Synthetic routes for a new family of chiral tetradentate ligands containing pyridine rings

Article abstract of DOI:10.1039/b210625f

A series of new tetradentate ligands containing two bipyridine groups or two pyridine moieties carrying amine substituents has been synthesised either from 5′- and 6′-substituted chiral bipyridines, or from chiral pyridine derivatives. These precursors ha

Full text of DOI:10.1039/b210625f

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Synthetic routes for a new family of chiral tetradentate ligands
containing pyridine rings†
Mathias Düggeli,a Catherine Goujon-Ginglinger,a Sarah Richard Ducotterd,a David Mauron,‡a
Christophe Bonte,a Alexander von Zelewsky,*a Helen Stoeckli-Evansb and Antonia Neelsb
a Department of Chemistry, University of Fribourg, Pérolles, 1700 Fribourg, Switzerland.
E-mail: alexander.vonzelewsky@unifr.ch; Fax: ϩ41-26-300 97 38; Tel: ϩ41-26-300 87 42
b Institute of Chemistry, University of Neuchâtel, Avenue de Bellevaux 51, 2007 Neuchâtel,
Switzerland
Received 30th October 2002, Accepted 10th April 2003
First published as an Advance Article on the web 28th April 2003
A series of new tetradentate ligands containing two bipyridine groups or two pyridine moieties carrying amine
substituents has been synthesised either from 5Ј- and 6Ј-substituted chiral bipyridines, or from chiral pyridine
derivatives. These precursors have been prepared from (Ϫ)-α-pinene or (Ϫ)-myrtenal, respectively. The structures
of three tetradentate-, and of five chiral bipyridine ligands have been determined by X-ray diffraction.
these cases the configuration at the metal centre is controlled
Introduction
by the ligand. Another derivative of [4,5]-pinene-bpy forms a
helical square with ZnII.7 Other derivatives of pinene-bpy,2i,8
and bis-pinene-bpy,9,2l–2n (each pyridine ring carries a pinene
group) have been successfully used in enantioselective catalytic
processes.
Herein we present the syntheses of new tetradentate ligands
(1a–c, 2a–c and 3, Fig. 2). All of them are C2-symmetric and
contain two halfs of either chiral bipyridines (cf. 1a–c, 2a–c)
or chiral pyridines with amine substituents (cf. 3), which are
linked via a p-xylene bridge (1a–c) or directly coupled together
(2a–c, 3). Starting from commercially available enantiopure
(Ϫ)-α-pinene (98% ee), the chiral bipyridines and amino sub-
stituted pyridines can be obtained easily following the strategy
of creating new pyridine rings.1,10
Since the introduction of an α-pinene moiety into bipyridine
(bpy) ligands by Hayoz1 in 1992, a large number of such
pineno-annellated ligands2 have been synthesised. These
ligands are easily accessible in enantiomerically pure forms
(generally ca. 98% ee) starting from commercially available
(Ϫ)-α-pinene, or (Ϫ)-myrtenal, respectively (Fig. 1).§
The first group of ligands (the {R}-[5,6]-CHIRAGEN[p-xyl]
1a–c)) is expected to show a similar behaviour as the unsub-
Fig. 1 [4,5]-Pinene-bpy and [5,6]-pinene-bpy and the corresponding
tetradentate CHIRAGEN[bridge] derivatives.
Two [4,5]-pinene-bpy¶ moieties can be linked together to form
tetradentate ligands with different bridges (Fig. 1). This type of
tetradentate ligands has been called [4,5]-CHIRAGEN ligands
(from CHIRAlity GENerators), due to their ability to induce
predetermined configuration at the metal centers.3 The analo-
gous [5,6]-CHIRAGEN derivatives starting from [5,6]-pinene-
bpy|| can assemble spontaneously to supramolecular aggregates
with AgI and CuI such as a sixfold circular helicate,4 or a
polymeric double helix,5 or they form mononuclear metal
complexes with several transition metals (AgI; PdII, ZnII).6 In all
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/ob/b2/b210625f/
‡ Deceased
§ In this publication always (S,S)-(Ϫ)-α-pinene (converted into (R,R)-
(ϩ)-pinocarvone) and (R,R)-(Ϫ)-myrtenal were used giving (R,R)-[5,6]-
pinene-bpy and (R,R)-[4,5]-pinene-bpy derivatives (Fig. 1).
¶ [4,5]-pinene-bpy: IUPAC name: (6R,8R)-5,6,7,8-tetrahydro-7,7-di-
methyl-3-(2Ј-pyridyl)-6,8-methanoisoquinoline.
|| [5,6]-pinene-bpy: IUPAC name: (5R,7R)-5,6,7,8-tetrahydro-6,6-di-
methyl-2-(2Ј-pyridyl)-5,7-methanoquinoline.
Fig. 2 Chiral tetradentate ligands.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 8 9 4 – 1 8 9 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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stituted [5,6]-CHIRAGEN[0].4 The second family ({R}-
CHIRAGEN[0](2a–c and 3)) is designed for the synthesis of
mononuclear complexes.6
Table 1 Suzuki cross-coupling reaction
Entry
Halides
Coupling producta
Yield
Conditions
1
2
3
4
10
7d
7d
4c
11b
7bc
7cb
1cb
99
91
64
99
5 d, reflux
2 h, rt
15 h, reflux
4 d, reflux
Results and discussion
All these tetradentate ligands can be obtained by coupling
reactions from the corresponding [5,6]-pinene-bpy compounds
4a–c and 5 (Scheme 1). The extended 6Ј-substituted pinene-bpy
ligand 4b, c and 6b, c, (Scheme 2) can be formed following two
different synthetic routes: either via the acetyl-pyridine deriv-
atives 7b and 7c or via the key intermediates 4d and 6d. Analo-
gous reactions with β-pinene have been described previously.11
6Ј-Substituted pinene-bpy derivatives are accessible in one step
from the bromo-compounds 4d and 6d. In this way 4c has been
obtained. Following the same methodology phenylene12 and
ferrocene13 bridged bis-pinene-bpy ligands were synthesised
in our research group. Other published 6Ј-pinene-bpy ligands
could also be synthesised via the key intermediates 4d and 6d.14
a Reaction of the halide with the boronic acid in a two phase system
(toluene–K2CO3 in water), Pd(PPh3)4 as catalyst. b p-Methoxyphenyl-
boronic acid was used. c Phenylboronic acid was used.
to described procedures.16 Compound 11 was obtained by a
Suzuki cross coupling reaction using 2-bromo-5-iodopyridine
(10) and p-methoxyphenylboronic acid in the presence of small
amounts of Pd(PPh3)4 as catalyst (Scheme 3 and Table 1,
entry 1).
The acetyl function in 7a and 7d was introduced by reaction
of 11 or 12, respectively, with n-butyllithium followed by the
addition of N,N-dimethylacetamide (Scheme 3).9b,17 Analogous
reaction conditions for the Suzuki cross-coupling were applied
for the formation of the 6Ј-substituted acetylpyridines 7b9b and
7c (Table 1, entry 2,3).
The key molecule for the synthesis of pinene-py derivative (5)
is the ketone 8, which is synthesised in two steps starting from
2-methylbutan-3-one (13) (Scheme 3). After bromination and
subsequent nucleophilic substitution, the desired ketone (8) is
obtained. The analogous reaction sequence starting with 1,1-
diphenylpropan-2-one (15) does not yield the corresponding
diphenylacetyl derivative, but rather the known N,N-dimethyl-
3,3-diphenylpropionamide (17)18 (Scheme 4) in nearly quanti-
tative yield. This is a new synthetic route for the formation of
17, which can be explained by a Favorskii rearrangement.19
The Kröhnke salts 18a, b,9b 20 and 19 (Scheme 5, Scheme 6)
d
are easily synthesised from the acetyl-pyridines 7a, b, d, and 8.
The reaction1,10 of the Kröhnke salts 18a, b, d and 19 with
(ϩ)-pinocarvone21 and dry ammonium acetate in acetic acid
leads to the [5,6]-pinene-bpy ligands 4a, b,9b d or 5, respectively
(Scheme 5, 6). Analogous reactions with myrtenal in form-
amide lead to the [4,5]-pinene-bpy ligands 6a, b, d. The reaction
via the bromo-pinene-bpy ligands 4d and 6d represent a new
versatile pathway for the synthesis of the pinene-bpy ligand9b
since several 6Ј-substituted pinene-bpy ligands (e.g. ligand 4c,
Table 1, entry 4) are available in a one step reaction via the
palladium-catalysed Suzuki cross-coupling.
Scheme 1 Reagents and conditions: i) LDA, THF, Ϫ40 ЊC, then
α,αЈ-dibromo-p-xylene; ii) LDA, THF, Ϫ40 ЊC, then I2.
As described previously,1 pinene annellated ligands can be
deprotonated with lithium-diisopropylamide in
a stereo-
selective manner. Addition of iodine to the deprotonated
species results in a direct oxidative coupling.22 Ligands 2a–c and
3 are synthesised in this way. Addition of α,αЈ-dibromo-(p)-
xylene3 leads to xylene-bridged CHIRAGEN ligands 1a–c
(Scheme 1). Whereas the coupling reaction with the xylene
derivative is completely stereoselective (the bridge is in anti-
position (S,S) with regard to the two methyl-groups of the
pinene), the coupling reaction with iodine leads to two different
diastereomers S,S (anti) and R,R (syn) in a ratio of 9 to 1
(determined by NMR-spectroscopy). According to the postu-
lated mechanism6 the two products are formed via a radical
lithium-templated intermediate.
Scheme 2 Retrosynthetic analysis for the synthesis of 4a–d, 5 and
6a–d.
Suitablecrystals**forX-rayanalysis23 wereobtainedfromthe
CHIRAGEN ligands 1b, 2c and 3 and from the [5,6]-pinene-
bpy ligands 4a–d and 6d. All three [5,6]-CHIRAGEN-ligands
have a molecular C2-axis. Whereas 2c and 3 keep this C2-axis in
the crystal, as in the [5,6]-CHIRAGEN[0],6 1b has no crystallo-
graphic C2-axis, (one bpy conformation is coplanar, the other
has a twist angle of about 23Њ). The plane angle between the
For the corresponding 5Ј-substituted pinene-bpy ligands 4a
and 6a as well as for ligand 5 only the first strategy via the
acetyl-pyridine 7a and 8, respectively, is feasible, because the
analogous bromo-substituted compounds are not available.
The published method15 to synthesise 5-p-methoxyphenyl-2-
acetylpyridine (7a) (4 steps) was replaced by a new three step
synthesis (Scheme 3) starting from the commercially available
2-amino-5-iodopyridine (9).
** CCDC reference numbers 196850,196851, 179702–179707. See http://
www.rsc.org/suppdata/ob/b2/b210625f/ for crystallographic data in .cif
or other electronic format.
The substitution of the amino function by bromine was
carried out under acidic conditions (HBr 65%, Br2) according
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 8 9 4 – 1 8 9 9
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Scheme 3 Reagents and conditions: i) HBr (65%), Br2, then NaNO2; ii) 7d/10 and p-methoxyphenylboronic acid in toluene, K2CO3 in H2O, reflux;
iii) n-BuLi, N,N-dimethylacetamide, THF, Ϫ60 ЊC; iv) 7d and phenylboronic acid in toluene, K2CO3 in H2O, reflux; v) Br2, CCl4, reflux;
vi) dimethylamine, EtOH, 0 ЊC to rt.
Scheme 4 Reagents and conditions: i) Br2, CCl4; ii) dimethylamine,
EtOH, 0 ЊC to rt.
two pyridine rings bearing the pinene moieties varies slightly,
Scheme 6 Reagents and conditions: i) I2, pyridine; ii) (ϩ)-pinocarvone,
for [5,6]-CHIRAGEN[0]6 a plane angle of 79Њ is found, for 1b
NH4OAc, acetic acid.
81Њ, 2c 85Њ and for 3 81Њ.
acetate was dried for several days under vacuum. Diethyl ether
and THF were distilled from sodium–benzophenone prior to
use.
Conclusion
The family of chiral tetradentate ligands containing pyridine is
significantly enlarged through the synthetic routes described in
the present publication. Therewith various applications, such
as the generation of stereochemically new supramolecular
architectures and the fabrication of more intricate molecular
structures can be envisaged.
NMR spectra were recorded on a ‘Varian Gemini 300’
(300.075 MHz) or on a ‘Bruker Avance DRX400’ (400.13
MHz) spectrometer, chemical shifts are given in ppm using the
solvent itself as internal standard, coupling constants J are
given in Hertz. Attribution of the 1H- and 13C signals was
performed by 1H,1H-COSY, DEPT, 13C–1H-HECTOR,
1H–13C-HMQC and 1H–13C-HMBC techniques. The numer-
ation of the ligands is given in Fig. 2. The diastereotopic
protons at carbon 9 of the pinene-moieties are labelled as Ha for
the endo-oriented protons and Hb for the exo-oriented protons.
The exo methyl groups are assigned as 12 and 12Ј, the endo
oriented ones as 13 and 13Ј, respectively. The diastereotopic
Experimental
General
Solvents and reagents were purchased from Fluka or Aldrich.
Pyridine was dried over KOH and freshly distilled. Ammonium
Scheme 5 Reagents and conditions: i) I2, pyridine; ii) (ϩ)-pinocarvone, NH4OAc, acetic acid; iii) (Ϫ)-myrtenal, NH4OAc, formamide.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 8 9 4 – 1 8 9 9
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protons at carbon 1Љ are labelled as Ha and Hb. For the
methoxy-phenyl derivatives, the proton 8Ј, 9Ј, 11Ј and 12Ј form
a spin-coupling system AAЈXXЈ, they are just labelled as doub-
pure 4c (3.59 g, 99%) was obtained. Analytical data are given in
the ESI†.
3
lets with the coupling constant JA,X. Mass spectral data were
S,S-{5Ј-p-Methoxyphenyl}-[4,5]-pinene-bpy (6a)
acquired a) on ‘VG Instrument 7070E’ equipped with a FAB
inlet system, b) on Hewlett Packard 5988A quadrupol mass
spectrometer with an electron ionisation (EI) source and c) on a
Bruker FTMS 4.7 T BioApex II using a standard electrospray
ion source (ESI). Elemental analysis was obtained from EIF
(Ecole d’ingénieurs de Fribourg, Switzerland).
A mixture of 1-[2-acetyl-5-(p-methoxyphenyl)pyridyl]pyridin-
ium iodide (18a) (223 mg, 0.52 mmol), ammonium acetate
(560 mg, dried under vacuum) and R,R-(Ϫ)-myrtenal (90 mg,
0.6 mmol) was suspended in formamide (20 ml) and stirred at
room temperature for 5 days, then it was slowly heated over
24 hours from 50 ЊC up to 100 ЊC. To the reaction mixture 50 ml
of water was added and extracted five times with hexane and
the combined organic layers were washed with water and dried
over magnesium sulfate with activated charcoal. The solvent
was evaporated under reduced pressure. The residual solid was
further purified by column chromatography (hexane–ethyl
acetate–triethylamine: 4 : 1 : 0.25), yielding the desired product
(85 mg, 24%). Analytical data are given in the ESI†.
S,S-{5Ј-p-Methoxyphenyl}-[5,6]-CHIRAGEN[p-xyl] (1a)
To dry THF (40 ml) at Ϫ40 ЊC diisopropylamine (0.2 ml,
1.4 mmol) was added, followed by n-butyllithium (0.85 ml,
1.35 mmol, 1.6 M in hexane). The temperature was allowed to
increase to 0 ЊC for 30 minutes and then lowered to Ϫ40 ЊC. S,S-
{5Ј-p-Methoxyphenyl}-[5,6]-pinene-bpy (4a) (400 mg, 1.12
mmol) dissolved in dry THF (10 ml) was added dropwise over
1 hour. After stirring the solution at Ϫ40 ЊC for 2 hours,
α,αЈ-dibromo-p-xylene (148 mg, 0.56 mmol) dissolved in THF
(10 ml) was injected slowly (1 hour). The solution was warmed
gradually to room temperature, and quenched by water (50 ml).
The aqueous solution was extracted three times with diethyl
ether. The combined organic layers were dried over magnesium
sulfate, and the solvent was evaporated. The residual solid was
further purified by column chromatography or recrystallisation
(hexane–ethyl acetate–triethylamine: 1 : 1 : 0.5), yielding a
slightly yellow powder (303 mg, 64%). Analytical data are given
in the ESI†.
The ligands S,S-{6Ј-phenyl}-[5,6]-CHIRAGEN[p-xyl] (1b),
S,S-{6Ј-p-methoxyphenyl}-[5,6]-CHIRAGEN[p-xyl] (1c), S,S-
{5Ј-p-methoxyphenyl}-[5,6]-CHIRAGEN[0] (2a), S,S-{6Ј-
phenyl}-[5,6]-CHIRAGEN[0] (2b), S,S-{6Ј-p-methoxyphenyl}-
[5,6]-CHIRAGEN[0] (2c) and S,S-{2-N,N-dimethylamino-
isopropyl}-[5,6]-CHIRAGEN[0] (3) were prepared analogously
to the procedure for 1a described above. More details are given
in the ESI†.
S,S-{6Ј-Phenyl}-[4,5]-pinene-bpy (6b) and S,S-{6Ј-bromo}-
[4,5]-pinene-bpy (6d) were prepared analogous to the procedure
for 6a described above. More details are given in the ESI†.
2-Acetyl-5-(p-methoxyphenyl)pyridine (7a)
The introduction of the acetyl function starting from
2-bromo-5-(p-methoxyphenyl)pyridine (11) was carried out in
similar manner as described for compound 7d.9b 2-Bromo-5-
(p-methoxyphenyl)pyridine (11) (2 g, 7.6 mmol) was dissolved
in dry diethyl ether (250 ml) under argon and cooled to Ϫ60 ЊC,
n-butyllithium (5 ml, 1.6 M in hexane) was added dropwise over
45 minutes. After stirring for 1¼ hours, N,N-dimethylacetamide
(0.75 ml, 8 mmol) in diethyl ether (10 ml) was added over an
hour. Overnight, the solution was allowed to warm to room
temperature, quenched with saturated ammonium chloride
solution and extracted five times with diethyl ether. Further
purification was carried out by column chromatography
(hexane– ethyl acetate–triethylamine: 8 : 1 : 0.5) yielding a white
solid (1.04 g, 60%). The spectral data was in accordance with
the literature.15 Analytical data are given in the ESI†.
2-Acetyl-6-phenyl pyridine (7b) was prepared analogous to
the procedure for 7a described above. More details are given in
the ESI†.
S,S-{5Ј-p-Methoxyphenyl}-[5,6]-pinene-bpy (4a)
A mixture of 1-[2-acetyl-5-(p-methoxyphenyl)pyridyl]pyridin-
ium iodide (18a) (3.8 g, 8.79 mmol), ammonium acetate
(6.93 g, dried under vacuum) and R,R-(ϩ)-pinocarvone (1.35 g,
9.0 mmol) was suspended in acetic acid (5 ml) and slowly heated
over 42 hours from 50 ЊC up to 115 ЊC. After addition of
water, the pH was adjusted to 9 by addition of sodium
carbonate. This aqueous solution was extracted ten times with
hexane and the combined organic layers were washed with
water and dried over magnesium sulfate with activated char-
coal. The solvent was evaporated under reduced pressure. The
residual solid was further purified by column chromatography
(hexane–ethyl acetate–triethylamine: 8 : 1 : 0.1) yielding a
slightly yellow product 4a (936 mg, 30%). Analytical data are
given in the ESI†.
2-Acetyl-6-(p-methoxyphenyl)pyridine (7c)
A mixture of 2-acetyl-6-bromopyridine (7d) (2.00 g, 10 mmol),
p-methoxyphenylboronic acid (347 mg, 10 mmol), and
Pd(PPh3)4 (0.2% eq., 0.02 mmol) as catalyst, was heated at
120 ЊC for 15 hours in a solvent mixture of toluene (100 ml) and
an aqueous solution of K2CO3 (50 ml, 8.5 M). After cooling
to room temperature the two layers were separated and the
aqueous layer extracted three times with dichloromethane. The
combined organic layers were washed with water until pH = 7,
dried over magnesium sulfate and the solvent was evaporated.
Further purifications by recrystallisation (ethyl acetate–hexane:
1 : 4) yielded compound 7c (1.45 g, 64%). Analytical data are
given in the ESI†.
S,S-{6Ј-Phenyl}-[5,6]-pinene-bpy (4b), S,S-{6Ј-bromo}-[5,6]-
pinene-bpy (4d) and S,S-{2-N,N-dimethylaminoisopropyl}-
[5,6]-pinene-py (5) were prepared analogous to the procedure
for 4a described above. More details are given in the ESI†.
2-N,N-Dimethylamino-2-methylbutan-3-one (8)
The synthesis was carried out according to the published pro-
cedure by Gaset.24 To a 0 ЊC cooled solution of 2-bromo-2-
methylbutan-3-one (14) (10 g, 0.06 mmol), dimethylamine
(22 ml, 0.12 mmol, 5.6 M in ethanol) was added over a period
of 5 minutes. The reaction solution was stirred overnight at
0 ЊC, then warmed to 40 ЊC for 70 minutes. After cooling to
room temperature the reaction mixture was filtered and the
residual solid was washed with cold ethanol. To the filtrate
hydrochloric acid (66 ml, 4 M) was added. Ethanol was
removed under reduced pressure. To the acidic solution, sodium
hydroxide (2 M) was added, until the pH > 7. The alkaline
solution was extracted three times with diethyl ether. The
S,S-{6Ј-p-Methoxyphenyl}-[5,6]-pinene-bpy (4c)
A mixture of {6Ј-bromo}-[5,6]-pinene-bpy (4d) (3.3 g, 10
mmol), p-methoxyphenylboronic acid (1.65 g, 10 mmol) and
Pd(PPh3)4 (0.2% eq.) as catalyst, was heated at 120 ЊC for 4 days
in a mixture of toluene (100 ml) and an aqueous solution of
K2CO3 (50 ml, 8.5 M). After cooling to room temperature the
two layers were separated and the aqueous layer extracted three
times with dichloromethane. The combined organic layers were
washed until pH = 7 with water, dried over magnesium sulfate
and the solvent was evaporated. Without further purification
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 8 9 4 – 1 8 9 9
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combined organic extracts were dried over magnesium sulfate
and the solvent was removed under reduced pressure. The
desired product was obtained (5.87 g, 76%). The spectral
properties correspond to those reported.24 Analytical data are
given in the ESI†.
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A mixture of 2-bromo-5-iodopyridine (10) (5.67 g, 20 mmol),
p-methoxyphenylboronic acid (3.34 g, 20 mmol) and Pd(PPh3)4
(0.02 mmol) as catalyst, was heated at 120 ЊC for 4 days in a
mixture of toluene (80 ml) and an aqueous solution of K2CO3
(80 ml, 80 g, 8.5 M). After cooling to room temperature, the two
layers were separated and the aqueous layer extracted three
times with dichloromethane. The combined organic layers were
washed until pH = 7 with water, dried over magnesium sulfate
and the solvent was evaporated. Further purification was
carried out by column chromatography (hexane–ethyl acetate–
triethylamine: 5 : 1 : 0.1), yielding the desired product (5.3 g,
99%). Analytical data are given in the ESI†.
2-Bromo-2-methylbutan-3-one (14)
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9, 3911; (b) P. Collomb and A. von Zelewsky, Tetrahedron:
Asymmetry, 1995, 6, 2903.
9 (a) D. Lötscher, S. Rupprecht, P. Collomb, P. Belser, H. Viebrock,
A. von Zelewsky and P. Burger, Inorg. Chem., 2001, 40, 5675;
(b) D. Lötscher, S. Rupprecht, H. Stoeckli-Evans and A. von
Zelewsky, Tetrahedron: Asymmetry, 2000, 11, 4341.
10 (a) W. Zecher and F. Kroehnke, Chem. Ber., 1961, 94, 690;
(b) W. Zecher and F. Kroehnke, Chem. Ber., 1961, 94, 698;
(c) W. Zecher and F. Kroehnke, Chem. Ber., 1961, 94, 707;
(d ) F. Kroehnke, Synthesis, 1976, 1.
11 F. Pezet, I. Sasaki, J.-C. Daran, J. Hydrio, H. Aït-Haddou and
G. Balavoine, Eur. J. Inorg. Chem., 2001, 2669.
12 L. E. Perret Aeby and A. Von Zelewsky, Synlett, 2002, 5, 773.
13 B. Quinodoz, and A. Von Zelewsky, submitted.
14 (a) G. Baum, E. C. Constable, D. Fenske, C. E. Housecroft and
T. Kulke, Chem. Eur. J., 1999, 5, 1862; (b) E. C. Constable, T. Kulke,
G. Baum and D. Fenske, Inorg. Chem. Commun., 1998, 1, 80;
(c) G. Baum, E. C. Constable, D. Fenske and T. Kulke, Chem.
Commun., 1997, 2043; (d ) G. Baum, E. C. Constable, D. Fenske,
C. E. Housecroft and T. Kulke, Chem. Commun., 1999, 195 and ref.
2m, 2n.
To a solution of 2-methylbutan-3-one (13) (25.85 g, 0.3 mol)
in carbon tetrachloride (120 ml), bromine (48.0 g, 0.3 mol) in
carbon tetrachloride (30 ml) was added dropwise under reflux
over a period of 2 hours. After the addition the reaction mix-
ture was kept under reflux for another 2 hours, then cooled
to room temperature. Unreacted bromine was destroyed with
sodium thiosulfate solution (10%). The organic layer was
separated, dried with magnesium sulfate, the solvent was
removed under reduced pressure. The crude product was fur-
ther purified by vacuum distillation (100 mbar, 60 ЊC), yielding
a colourless liquid (30.1 g, 60%). The spectral properties corre-
spond to those reported.25 Analytical data are given in the ESI†.
1-Bromo-1,1-diphenylpropan-2-one (16) was prepared
analogously to the procedure for 14 described above. More
details are given in the ESI†.
N,N-Dimethyl-3,3-diphenylpropionamide (17)
To a 0 ЊC cooled solution of 1-bromo-1,1-diphenylpropan-2-
one (16) (2.0 g, 6.9 mmol), dimethylamine (2.5 ml, 13.8 mmol,
5.6 M in ethanol) was added over a period of 5 minutes. The
reaction solution was stirred overnight at 0 ЊC, then warmed to
40 ЊC for 70 minutes. After cooling to room temperature,
hydrochloric acid (50 ml, 4 M) was added to the reaction
mixture. Ethanol was removed under reduced pressure. To the
acidic solution, sodium hydroxide (2 M) was added, until the
pH > 7. The alkaline solution was extracted three times with
diethyl ether. The combined organic layers were dried over
magnesium sulfate and the solvent was removed under reduced
pressure, yielding product 17 (1.66 g, 95%). The spectral
properties correspond to those reported.18 Analytical data are
given in the ESI†.
1-[2-Acetyl-5-(p-methoxyphenyl)pyridyl]pyridinium iodide (18a)
15 J.-P. Sauvage and M. Ward, Inorg. Chem., 1991, 30, 3869.
16 (a) F. H. Case, J. Am. Chem. Soc., 1946, 68, 2574; (b) H.-P. Hsieh and
L. W. McLaughlin, J. Org. Chem., 1995, 60, 5356; (c) F. Vögtle,
R. Hochberg, F. Kochendörfer, P.-M. Windscheif, M. Volkmann
and M. Jansen, Chem. Ber., 1990, 123, 2181; (d ) P. M. Windscheif
and F. Voegtle, Synthesis, 1994, 87.
17 (a) J. E. Parks, B. E. Wagner and R. H. Holm, J. Organomet. Chem.,
1973, 56, 53; (b) M. A. Peterson and J. R. Mitchell, J. Org. Chem.,
1997, 62, 8237.
18 (a) Gilbert, J. Am. Chem. Soc., 1955, 77, 4413; (b) T. Yamashita,
K. Shiomori, M. Yasuda and S. Kensuke, Bull. Chem. Soc. Jpn.,
1991, 64, 366; (c) T. Yamashita, M. Watanabe, R. Kojima,
T. Shiragami, K. Shima and M. Yasuda, J. Photochem. Photobiol. A,
1998, 118, 165.
19 (a) A. Favorskii, J. Prakt. Chem., 1895, 51, 533; (b) A. S. Kende,
Org. React., 1960, 11, 261.
A mixture of pyridine (10 ml), iodine (280 mg, 1.1 mmol) and
2-acetyl-5-(p-methoxyphenyl)pyridine (7a) (210 mg, 0.925
mmol) was kept at 100 ЊC for 2 hours and at 0 ЊC for 20 min.
After addition of dry diethyl ether, the desired product and
pyridinium iodide precipitated and was filtered. The crude
product (305 mg) was used without further purification. The
ratio between 18a (1.3 eq., 223 mg, 59%) and the pyridinium
iodide (1 eq., 82 mg) was determined by 1H-NMR-spectro-
scopy. Analytical data are given in the ESI†.
1-(2-Acetyl-6-phenylpyridyl)pyridinium iodide (18b), 1-(2-
acetyl-6-bromopyridyl)pyridinium iodide (18d) and 1-(3-N,N-
dimethylamino-3-methyl-2-oxobutyl)pyridinium iodide (19)
were prepared analogously to the procedure for 18a described
above. More details are given in the ESI†.
20 G. R. Newkome, D. C. Hager and G. E. Kiefer, J. Org. Chem., 1986,
51, 850.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 8 9 4 – 1 8 9 9
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21 (Ϫ)-α-Pinene is transformed into (ϩ)-pinocarvone according to
published procedure: E. D. Mihelich and D. J. Eickhoff, J. Org.
Chem.,, 1983, 48, 4135.
22 N. C. Fletcher, F. R. Keene, M. Ziegler, H. Stoeckli Evans,
H. Viebrock and A. Von Zelewsky, Helv. Chim. Acta, 1996, 79, 1192.
23 (a) G. M. Sheldrick, Acta Crystallogr., Sect. A, 1990, 46, 467;
(b) G. M. Sheldrick, SHELXL-97 Program for Crystal Structure
Refinement, 1999, Universität Göttingen, Göttingen, Germany;
(c) A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi,
A. G. G. Moliterni, M. C. Burla, G. Polidori, M. Camalli and
R. Spagna, 1997 SIR97 – A package for crystal structure solution
by direct methods and refinement, c/o Istituto di Ricerca per lo
Sviluppo di Metodologie Cristallografiche, CNR, & Dipartimento
Geomineralogico, Campus Universitario, Via Orabona 4, 70125
Bari.
24 A. Gaset, A. Verdier and A. Lattes, Spectrochim. Acta. Part A, 1975,
31, 727.
25 F. Ros, J. de la Rosa and J. Enfedaque, J. Org. Chem., 1995, 60, 541.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 8 9 4 – 1 8 9 9
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