 (q), 156.55
(C-4) ppm; IR (KBr): w=3026, 1599, 1566, 1497, 1447,
1431 cm−1; MS (70 eV, EI), m/z (%): 433 (100) [M+],
329 (51), 238 (21), 196 (20), 106 (23), 104 (64), 91 (54);
HRMS C31H31NO calcd: 433.2406, found: 433.2406.
4.3. 1,2-Addition to imines
4.3.1.
hydroxy[2.2]paracyclophane (Sp,S,R)-11. To a solution
of (Sp,S)-5-[(1%-phenylethylimino)methyl]-4-hydroxy-
(Sp,S,R)-5-[1%-(1¦-Phenylethylamino)ethyl]-4-
[2.2]paracyclophane (Sp,S)-5 (55 mg, 0.15 mmol) in
THF (10 mL) was added at −78°C methyllithium (1
mL, 5% in Diethylether, 1.6 mmol) under argon. The
solution was allowed to warm to rt over 15 h. The
mixture was quenched with water and extracted with
dichloromethane. After drying over MgSO4 and
removal of the solvent, the title compound was
obtained as a white solid (50 mg, 84%): Rf=0.33 (pen-
4.4.2.
(Rp)-5-[(Benzylmethylamino)methyl]-4-hydroxy-
[2.2]paracyclophane (Rp)-15. To a solution of (Rp)-5-for-
myl-4-hydroxy[2.2]paracyclophane (Rp)-4 (100 mg, 0.40
mmol) in 10 mL of methanol was added at rt methyl-
benzylamine (242 mg, 2.0 mmol) and conc. HCl (80
mL). After stirring for 0.5 h, Na(CN)BH3 (50 mg, 0.80
mmol) was added and the mixture was stirred for a
further 2 h at rt. The mixture was quenched with water,
neutralized with NaHCO3 solution and extracted sev-
eral times with dichloromethane. After chromatography
on neutral aluminum oxide (1.7×20 cm, pentane/
ether=9:1), the title compound was obtained as a white
solid (50 mg, 35%): Rf=0.6 (pentane/ether=9:1, neu-
1
tane/ether=1:1); [h]2D0=−140 (c 1.0, CHCl3); H NMR
(400 MHz, CDCl3): l 1.10 (d, J=6.3 Hz, 3H,
NCH(CH3)Ph), 1.59 (d, J=6.6 Hz, 3H, pcCH(CH3)N),
2.50–2.63 (m, 3H), 2.84–2.93 (m, 1H), 2.97–3.07 (m,
2H), 3.10–3.18 (m, 1H), 3.39–3.47 (m, 1H), 3.73 (q,
J=6.6 Hz, 1H, NCH(CH3)Ph), 3.99 (q, br, J=6.3 Hz,
1H, pcCH(CH3)N), 6.05 (d, J=7.7 Hz, 1H), 6.20 (dd,
J=8.0 Hz, 1.9 Hz, 1H), 6.28 (d, J=7.7 Hz, 1H), 6.46
(dd, J=8.0 Hz, 1.9 Hz, 1H), 6.56 (dd, J=8.0 Hz, 1.9
Hz, 1H), 7.33–7.51 (m, 5H, HAr) ppm; 13C NMR (100
MHz, CDCl3): l 20.29 (p, NCH(CH3)Ph), 24.29 (p,
pcCH(CH3)N), 30.08 (s), 32.92 (s), 33.96 (s), 34.45 (s,
C-1, C-2, C-9, C-10), 51.31 (t, pcCH(CH3)N), 53.98 (t,
NCH(CH3)Ph), 125.91 (q), 126.25 (t), 126.27 (q),
1
tral alox); [h]2D0=+132 (c 1.6, CHCl3); H NMR (400
MHz, CDCl3): l 2.18 (s, 3H, CH3), 2.51–2.74 (m, 3H),
2.94–3.08 (m, 4H), 3.24 (d, J=14.0 Hz, 1H, NCH2Ar),
3.28–3.36 (m, 2H), 3.38 (d, J=14.0 Hz, 1H, NCH2Ar),
3.74 (d, J=12.6 Hz, 1H, NCH2Ar), 6.11 (d, J=7.7 Hz,
1H), 6.28 (d, br, J=7.7 Hz, 1H), 6.41 (d, J=7.7 Hz,
1H), 6.47 (s, br, 2H), 6.66 (d, br, J=8.0 Hz, 1H),
7.27–7.40 (m, 5H, HAr) ppm; 13C NMR (100 MHz,
CDCl3): l 29.96, 32.78, 34.15 (C-1, C-2, C-9, C-10),

2850
S. Dahmen, S. Bra¨se / Tetrahedron: Asymmetry 12 (2001) 2845–2850
42.29 (p, CH3), 57.50 (s, pcCH2N), 61.97 (s, br,
NCH2Ar), 121.45 (q), 124.34 (t), 125.67 (q), 126.11 (t),
127.24 (t), 127.80 (t), 128.64 (t, C-Ar), 129.52 (t, C-Ar),
132.44 (t), 132.88 (t), 133.00 (t), 137.00 (q), 137.32 (q),
139.64 (q), 139.89 (q), 156.48 (C-4) ppm; IR (KBr):
w=3064, 1600, 1569, 1498, 1454, 1423 cm−1; MS (70 eV,
EI), m/z (%): 357 (100) [M+], 253 (67), 120 (32), 104
(69), 91 (22); HRMS C25H27NO calcd: 357.2093, found:
357.2093.
Quici, S. J. Mol. Catal. A 1996, 113, 77; (b) Belokon, Y.;
Moscalenko, M.; Ikonnikov, N.; Yashkina, L.; Antonov,
D.; Vorontsov, E.; Rozenberg, V. Tetrahedron: Asymmetry
1997, 19, 3245; (c) Pye, P. J.; Rossen, K.; Reamer, R. A.;
Tsou, N. N.; Volante, R. P.; Reider, P. J. J. Am. Chem.
Soc. 1997, 119, 6207; (d) Rossen, K.; Pye, P. J.; Maliakal,
A.; Volante, R. P. J. Org. Chem. 1997, 62, 6462; (e) Pye,
P. J.; Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider,
P. J. Tetrahedron Lett. 1998, 39, 4441; (f) Vetter, A. H.;
Berkessel, A. Tetrahedron Lett. 1998, 39, 1741; (g) Wo¨rs-
do¨rfer, U.; Vo¨gtle, F.; Nieger, M.; Waletzke, M.; Grimme,
S.; Glorius, F.; Pfaltz, A. Synthesis 1999, 597; (h) Wo¨rsdo¨r-
fer, U.; Vo¨gtle, F.; Glorius, F.; Pfaltz, A. J. Prakt. Chem.
1999, 341, 445; (i) Masterson, D. S.; Hobbs, T. L.;
Glatzhofer, D. T. J. Mol. Catal. A: Chem. 1999, 145, 75;
(j) Masterson, D. S.; Glatzhofer, D. T. J. Mol. Catal. A:
Chem. 2000, 161, 65; (k) Hou, X.-L.; Wu, X.-W.; Dai, L.-X.;
Cao, B.-X.; Sun, J. Chem. Commun. 2000, 1195; (l) Burk,
M. J.; Hems, W.; Herzberg, D.; Malan, C.; Zanotti-Gerosa,
A. Org. Lett. 2000, 2, 4173; (m) Bolm, C.; Ku¨hn, T. Synlett
2000, 899; (n) Rozenberg, V. I.; Antonov, D. Y.; Zhuravsky,
R. O.; Vorontsov, E. V.; Khrustalev, V. N.; Ikonnikov, N.
S.; Belokon, Y. N. Tetrahedron: Asymmetry 2000, 11, 2683;
(o) Tanji, S.; Ohno, A.; Sato, I.; Soai, K. Org. Lett. 2001,
3, 287; (p) Wu, X.-W.; Hou, X.-L.; Dai, L.-X.; Tao, J.; Cao,
B.-X.; Sun, J. Tetrahedron: Asymmetry 2001, 12, 529.
5. For a recent review of diethylzinc additions, see: Ref. 6.
For recent examples of transfer hydrogenation, see: (a)
Petra, D. G. I.; Reek, J. N. H.; Handgraaf, J.-W.; Meijer,
E. J.; Dierkes, P.; Kamer, P. C. J.; Brussee, J.; Schoemaker,
H. E.; van Leeuwen, P. W. N. M. Chem. Eur. J. 2000, 6,
2818; (b) Alonso, D. A.; Brandt, P.; Nordin, S. J. M.;
Andersson, P. G. J. Am. Chem. Soc. 1999, 121, 9580. For
CBS reduction of ketones, see: (c) Corey, E. J.; Bakshi, R.
K.;Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551;(d)Corey,
E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K.
J. Am. Chem. Soc. 1987, 109, 7925.
4.4.3.
(Rp)-5-[(Piperidinyl)methyl]-4-hydroxy[2.2]para-
cyclophane (Rp)-16. To a solution of (Rp)-5-formyl-4-
hydroxy[2.2]paracyclophane (Rp)-4 (100 mg, 0.40
mmol) in methanol (10 mL) at rt was added piperidine
(170 mg, 2.0 mmol) and conc. HCl (80 mL). After
stirring the mixture for for 0.5 h, Na(CN)BH3 (50 mg,
0.80 mmol) was added and the mixture was stirred for
another 2 h at rt. The reaction was quenched with
water, neutralized with NaHCO3 solution and extracted
several times with dichloromethane. After chromatog-
raphy on neutral aluminum oxide (1.7×20 cm, pentane/
ether=9:1), the title compound was obtained as a white
solid (60 mg, 48%): Rf=0.5 (pentane/ether=9:1, neu-
1
tral alox); [h]2D0=+207 (c 1.0, CHCl3); H NMR (400
MHz, CDCl3): l 1.4 (s, br, 1H, OH), 1.52 (s, br, 6H),
2.44 (s, br, 4H, all H-piperidyl), 2.52–2.60 (m, 1H),
2.65–2.74 (m, 2H), 2.95–3.09 (m, 4H), 3.27–3.35 (m,
1H), 3.27 (d, J=12.0 Hz, 2H, NCH2pc), 6.09 (d, J=7.7
Hz, 1H), 6.40 (d, J=7.7 Hz, 1H), 6.52 (m, 2H), 6.68
(dd, J=7.7 Hz, 1.4 Hz, 1H), 6.83 (dd, J=8.0 Hz, 1.4
Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): l 24.23,
26.07, 29.91, 32.67 (C-1, C-2, C-9, C-10), 34.24 (s),
54.45 (s), 59.46 (s, NCH2pc), 121.42 (q), 124.19 (t),
125.41 (q), 126.11 (t), 127.15 (t), 132.60 (t), 132.87 (t),
133.02 (t), 137.54 (q), 139.66 (q), 140.04 (q, all C-Arpc),
156.69 (q, C-4) ppm; IR (KBr): w=2932, 1598, 1567,
1500, 1451, 1432 cm−1; MS (70 eV, EI), m/z (%): 321
(96) [M+], 218 (16), 217 (100), 104 (37), 84 (45); HRMS
C22H27NO calcd: 321.2093, found: 321.2091.
6. Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757.
7. (a) Rozenberg, V.; Kharitonov, V.; Antonov, D.; Sergeeva,
E.; Aleshkin, A.; Ikonnikov, N.; Orlova, S.; Belokon, Y.
Angew. Chem. 1994, 106, 106; Angew. Chem., Int. Ed. Engl.
1994, 33, 91; (b) Antonov, D. Y.; Belokon, Y. N.;
Ikonnikov, N. S.; Orlova, S. A.; Pisaevsky, A. P.; Raevski,
N. I.; Rozenberg, V. I.; Sergeeva, E. V.; Struchkov, Y. T.;
Tararov, V. I.; Vorontsov, E. V. J. Chem. Soc., Perkin
Trans. 1 1995, 1873.
8. (a) Hopf, H.; Barrett, D. G. Liebigs Ann. 1995, 449; (b)
Cipiciani, A.; Fringuelli, F.; Mancini, V.; Piermatti, O.;
Pizzo, F.; Ruzziconi, R. J. Org. Chem. 1997, 62, 3744; (c)
Pamperin, D.; Schulz, C.; Hopf, H.; Syldatk, C.; Pietzsch,
M. Eur. J. Org. Chem. 1998, 1441.
9. (a) Reich, H.; Cram, D. J. Am. Chem. Soc. 1969, 91, 3534;
(b) Hoffman, W.; Ditrich, K. Synthesis 1983, 107; (c)
Krohn, K.; Rieger, H.; Hopf, H.; Barrett, D.; Jones, P. G.;
Doring, D. Chem. Ber. 1990, 123, 1729.
10. Rozenberg, V.; Danilova, T.; Sergeeva, E.; Vorontsov, E.;
Starikova, Z.; Lysenko, K.; Belokon, Y. Eur. J. Org. Chem.
2000, 3295.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (SFB
380, BR1750/2) and the Fonds der Chemischen Industrie
for financial support. K. Hennig and T. Beck are
acknowledged for technical assistance and K. Wenz for
carefully reading the manuscript.
References
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