Synthesis of catalytically active ruthenium complexes with a remote chiral lactam as hydrogen-bonding motif

Article abstract of DOI:10.1055/s-0030-1258424

A terminal alkyne was prepared, which is linked by a carbon-carbon bond to a conformationally restricted, U-shaped chiral lactam, that is, more precisely, to carbon atom C7 of 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-one. The alkyne was connected to var

Full text of DOI:10.1055/s-0030-1258424

PAPER
961
Synthesis of Catalytically Active Ruthenium Complexes with a Remote Chiral
Lactam as Hydrogen-Bonding Motif
R
utheniumCo
e
mplexes lix Voss,1 Florian Vogt,2 Eberhardt Herdtweck, Thorsten Bach*
Department Chemie and Catalysis Research Center (CRC), Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315; E-mail: thorsten.bach@ch.tum.de
Received 7 January 2011
It was envisioned that catalysts of type A could be acces-
Abstract: A terminal alkyne was prepared, which is linked by a
sible by attaching appropriate ligands to the alkyne part of
1 and by subsequent coordination to a metal center. In this
paper, we present an optimized procedure for the prepara-
carbon–carbon bond to a conformationally restricted, U-shaped
chiral lactam, that is, more precisely, to carbon atom C7 of 1,5,7-tri-
methyl-3-azabicyclo[3.3.1]nonan-2-one. The alkyne was connected
to various ligands (bipyridine, terpyridine, pybox) by Sonogashira tion of template 1. Several ligands were attached to the
cross-coupling with the respective bromides or triflates. The result-
alkyne part of the template employing the Sonogashira
cross-coupling reaction.8 Subsequent formation of ruthe-
ing products were converted into four defined ruthenium complexes
(58–94% yield). The complexes contain a catalytically active metal
nium complexes was successfully attempted employing
center, which is spatially remote from the hydrogen-bonding motif
these ligands. In addition, preliminary results on the use of
the chiral ruthenium complexes in enantioselective reac-
tions are reported.
of the chiral lactam. Preliminary experiments with one of these
complexes proved that the complex shows catalytic activity in oxi-
dation reactions and that enantioselectivity is achieved due to sub-
strate coordination to the chiral lactam.
Imide 6 was a key intermediate in the synthesis of alkyne
1 and its enantiomer ent-1. Imide 6 was prepared starting
from primary alcohol 2 by modifying a reported proce-
dure.9 Oxidation of this alcohol had been earlier conducted
with pyridinium chlorochromate in CH2Cl2 (84%). When
upscaling the reaction we found the removal of the inor-
ganic by-products to be tedious and impractical leading to
a diminished yield. Instead, the Swern oxidation was em-
ployed for this transformation, delivering cleanly the de-
sired aldehyde 3 on multigram scale. For the N-protection
with PMBCl (PMB = p-methoxybenzyl) we found the
conditions reported earlier by Ozaki et al.10 (DBU = 1,8-
diazabicyclo[5.4.0]undec-7-ene) to lead to a cleaner prod-
uct 4 than the original conditions (NaH, PMBCl, NaI in
DMF). The final alkyne formation was conducted with the
Bestmann–Ohira reagent (5)11 as reported in the literature
procedure9 (Scheme 2).
Key words: supramolecular chemistry, hydrogen bonds, catalysis,
coordination chemistry, cross-coupling reactions
In enantioselective transition-metal catalysis, the transfer
of the chiral information occurs mostly in close proximity
to the catalytically active metal center.3 Chiral ligands fre-
quently induce an efficient differentiation of enantiotopic
faces or positions upon substrate coordination. A concep-
tually different approach to enantioselective transition-
metal catalysis aims at a spatial separation of the catalyti-
cally active site from the site, which binds the substrate
and induces enantioselectivity.4–6 The apparent advantage
of such an approach is the fact that different substrate
classes could – depending on the catalytically active site –
undergo different reactions as long as they have a com-
mon binding motif. We have recently introduced the tem-
plate 1, which contains an alkyne group for further
functionalization and which contains a rigid 1,5,7-tri-
methyl-3-azabicyclo[3.3.1]nonan-2-one scaffold capable
of binding lactam substrates (Scheme 1).7
H
H
N
OH
N
O
O
O
PMBCl, DBU
(MeCN)
(COCl)2, DMSO
Et3N (CH2Cl2)
O
O
91%
75%
2
3
catalytically active site
M
PMB
N
PMB
N
Ac
PO(OMe)2
H
H
binding site
for lactams
O
N
O
N
O
O
O
N2
5
O
O
K2CO3 (THF–MeOH)
70%
A
1
4
6
Scheme 1 Structure of a generic transition-metal complex A
(M = transition metal) and its potential congener 1
Scheme 2 Preparation of alkyne 6 from alcohol 2 according to a
modified protocol based on the procedure by Diederich et al.9
When attempting to further transform imide 6 into lactam
1, we initially checked possible reduction methods prior
to a removal of the protecting group. Reduction reactions
SYNTHESIS 2011, No. 6, pp 0961–0971
Advanced online publication: 08.02.2011
DOI: 10.1055/s-0030-1258424; Art ID: Z10111SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1

962
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with NaBH4 (in EtOH or MeOH) and with DIBAL-H (in which can undergo a rapid intramolecular Friedel–Crafts
Et2O) failed, however, and the starting material was reiso- alkylation.14
lated. The reduction with LiBEt3H proved to be more suc-
Gratifyingly, the imide reduction turned out to be far less
cessful and delivered the hemiaminal as the expected
capricious after the PMB group had been removed. To this
reduction product (Scheme 3). Immediate acetylation
end, the protected imide was treated with cerium ammo-
with acetic anhydride delivered the racemic product rac-7
as a mixture of diastereoisomers. Applying typical condi-
nium nitrate (CAN) in a mixture of MeCN and water
(Scheme 4).15 The resulting imide 11 could be reduced
tions (Et3SiH in TFA) to reduce intermediates of this type
under conditions, which have been previously employed
to the respective lactam12 did, however, not deliver the de-
for the reduction of related imides.12 With racemic com-
sired PMB-protected product. Instead a new compound
was isolated, to which we assign the structure rac-10.
pound rac-1 in hand, its separation into the antipodes 1
and ent-1 was approached. Presumably due to the similar
Mechanistically, the formation of its pentacyclic skeleton
acidity of the lactam and alkyne group, a selective N-acy-
can be explained by an intramolecular attack of the alkyne
lation with a chiral acylating reagent turned out to be dif-
ficult. We therefore relied on a HPLC separation of the
two enantiomers, which was conducted on semiprepara-
triple bond at intermediate iminium ion rac-8.13 Reduc-
tion of the resulting vinyl cation delivers product rac-9,
tive scale.
PMB
N
PMB
N
Based on literature precedence16 bi- and terpyridines were
identified as preferred ligands capable to coordinate to a
ruthenium metal center. Initial attempts centered on the
preparation of a terpyridine ligated to alkyne 1 or its enan-
tiomer ent-1. Preliminary optimization experiments were
conducted with tert-butylacetylene, which resembles
alkynes 1 and ent-1 regarding the quaternary carbon cen-
ter at the internal alkyne carbon atom. Literature known
triflate 1217 was successfully attached to the test substrate
and also to enantiomerically pure alkyne ent-1 using
Sonogashira cross-coupling conditions8 in THF as the
solvent18 at slightly elevated temperature (50 °C). With
the latter alkyne, product 13 was obtained in a very good
yield. Due to its basicity, purification of the terpyridine
was performed on neutral alumina. Crystallization from
dichloromethane–pentane delivered crystals suitable for
X-ray crystal structure analysis (Scheme 5).19 The crystal
structure nicely illustrates the large distance between the
hydrogen-bonding lactam part from the metal-binding
terpyridine ligand.
1. LiBEt3H
(THF–CH2Cl2)
2. Ac2O
Et3SiH
(TFA)
O
O
OAc
6
56%
rac-7
rac-8
OMe
OMe
N
N
H
O
O
rac-9
rac-10
Scheme 3 Attempted stepwise reduction of imide 6 yielding the
pentacyclic product rac-10
H
CAN
(MeCN–H2O)
N
1. NaBH4, H2O (THF)
2. Et3SiH, TFA (CH2Cl2)
O
O
6
rac-1
quant.
Ruthenium coordination to ligand 13 was performed em-
ploying the complex (tpy)RuCl3 (tpy = terpyridine) in re-
fluxing ethanol.20 The complex was isolated as
hexafluorophosphate salt 14 following an anion exchange
(Scheme 6). The deep red-colored compound showed
72%
11
Scheme 4 Synthesis of racemic alkyne rac-1, which can be separa-
ted into the enantiomers 1 and ent-1 by chiral HPLC
Scheme 5 Synthesis of the chiral terpyridine ligand 13 from alkyne ent-1 and the structure of the ligand in the crystal
Synthesis 2011, No. 6, 961–971 © Thieme Stuttgart · New York

PAPER
Ruthenium Complexes
963
similar photophysical behavior as the known bromo-2,2¢-bipyridine24 gave ligand 16 in 76% yield,
Ru(tpy)2(PF6)2 complex exhibiting a broad MLCT band at which in turn was further converted into the tris(bipyri-
around l = ~480 nm in the UV-Vis spectrum.21
dine) complex 17. Following a known procedure25 ligand
16 was reacted with (bpy)2RuCl2 (bpy = bipyridine) in an
EtOH–H2O solution under reflux. Subsequent anion ex-
change and washing with water delivered the desired
complex 17, which was – due to the newly formed stereo-
genic metal center – isolated as a 1:1 mixture of diastereo-
isomers.
N
1. (tpy)RuCl3
N-ethylmorpholine
(EtOH)
N
N
N
Ru
N
2
2. NH4PF6
13
Another complex with dipicolinic acid was prepared from
the pyridine-bisoxazoline (pybox) ligand 18, which was in
turn obtained from template 1 and the respective 4-
bromopyridine26 by a Sonogashira cross-coupling in
quantitative yield. In full analogy to the preparation of
complex 15, the starting material 18 was treated with di-
picolinic acid and [RuCl2(p-cymene)]2 to yield product 19
as a purple solid (Scheme 8).
N
94%
2 PF6
O
O
H
N
N
Ru
N
O
[RuCl2(p-cymene)]2
O
N
O
N
HOOC
N
COOH
NaOH
14
(MeOH–H2O)
75%
O
O
N
Ru
N
N
N
[RuCl2(p-cymene)]2
O
N
O
N
N
H
N
O
O
O
HOOC
N
COOH
NaOH
(MeOH–H2O)
H
O
O
N
15
O
58%
Scheme 6 Preparation of the ruthenium(II)–terpyridine complexes
14 and 15 from chiral terpyridine ligand 13
H
N
O
18
Employing dipicolinic acid (pyridine-2,6-dicarboxylic
acid) and [RuCl2(p-cymene)]2 in a solution of NaOH in
H2O–MeOH, the enantiomerically pure complex 15 was
synthesized. Related mixed ruthenium complexes with di-
picolinic acid as ligand have been earlier described by
Nishiyama et al.22 and were used among others by
Nishiyama et al. and by Beller et al. as chiral epoxidation
catalysts.22,23 Purification of the polar complex 15 was
achieved by recrystallization.
19
Scheme 8 Preparation of the ruthenium(II)–pybox complex 19
from chiral pybox ligand 18 (prepared from alkyne 1).
Preliminary oxidation reactions were performed with
quinolones or related substrates because it was earlier
observed that quinolones show a high association to com-
pounds with a 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-
2-one scaffold.27 In these experiments, the dipicolinic
acid-based catalyst 19 was exclusively used. Since
Nishiyama et al. had shown that stilbenes are very good
substrates for an epoxidation catalyzed by ruthenium–
pyridinedicarboxylate complexes22 a stilbene analogue
was required in which one aromatic ring was a quinolone.
Suzuki cross-coupling28 of literature known29 3-bromo-
quinolone (20) with (E)-styrylboronic acid30 gave in high
yield the desired quinolone 21, which could be N-methyl-
ated with NaH/MeI (Scheme 9).
Bipyridine ligand 16 (Scheme 7) was accessible by
Sonogashira cross-coupling following the procedure used
for the preparation of terpyridine 13. Template 1 and 5-
N
1. [(bpy)2RuCl2]
(EtOH–H2O)
2. KPF6
N
N
N
N
N
N
Ru
N
2
90%
Upon treatment with bis(acetoxy)iodobenzene in toluene
in the presence of 5 mol% of catalyst 19, substrate 21 was
converted into the respective epoxide 23 (Scheme 10).
The reaction was relatively slow, however. At ambient
temperature a 40% conversion was achieved after two
days, at –25 °C the conversion was 28% after five days.
Despite the limited reactivity, a small but detectable enan-
tiomeric excess (ee) indicated that hydrogen bonds might
H
H
N
N
O
O
2 PF6
16
17
Scheme 7 Preparation of the ruthenium(II)–tris(bipyridine) com-
plex 17 from chiral bipyridine ligand 16 (prepared from alkyne 1)
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964
F. Voss et al.
PAPER
Ph
O
S
PhIO
19 (10 mol%)
–25 °C (PhMe)
(HO)2B
S
[Pd(OAc)2, PPh3]
NaOH (THF)
Br
O
Ph
80%
N
H
O
N
H
O
87%
N
N
R
O
H
27
28 (12% ee)
20
21 R = H
NaH, MeI
(THF)
Scheme 11 Attempted enantioselective epoxidation of sulfide 27 in
the presence of catalyst 19
22 R = Me
82%
Scheme 9 Preparation of the oxidation substrate 21 and its
N-methyl derivative 22
slightly improved enantioselectivity and higher yields
were realized with the latter oxidant (Scheme 11).
In summary, four new ruthenium complexes 14, 15, 17
and 19 were prepared from alkynes 1 or ent-1. They ex-
hibit a catalytically active metal center and a spatially re-
mote site – a lactam – for hydrogen bonding. Preliminary
experiments with catalyst 19 indicate that enantioselec-
tive catalytic reactions are possible with these catalysts,
although enantioselectivities have yet remained low. Fur-
ther experiments will show whether the catalytic perfor-
mance can be improved in other reactions. By adapting
the three-dimensional structure of the hydrogen-bonding
catalysts to the requirements of the substrate higher enan-
tioselectivities should be possible.
indeed help to associate the substrate to the active catalyst.
In a control experiment N-methylquinolone 22 was used,
which gave under identical conditions no enantioselectiv-
ity. Only racemic epoxide 24 was obtained. Since it was
expected that a more electron-rich substrate reacted more
readily, the anisyl analogue 25 of compound 21 was pre-
pared from 3-bromoquinolone (20).
PhI(OAc)2
19 (5 mol%)
O
Ph
Ph
–25 °C (PhMe)
N
R
O
N
R
O
All reactions involving moisture-sensitive chemicals were carried
out in flame-dried glassware with magnetic stirring under argon.
21
22
R = H
R = Me
23 (9% ee)
24 (0% ee)
TLC was performed on silica coated glass plates (silica gel 60 F254
)
with detection by UV (254 nm) or KMnO4 (0.5% in H2O) with sub-
sequent heating. Flash chromatography was performed on silica gel
60 (Merck, 230–400 mesh) and on neutral alumina (Merck, Brock-
mann type 1) with the indicated eluent. Common solvents for chro-
matography [pentane (P), cyclohexane (CH), EtOAc, CH2Cl2,
MeOH, THF] were distilled prior to use. HPLC analyses were per-
formed using a chiral stationary phase [ChiralPak AD-H (250 × 4.6
mm), Chiralpak AS-H (250 × 4.6 mm)], employing hexane–i-PrOH
as eluent mixture and UV-detection at 20 °C. Semipreparative
HPLC separation was performed using a chiral stationary phase
[Chiralpak AS-H (250 × 20 mm, 5 mm), Daicel Chemical Indus-
tries] employing hexane–i-PrOH (70:30) as eluent (flow rate:
19 mL/min) and UV-detection. IR: Jasco IR-4100 (ATR). MS/
HRMS: Finnigan MAT 8200 (EI)/Agilent 5937 mass selective GC-
MS detector (EI)/Finnigan MAT 95S (HR-EI)/Finnigan LCQ clas-
sic (ESI)/Thermo Finnigan LTQ FT (HRMS-ESI). 1H and 13C
NMR: Bruker AV-250, Bruker AV-360, Bruker AV-500, recorded
at 303 K. Chemical shifts are reported relative to the used solvent
(CHCl3, CH2Cl2, DMSO, MeCN, MeOH).31 The multiplicities of
the 13C NMR signals were determined by DEPT experiments. Ab-
breviations: ar: aromatic; al: aliphatic. Optical rotations were mea-
sured using a Perkin-Elmer 241 MC Polarimeter. Elemental
analyses were carried out on a Elementar Vario EL in the chemistry
department at the Technische Universität München. UV-Vis spectra
were recorded on a Perkin-Elmer Lambda 35 UV-Vis spectrometer.
PhI(OPiv)2
19 (10 mol%)
r.t. (PhMe)
O
An
An
N
H
O
43%
N
H
O
25
26 (20% ee)
Scheme 10 Attempted enantioselective epoxidation of styryl-
substituted quinolones 21, 22 and 25 in the presence of catalyst 19
(An = 4-methoxyphenyl; Piv = trimethylacetyl)
Indeed, the epoxidation of olefin 25 proceeded faster than
the reaction of olefin 21. Unfortunately, the product ep-
oxide turned out to be unstable under the reaction condi-
tions and a number of by-products were detected. The
most significant by-products were aldehydes, which ap-
pear to be formed by oxidative cleavage of the epoxide.
When the oxidant bis(acetoxy)iodobenzene was replaced
by the better soluble bis(pivaloyloxy)iodobenzene and
when the amount of catalyst was raised to 10 mol%, the
conversion to epoxide 26 was further accelerated and the
formation of by-products was successfully suppressed.
Although the reaction remained incomplete after three
days at ambient temperature, it was possible to isolate the
desired product in 43% yield and with 20% ee.
1,5,7-Trimethyl-2,4-dioxo-3-azabicyclo[3.3.1]nonan-7-carbal-
dehyde (3)
A solution of DMSO (2.49 mL, 35.0 mmol, 2.50 equiv) in CH2Cl2
(8.2 mL) was added in 15 min to a solution of oxalyl chloride
(1.45 mL, 16.8 mmol, 1.20 equiv) in CH2Cl2 (33 mL) at –78 °C. A
solution of alcohol 29 (3.16 g, 14.0 mmol, 1.00 equiv) in CH2Cl2
(52 mL) was subsequently added in 30 min and the reaction mixture
was stirred at –78 °C for three hours. Et3N (9.70 mL, 70.0 mmol,
5.00 equiv) was added and the reaction mixture was warmed to r.t.
In a second set of preliminary oxidation studies with ru-
thenium catalyst 19, the commercially available sulfide 27
was employed. It reacted in the presence of complex 19
both with bis(acetoxy)iodobenzene and iodosobenzene as
the oxidant resulting in the formation of sulfoxide 28.6b A
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PAPER
Ruthenium Complexes
965
overnight. H2O (100 mL) was added, the layers were separated, and
the aqueous layer was extracted with CH2Cl2 (4 × 150 mL). The
combined organic layers were washed with brine (100 mL), dried
(Na2SO4), filtered, and the solvent was removed in vacuo. The
crude product was purified by flash chromatography (SiO2,
5.5 × 14 cm, P–EtOAc, 3:1 → 1:2) to yield 2.84 g (91%) of alde-
hyde 3 as a white solid; mp 205 °C; Rf = 0.73 (P–EtOAc, 1:1) [UV/
KMnO4].
NaHCO3 (150 mL). The layers were separated; the organic layer
was dried (Na2SO4), filtered, and the solvent was removed in vacuo.
The crude product was purified by flash chromatography (SiO2,
3.5 × 16 cm, P–Et2O, 3:1) to yield 1.73 g (70%) of alkyne 6 as a
white solid; mp 110 °C; Rf = 0.75 (P–Et2O, 1:1) [UV/KMnO4].
IR: 3271, 2923, 2900, 2352, 1663, 1606, 1513, 1460, 1372, 1300,
1231, 1159, 1034, 999, 815 cm–1.
1H NMR (360 MHz, CDCl3): d = 7.34 (d, 3J = 8.6 Hz, 2 H, PMB-m-
IR: 3224, 2972, 2871, 1726, 1687, 1455, 1382, 1202, 887, 805 cm–1.
3
CH), 6.80 (d, J = 8.6 Hz, 2 H, PMB-o-CH), 4.75 (s, 2 H, PMB-
1H NMR (360 MHz, CDCl3): d = 9.28 (br s, 1 H, CHO), 7.62 (br s,
CH2), 3.77 (s, 3 H, OCH3), 2.16 (d, 2J = 12.8 Hz, 2 H, CHH), 1.94
1 H, NH), 2.47–2.43 (m, 2 H, CHH), 1.94 (dt, 2J = 13.4 Hz,
(d, J = 13.2 Hz, 1 H, CHH), 1.85 (s, 1 H, C≡CH), 1.32–1.27 (m,
2
2
4J = 2.2 Hz, 1 H, CHH), 1.35 (d, J = 13.4 Hz, 1 H, CHH), 1.25–
5 H, CHH, CH3), 1.25–1.23 (m, 7 H, CHH, CH3).
1.21 (m, 8 H, CHH, CH3), 0.93 (s, 3 H, CH3).
13C NMR (90.6 MHz, CDCl3): d = 176.8 (s, CO), 158.7 (s, PMB-C–
OCH3), 130.6 (d, PMB-m-CH), 129.6 (s, PMB-p-C), 113.6 (d,
PMB-o-CH), 88.7 (s, C≡CH), 69.4 (d, C≡CH), 55.2 (q, OCH3), 48.0
(t, CH2), 43.0 (t, CH2), 42.8 (t, CH2), 40.3 (s, Cal), 33.1 (q, CH3),
30.3 (s, Cal), 26.1 (q, CH3).
MS (EI, 70 eV): m/z (%) = 339 (25) [M+], 311 (13) [(M – CO)+],
283 (100) [(M – C2O2)+], 254 (23), 228 (53), 175 (24), 162 (20), 121
(97) [C8H9O+], 69 (41).
13C NMR (90.6 MHz, CDCl3): d = 202.6 (d, CHO), 176.1 (s, NCO),
46.3 (s, Cal), 43.5 (t, CH2), 42.0 (t, CH2), 39.9 (s, Cal), 26.0 (q, CH3),
24.4 (q, CH3).
MS (EI, 70 eV): m/z (%) = 224 (2) [(M + H)+], 195 (95) [(M –
CO)+], 167 (36), 139 (100), 123 (53), 110 (73), 41 (27).
Anal. Calcd for C12H17NO3: C, 64.55; H, 7.67; N, 6.27.
Found: C, 64.43; H, 7.68; N, 6.14.
Anal. Calcd for C21H25NO3: C, 74.31; H, 7.42; N, 4.13.
Found: C, 74.02; H, 7.36; N, 4.04.
3-(4-Methoxybenzyl)-1,5,7-trimethyl-2,4-dioxo-3-azabicyc-
lo[3.3.1]nonan-7-carbaldehyde (4)
DBU (3.79 mL, 25.5 mmol, 3.64 equiv) was added to a solution of
imide 3 (1.60 g, 7.17 mmol, 1.00 equiv) and 4-methoxybenzyl
chloride (1.42 mL, 10.8 mmol, 1.50 equiv) in MeCN (51 mL) and
the reaction mixture was heated to 60 °C for 48 h. After cooling to
r.t., the solvent was removed in vacuo and the crude product was
purified by flash chromatography (SiO2, 3.5 × 16 cm, P–
Et2O = 5:1 → 1:1) to yield 1.85 g (75%) of aldehyde 4 as a white
greasy solid and 320 mg (20%) of reisolated starting material 3;
mp 97 °C; Rf = 0.30 (P–Et2O, 1:1) [UV/KMnO4].
rac-11-Methoxy-2,3a,5-trimethyl-1,3,3a,3a1,4,5,8,12b-octahy-
dro-2,5-methanopyrido[3,2,1-de] phenanthridin-6(2H)-one
(rac-10)
LiBEt3H (1 M in THF, 55.0 mL, 55.0 mmol, 1.25 equiv) was added
to a solution of alkyne 6 (15.0 mg, 44.2 mmol, 1.00 equiv) in
CH2Cl2 (0.8 mL) at –60 °C and the reaction mixture was stirred for
2 h at this temperature. Subsequently, Ac2O (8.3 mL, 88.4 mmol,
2.00 equiv) was added and the reaction mixture was warmed to r.t.
overnight. Sat. aq NaHCO3 (5 mL) was added and the mixture was
extracted with CH2Cl2 (5 × 8 mL). The combined organic layers
were dried (Na2SO4) and filtered. The solvents were removed in
vacuo to yield 18.0 mg of a colorless resin, which was dissolved in
trifluoroacetic acid (500 mL) and treated with Et3SiH (53.0 mL,
334 mmol, 8.00 equiv) at r.t. The mixture was stirred for 3 h and the
solvent was removed in vacuo. The residue was treated with sat. aq
NaHCO3 (5 mL) and was extracted with CH2Cl2 (5 × 8 mL). The
combined organic layers were dried (Na2SO4), filtered, and the sol-
vent was removed in vacuo. The crude product was purified by flash
chromatography (SiO2, 1.5 × 16 cm, P–Et2O, 1:1) to yield 8.1 mg
(56%) of amide rac-10 as a white resin; Rf = 0.31 (P–Et2O) [UV/
KMnO4].
IR: 2962, 1726, 1668, 1509, 1426, 1348, 1241, 1159, 1038, 999,
820 cm–1.
1H NMR (360 MHz, CDCl3): d = 9.16 (br s, 1 H, CHO), 7.28–7.24
(dd, 3J = 6.7 Hz, 4J = 2.2 Hz, 2 H, PMB-m-CH), 6.80–6.77 (dd,
3J = 6.7 Hz, 4J = 2.2 Hz, 2 H, PMB-o-CH), 4.60 (s, 2 H, PMB-
CH2), 3.76 (s, 3 H, OCH3), 2.48 (dd, 2J = 14.8 Hz, 4J = 1.8 Hz, 2 H,
4
CHH), 1.87 (dt, 2J = 13.3 Hz, J = 2.0 Hz, 1 H, CHH), 1.36 (d,
2J = 13.3 Hz, 1 H, CHH), 1.28–1.27 (m, 8 H, CHH, CH3, 0.96 (s,
3 H, CH3).
13C NMR (90.6 MHz, CDCl3): d = 202.6 (d, CHO), 176.2 (s, NCO),
158.8 (s, PMB-C–OCH3), 130.5 (d, PMB-m-CH), 129.3 (s, PMB-p-
C), 113.6 (d, PMB-o-CH), 55.2 (q, OCH3), 46.3 (s, Cal), 42.9 (t,
CH2), 42.5 (t, CH2), 42.4 (t, CH2), 40.1 (s, Cal), 25.7 (q, CH3), 25.6
(q, CH3).
IR: 2928, 2337, 1655, 1606, 1500, 1448, 1419, 1376, 1309, 1275,
1150, 1044, 814 cm–1.
1H NMR (360 MHz, CDCl3): d = 6.93 (d, 3J = 8.1 Hz, 1 H, CHar),
6.68–6.64 (m, 2 H, CHar), 5.96 (d, 2J = 16.8 Hz, 1 H, NCHH), 3.87
(d, 2J = 16.8 Hz, 1 H, NCHH), 3.77 (s, 3 H, OCH3), 3.37 (d,
3J = 7.8 Hz, 1 H, NCH), 2.53 (virt. t, J = ~13.1 Hz, 1 H, CHH), 2.18
(dd, 2J = 13.6 Hz, 3J = 4.7 Hz, 1 H, CHH), 1.92 (ddd, 3J = 12.5 Hz,
MS (EI, 70 eV): m/z (%) = 343 (30) [M+], 315 (10) [(M – CO)+],
121 (100) [C8H9O+].
HRMS (EI): m/z [M+] calcd for C20H25NO4: 343.1784;
found: 343.1775.
3
3J = 7.8 Hz, J = 4.7 Hz, 1 H, CH), 1.72 (d, 2J = 14.2 Hz, 1 H,
Anal. Calcd for C20H25NO4: C, 69.95; H, 7.34; N, 4.08.
Found: C, 69.98; H, 7.55; N, 4.06.
CHH), 1.64 (d, 2J = 12.4 Hz, 1 H, CHH), 1.40–1.37 (m, 2 H, CHH,
CHH), 1.26–1.17 (m, 5 H, CHH, CH3), 1.14 (s, 3 H, CH3), 0.95 (s,
3 H, CH3).
7-Ethynyl-3-(4-methoxybenzyl)-1,5,7-trimethyl-3-azabicyc-
lo[3.3.1]nonan-2,4-dione (6)
13C NMR (90.6 MHz, CDCl3): d = 179.5 (s, CO), 158.3 (s, Ar-C–
OCH3), 136.9 (s, Car), 131.1 (d, CHar), 130.0 (s, Car), 113.1 (d,
CHar), 111.9 (d, CHar), 65.9 (d, NCH), 55.6 (d, CHal), 54.3 (q,
OCH3), 54.9 (t, NCH2), 49.5 (t, CH2), 47.8 (t, CH2), 43.0 (s, Cal),
41.0 (s, Cal), 39.8 (t, CH2), 39.7 (s, Cal), 28.1 (t, CH2), 26.8 (q, CH3),
25.1 (q, CH3), 24.6 (q, CH3).
Anhyd K2CO3 (2.36 g, 17.1 mmol, 2.34 equiv) was added to a solu-
tion of dimethyl 1-diazo-2-oxopropylphosphonate11 (5; 2.80 g,
14.6 mmol, 2.00 equiv) in MeOH (29 mL) at 0 °C and the resulting
yellow suspension was stirred for 1 h. Subsequently, a solution of
aldehyde 4 (2.50 g, 7.28 mmol, 1.00 equiv) in THF (33 mL) was
added within 15 min and the reaction mixture was stirred for 2 h at
0 °C and for 16 h at r.t. The solvents were removed in vacuo and the
residue was dissolved in a mixture of Et2O (150 mL) and sat. aq
MS (EI, 70 eV): m/z (%) = 325 (100) [M+], 297 (11) [(M – CO)+],
240 (20), 189 (8), 134 (23), 121 (13), 91 (9).
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F. Voss et al.
PAPER
HRMS (EI): m/z [M+] calcd for C21H27NO2: 325.2042;
found: 325.2035.
13C NMR (90.6 MHz, CDCl3): d = 176.2 (s, CO), 89.6 (s, C≡CH),
67.7 (d, C≡CH), 52.3 (t, NCH2), 51.2 (t, CH2), 47.9 (t, CH2), 44.1 (t,
CH2), 38.1 (s, Cal), 34.3 (q, CH3), 30.5 (s, Cal), 30.1 (s, Cal), 29.8 (q,
CH3), 25.5 (q, CH3).
MS (EI, 70 eV): m/z (%) = 205 (29) [M+], 190 (34) [(M – CH3)+],
177 (40) [(M – CO)+], 162 (71) [(M – C2H3O)+], 148 (27), 134 (24),
122 (100), 107 (50), 96 (70), 91 (59).
7-Ethynyl-1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2,4-dione
(11)
Cerium ammonium nitrate (8.56 g, 15.6 mmol, 5.00 equiv) was
added to a solution of alkyne 6 (1.06 g, 3.13 mmol, 1.00 equiv) in a
mixture of MeCN (204 mL) and H2O (24 mL) at 0 °C. The reaction
mixture was stirred for 15 min at 0 °C and for 15 h at r.t. It was sub-
sequently diluted with H2O (100 mL) and the aqueous layer was ex-
tracted with EtOAc (3 × 100 mL). The combined organic layers
were dried (Na2SO4), filtered, and the solvent was removed in vac-
uo. The crude product was purified by flash chromatography (SiO2,
2.0 × 17 cm, P–EtOAc, 6:1 → 1:1) to yield 685 mg (>99%) of
amide 11 as a white solid; mp 133 °C; Rf = 0.77 (P–EtOAc, 1:1)
[UV/KMnO4].
HRMS (EI): m/z [M+] calcd for C13H19NO: 205.1467;
found 205.1469.
The enantiomers 1 and ent-1 were separated by semipreparative
HPLC (AS-H, hexane–i-PrOH, 70:30, 19 mL/min, 50 mg/injec-
tion), and the absolute configuration was elucidated by NMR titra-
tion experiments.32
(1S,5R,7S)-7-Ethynyl-1,5,7-trimethyl-3-azabicyc-
lo[3.3.1]nonan-2-one (1)
IR: 3288, 2965, 2928, 1716, 1691, 1453, 1381, 1327, 1219, 1197,
841, 800, 661 cm–1.
[a]D20 –55.0 (c = 0.9, CHCl3).
1H NMR (360 MHz, CDCl3): d = 7.70 (br s, 1 H, NH), 2.17 (d,
2J = 14.4 Hz, 2 H, CHH), 2.09–2.03 (m, 2 H, CHH, C≡CH), 1.37–
1.26 (m, 12 H, CHH, CH3).
13C NMR (90.6 MHz, CDCl3): d = 177.0 (s, CO), 87.9 (s, C≡CH),
70.5 (d, C≡CH), 47.4 (t, CH2), 44.0 (t, CH2), 40.0 (s, Cal), 33.5 (q,
CH3), 30.2 (s, Cal), 24.9 (q, CH3).
MS (EI, 70 eV): m/z (%) = 219 (14) [M+], 191 (40) [(M – CO)+],
176 (57), 163 (100) [(M – C2O2)+], 148 (79), 136 (90), 121 (36), 108
(54), 91 (77).
HPLC (AS-H, 250 × 20 mm, hexane–i-PrOH, 70:30, 19 mL/
min): tR = 6.8 min.
(1R,5S,7R)-7-Ethynyl-1,5,7-trimethyl-3-azabicyc-
lo[3.3.1]nonan-2-one (ent-1)
[a]D20 +50.2 (c = 1.0, CHCl3).
HPLC (AS-H, 250 × 20 mm, hexane–i-PrOH, 70:30, 19 mL/
min): tR = 10.1 min.
(1R,5S,7R)-7-[2,6-Bis(2-pyridyl)pyridin-4-ylethynyl]-1,5,7-tri-
methyl-3-azabicyclo[3.3.1]nonan-2-one (13)
HRMS (EI): m/z [M+] calcd for C13H17NO2: 219.1259;
found: 219.1256.
A dry Schlenk tube was charged with alkyne ent-1 (24.5 mg,
119 mmol, 1.00 equiv) and triflate 1217 (50.1 mg, 131 mmol,
1.10 equiv) in THF (1.65 mL). The solution was degassed under ar-
gon by three freeze-pump-thaw cycles. CuI (2.3 mg, 7.31 mmol,
0.10 equiv), [Pd(PPh3)2Cl2] (4.2 mg, 5.95 mmol, 0.05 equiv) and
Et3N (312 mL, 2.26 mmol, 19.0 equiv) were added and the resulting
mixture was degassed by another four freeze-pump-thaw cycles.
The reaction solution was heated under argon to 50 °C for 12 h. Af-
ter cooling to r.t., H2O (15 mL) was added, and the mixture was ex-
tracted with EtOAc (5 × 20 mL). The combined organic layers were
washed with brine (15 mL), dried (Na2SO4), filtered, and the sol-
vent was removed in vacuo. The crude product was purified by flash
chromatography (Al2O3, 2.5 × 18 cm, THF–CH, 2:1 → 1:1) to
yield 52 mg (93%) of terpyridine 13 as a colorless resin; mp 247 °C;
Rf = 0.33 (Al2O3 neutral, Act. 1; THF–CH, 1:1) [UV, KMnO4];
[a]D20 +27.6 (c = 1.1, CHCl3).
rac-7-Ethynyl-1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-one
(rac-1)
NaBH4 (1.03 g, 27.2 mmol, 10.1 equiv) and H2O (250 mL,
13.9 mmol, 5.13 equiv) were consecutively added to a solution of
imide 11 (595 mg, 2.71 mmol, 1.00 equiv) in THF (55 mL) at r.t.
After 18 h, another portion of H2O (100 mL, 5.56 mmol, 2.05 equiv)
was added and the reaction mixture was stirred for another 8 h until
(according to TLC) the starting material had been completely con-
sumed. Sat. aq NH4Cl (100 mL) was added and the mixture was ex-
tracted with EtOAc (3 × 100 mL). The combined organic layers
were dried (Na2SO4). After filtration, the solvent was removed in
vacuo to yield 756 mg of a white foam, which was subsequently dis-
solved in CH2Cl2 (60 mL). To this solution were consecutively add-
ed Et3SiH (3.50 mL, 21.7 mmol, 8.00 equiv) and trifluoroacetic
acid (1.00 mL, 13.6 mmol, 5.00 equiv) at 0 °C and the reaction mix-
ture was stirred at r.t. for 25 h. Sat. NaHCO3 (50 mL) was added, the
layers were separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 50 mL). The combined organic layers were dried
(Na2SO4), filtered, and the solvent was removed in vacuo. The
crude product was purified by flash chromatography (SiO2,
2.5 × 17 cm, P–EtOAc–MeOH, 2:1:0 → 0:19:1) to yield 420 mg
(76%) of amide rac-1 as a white solid; mp 103 °C; Rf = 0.30 (P–
EtOAc, 1:1) [UV/KMnO4].
IR: 2956, 1670, 1600, 1581, 1566, 1465, 1446, 1269, 1112, 898,
815, 748, 734 cm–1.
1H NMR (360 MHz, CDCl3): d = 8.68 (ddd, 3J = 4.8 Hz,
4J = 1.8 Hz, 5J = 1.0 Hz, 2 H, CHar), 8.55 (dt, 3J = 7.9 Hz,
5J = 1.0 Hz, 2 H, CHar), 8.37 (s, 2 H, CHar), 7.82 (m, 2 H, CHar),
7.13 (ddd, 3J = 7.5 Hz, 3J = 4.8 Hz, 4J = 1.2 Hz, 2 H CHar), 5.85 (br
s, 1 H, NH), 3.49 (ddd, 3J = 11.6 Hz, 4J = 3.1 Hz, 4J = 1.5 Hz, 1 H,
NCHH), 3.18 (d, 2J = 11.6 Hz, 1 H, NCHH), 2.25 (dt, 2J = 13.7 Hz,
2
4
4J = 2.0 Hz, 1 H, CHH), 1.99 (dt, J = 14.1 Hz, J = 2.1 Hz, 1 H,
IR: 3304, 2967, 2116, 1660, 1496, 1453, 1415, 1318, 1275, 1231,
1117, 1083, 819, 655 cm–1.
CHH), 1.76 (dt, 2J = 12.6 Hz, 4J = 2.1 Hz, 1 H, CHH), 1.36 (s, 3 H,
2
4
CH3), 1.33 (dd, J = 13.7 Hz, J = 1.5 Hz, 1 H, CHH), 1.20 (dd,
1H NMR (360 MHz, CDCl3): d = 5.73 (br s, 1 H, NH), 3.42 (ddd,
2J = 11.9 Hz, 4J = 3.3 Hz, 4J = 1.7 Hz, 1 H, NCHH), 3.16 (ddd,
2J = 11.9 Hz, 4J = 1.7 Hz, 4J = 0.8 Hz, 1 H, NCHH), 2.10 (dt,
2J = 12.6 Hz, J = 1.6 Hz, 1 H, CHH), 1.19–1.15 (m, 4 H, CHH,
4
CH3), 1.01 (s, 3 H, CH3).
13C NMR (90.6 MHz, CDCl3): d = 176.0 (s, CO), 155.8 (s, Car),
155.4 (s, Car), 149.1 (d, CHar), 136.8 (d, CHar), 134.0 (s, Car), 123.8
(d, CHar), 123.0 (d, CHar), 121.2 (d, CHar), 100.7 (s, C≡CAr), 78.2
(s, C≡CAr), 52.5 (t, NCH2), 51.3 (t, CH2), 48.2 (t, CH2), 44.2 (t,
CH2), 38.3 (s, Cal), 33.8 (q, CH3), 31.1 (s, Cal), 30.6 (s, Cal), 29.8 (q,
CH3), 25.5 (q, CH3).
4
2J = 13.5 Hz, J = 2.1 Hz, 1 H, CHH), 1.99 (s, 1 H, C≡CH), 1.87
2
4
2
(dt, J = 13.8 Hz, J = 2.1 Hz, 1 H, CHH), 1.76 (dt, J = 12.8 Hz,
4J = 2.3 Hz, 1 H, CHH), 1.26 (s, 3 H, CH3), 1.22 (dd, 2J = 13.8 Hz,
4J = 1.7 Hz, 1 H, CHH), 1.16 (dd, J = 12.8 Hz, J = 1.7 Hz, 1 H,
CHH), 1.15 (s, 3 H, CH3), 1.07 (d, 2J = 13.5 Hz, 1 H, CHH), 1.00 (s,
3 H, CH3).
2
4
Synthesis 2011, No. 6, 961–971 © Thieme Stuttgart · New York

PAPER
Ruthenium Complexes
967
MS (EI, 70 eV): m/z (%) = 437 (100) [(M + H)+], 357 (10) [(M –
C5H5N)+], 277 (56) [(M – C10H11N2)+], 218 (12), 201 (16), 183 (11),
84 (29), 49 (37).
HRMS (EI): m/z calcd for C28H29N4O [(M + H)+]: 437.2341; found:
437.2339.
13C NMR (90.6 MHz, CD3CN): d = 158.9 (s, Car), 158.6 (s, Car),
156.2 (s, Car), 156.1 (s, Car), 153.4 (d, CHar), 139.1–139.0 (d, CHar),
136.9 (d, CHar), 136.7 (d, CHar), 132.3 (s, Car), 128.5 (d, CHar),
128.4 (d, CHar), 126.5 (d, CHar), 125.4-125.3 (d, CHar), 124.7 (d,
CHar), 107.2 (s, C≡CAr), 78.0 (s, C≡CAr), 53.4 (t, NCH2), 51.3 (t,
CH2), 49.1 (t, CH2), 44.5 (t, CH2), 39.2 (s, Cal), 33.4 (q, CH3), 32.2
(s, Cal), 31.3 (s, Cal), 29.8 (q, CH3), 25.9 (q, CH3). Despite prolonged
data acquisition time, the signal for the quaternary C=O carbon was
not detected.
X-ray Single Crystal Structure Determination of Compound 13
Crystal data: Formula: C28H28N4O; Mr = 436.54; crystal color and
shape: colorless plate, crystal dimensions = 0.15 × 0.41 × 0.46 mm;
crystal system: orthorhombic; space group Pbca (no. 61);
a = 15.2471(4), b = 11.4932(3), c = 27.2824(8) Å; V = 4780.9(2)
Å3; m(MoKa) = 0.075 mm–1; rcalcd = 1.213 g cm–3; q-range = 1.49–
25.35°; data collected: 79515; independent data [Io>2s(Io)/all data/
Rint]: 3686/4359/0.032; data/restraints/parameters: 4359/0/410; R1
[Io>2s(Io)/all data]: 0.0382/0.0471; wR2 [Io>2s(Io)/all data]:
0.0993/0.1092; GOF = 1.077; Drmax/min: 0.17/–0.17 e Å–3.
HRMS (+ESI): m/z calcd for C43H39F6N7OPRu [(M – PF6)+]:
916.1896; found: 916.1869; m/z calcd for C43H39N7ORu [(M – 2
PF6)2+]: 385.6125; found: 385.6116.
UV-Vis (CH2Cl2): lmax (e) = 484 (22 115), 310 (67 308), 274 nm
(56 731).
{(1R,5S,7R)-7-[(2,6-Bis(2-pyridyl)pyridin-4-ylethynyl)-1,5,7-
trimethyl-3-azabicyclo[3.3.1]nonan-2-one][2,6-dicarboxylate-
pyridine]}ruthenium(II) (15)
Suitable single crystals for the X-ray diffraction study were grown
from a saturated solution of 13 in a CH2Cl2–pentane mixture. Crys-
tals were stored under perfluorinated ether and fixed on the top of
a glass fiber. Preliminary examination and data collection were car-
ried out on an area detecting system (Bruker AXS, APEX II, k-
CCD; FR591 rotating anode) and graphite-monochromated Mo-Ka
radiation (l = 0.71073 Å). The unit cell parameters were obtained
by full-matrix least-squares refinements during the scaling proce-
dure. Data collection was performed at 293 K. The selected crystal
was measured with a couple of data sets (seven runs; 2985 frames)
in rotation scan modus (Dj/Dw = 0.50°; dx = 65 mm). Intensities
were integrated and the raw data were corrected for Lorentz, polar-
ization, and, arising from the scaling procedure for latent decay and
absorption effects. The structure was solved by a combination of di-
rect methods and difference Fourier syntheses. All non-hydrogen
atoms were refined with anisotropic displacement parameters. All
hydrogen atom positions were found in the difference Fourier map
calculated from the model containing all non-hydrogen atoms. The
hydrogen positions were refined with individual isotropic displace-
ment parameters. Full-matrix least-squares refinements were car-
ried out by minimizing Sw(Fo2 – Fc2)2 with the Shelxl-97 weighting
scheme and stopped at shift/err <0.001. The final residual electron
density maps showed no remarkable features. Neutral atom scatter-
ing factors for all atoms and anomalous dispersion corrections for
the non-hydrogen atoms were taken from International Tables for
Crystallography. All calculations were performed with the Wingx
system, including the programs Platon, Shelxl-97, and Sir92.
A solution of dipicolinic acid (12.6 mg, 76.6 mmol, 1.00 equiv) and
NaOH (6.1 mg, 152 mmol, 2.01 equiv) in MeOH (0.8 mL) and H2O
(0.4 mL) was degassed for 10 min by purging with argon and was
then added to a solution of terpyridine 13 (33.0 mg, 76.6 mmol,
1.00 equiv) and [dichloro(p-cymene)ruthenium(II)]2 (23.0 mg,
37.8 mmol, 0.500 equiv) in anhyd MeOH (1.1 mL). The mixture
was heated to 65 °C for 1 h. After cooling to r.t., the reaction flask
was stored in a freezer at –30 °C overnight resulting in the forma-
tion of a purple solid, which was isolated through filtration. After
drying in vacuo, 39.1 mg (73%) of ruthenium complex 15 was ob-
tained as a purple solid.
IR: 3082, 2914, 2116, 1650, 1621, 1500, 1481, 1395, 1328, 1217,
1150, 1035, 871, 679 cm–1.
1H NMR (360 MHz, CD2Cl2): d = 8.68 (d, 3J = 8.7 Hz, 2 H, CHar),
8.58 (d, 3J = 7.9 Hz, 2 H, CHar), 8.35 (s, 1 H, CHar), 8.31 (s,
3J = 7.7 Hz, 1 H, CHar), 7.86 (td, 3J = 7.8 Hz, 4J = 1.6 Hz, 2 H,
CHar), 7.70–7.63 (m, 1 H, CHar), 7.50–7.47 (m, 1 H, CHar), 7.34 (dd,
3J = 6.6 Hz, 4J = 4.9 Hz, 2 H, CHar), 7.21–7.14 (m, 1 H, CHar), 5.61
(br s, 1 H, NH), 3.43–3.39 (m, 1 H, NCHH), 3.18 (d, 2J = 11.9 Hz,
1 H, NCHH), 2.20 (d, 2J = 13.4 Hz, 1 H, CHH), 2.01 (d,
2J = 14.0 Hz, 1 H, CHH), 1.81 (d, 2J = 12.8 Hz, 1 H, CHH), 1.24–
1.02 (m, 9 H, CHH, CH3), 0.87–0.85 (m, 3 H, CH3).
A
13C NMR spectrum could not be recorded due to the very poor
solubility of complex 15,
MS (+ESI): m/z = 704 (100) [(M + H)+].
{(1R,5S,7R)-7-[(2,6-Bis(2-pyridyl)pyridin-4-ylethynyl)-1,5,7-
trimethyl-3-azabicyclo[3.3.1]nonan-2-one][2,6-bis(2-py-
ridyl)pyridine]}ruthenium(II) Bis(hexafluorophosphate) (14)
A suspension of [(tpy)RuCl3]33 (50.0 mg, 113 mmol, 1.00 equiv),
terpyridine 13 (35.0 mg, 113 mmol, 1.00 equiv) and N-ethylmor-
pholine (5 drops) in anhyd EtOH (7.0 mL) was heated to reflux for
18 h. After cooling to r.t., the mixture was filtered and the deep-red
solution was treated with NH4PF6 (92.0 mg, 565 mmol, 5.00 equiv),
which resulted in the precipitation of a red solid. The precipitate was
isolated by filtration and washed with EtOH (2 × 5 mL). After dry-
ing in vacuo, 81.0 mg (68%) of ruthenium complex 14 were ob-
tained as a deep-red solid; [a]D20 –7.3 (c = 0.1, CHCl3).
HRMS (+ESI): m/z calcd for C37H35N6O5Ru [(M + CH3CN +
H)+]: 745.1712; found: 745.1709.
UV-Vis (MeOH): lmax (e) = 403 (3158), 322 (5965), 283 nm
(9123).
(1S,5R,7S)-7-(2,2¢-Bipyridin-5-ylethynyl)-1,5,7-trimethyl-3-
azabicyclo[3.3.1]nonan-2-one (16)
A dry Schlenk tube was charged with alkyne 1 (20.0 mg, 97.4 mmol,
1.00 equiv) and 5-bromo-2,2¢-bipyridine24 (25.2 mg, 107 mmol,
1.10 equiv) in THF (1.5 mL). This solution was degassed under ar-
gon by three freeze–pump–thaw cycles. CuI (2.0 mg, 9.74 mmol,
0.10 equiv), [Pd(PPh3)2Cl2] (3.4 mg, 8.87 mmol, 0.05 equiv) and
Et3N (256 mL, 187 mg, 1.85 mmol, 19.0 equiv) were added and the
resulting mixture was degassed by another four freeze–pump–thaw
cycles. The reaction solution was heated to 50 °C for 16 h. After
cooling to r.t., sat. aq NH4Cl (10 mL) was added and the mixture
was extracted with EtOAc (3 × 15 mL). The combined organic lay-
ers were washed with brine (10 mL), dried (Na2SO4), filtered, and
the solvent was removed in vacuo. The crude product was purified
by flash chromatography (SiO2, 2.5 × 18 cm, EtOAc–MeOH, 95:5)
to yield 26.5 mg (76%) of bipyridine 16 as a colorless resin; mp
IR: 2912, 2111, 1766, 1650, 1601, 1476, 1448, 1390, 1155, 1112,
1030, 833, 756 cm–1.
1H NMR (360 MHz, CD3CN): d = 8.79–8.74 (m, 4 H, CHar), 8.51–
8.39 (m, 5 H, CHar), 7.94–7.89 (m, 4 H, CHar), 7.38–7.33 (m, 4 H,
CHar), 7.18–7.14 (m, 4 H, CHar), 6.34 (br s, 1 H, NH), 3.51 (dd,
2J = 12.3 Hz, 4J = 4.4 Hz, 1 H, NCHH), 3.29 (d, 2J = 12.3 Hz, 1 H,
2
4
NCHH), 2.21 (dt, J = 13.5 Hz, J = 1.9 Hz, 1 H, CHH), 2.10 (d,
2J = 13.9 Hz, 1 H, CHH), 1.95–1.91 (m, 1 H, CHH), 1.55 (dd,
2J = 13.9 Hz, 4J = 1.6 Hz, 1 H, CHH), 1.49 (s, 3 H, CH3), 1.44–1.37
(m, 2 H, CHH), 1.20 (s, 3 H, CH3), 1.11 (s, 3 H, CH3).
Synthesis 2011, No. 6, 961–971 © Thieme Stuttgart · New York

968
F. Voss et al.
PAPER
(1R,5S,7R)-7-{2-[2,6-Bis(4,5-dihydrooxazol-2-yl)pyridin-4-
147 °C; Rf = 0.23 (EtOAc–MeOH, 95:5); [a]D20 +9.1 (c = 1.0,
CHCl3).
IR: 3200, 2962, 2924, 1663, 1494, 1450, 853, 795, 752, 733 cm–1.
1H NMR (360 MHz, CDCl3): d = 8.67 (d, 3J = 4.8 Hz, 1 H, CHar),
8.64 (d, J = 2.0 Hz, 1 H, CHar), 8.37 (d, J = 8.0 Hz, 1 H, CHar),
yl]ethynyl}-1,3,5-trimethyl-3-azabicyclo[3.3.1]nonan-2-one(18)
A dry Schlenk tube was charged with alkyne ent-1 (10.0 mg, 49.0
mmol, 1.00 equiv) and 4-bromo-2,6-bis(4,5-dihydrooxazol-2-
yl)pyridine26 (15.0 mg, 51.0 mmol, 1.05 equiv) in THF (1.0 mL).
The solution was degassed under argon by three freeze–pump–thaw
cycles. CuI (0.9 mg, 4.90 mmol, 0.10 equiv), [Pd(PPh3)2Cl2]
(1.7 mg, 2.45 mmol, 0.05 equiv) and Et3N (330 mL, 2.32 mmol,
47.3 equiv) were added and the resulting mixture was degassed by
another three freeze–pump–thaw cycles. The reaction solution was
heated to 60 °C for 16 h and after cooling to r.t., the solvents were
removed in vacuo. The residue was dissolved in EtOAc (20 mL)
and washed with aq NaOH (0.1 M, 10 mL). The organic layer was
dried (Na2SO4), filtered, and the solvent was removed in vacuo. The
crude product was purified by flash chromatography (1.0 × 15 cm,
CH2Cl2–MeOH, 19:1 → 15:1 → MeOH) to yield 19.0 mg (92%) of
the pybox ligand 18 as a colorless solid; Rf = 0.05 (CH2Cl2–
MeOH, 9:1) [UV, KMnO4]; [a]D20 +16.0 (c = 1.15, CHCl3).
4
3
3
8.31 (d, J = 8.2 Hz, 1 H, CHar), 7.84–7.78 (m, 2 H, CHar), 7.32–
7.27 (m, 1 H, CHar), 5.52 (br s, 1 H, NH), 3.44 (ddd, 2J = 11.8 Hz,
4J = 3.0 Hz, J = 1.6 Hz, 1 H, NCHH), 3.19 (d, J = 11.8 Hz, 1 H,
4
2
2
4
NCHH), 2.26 (dt, J = 13.5 Hz, J = 1.7 Hz, 1 H, CHH), 2.01 (dt,
2J = 13.8 Hz, 4J = 1.9 Hz, 1 H, CHH), 1.83 (dt, 2J = 12.8 Hz,
4J = 2.1 Hz, 1 H, CHH), 1.37 (s, 3 H, CH3), 1.35 (dd, 2J = 12.8 Hz,
4J = 1.3 Hz, 1 H, CHH), 1.27–1.22 (m, 1 H, CHH), 1.21 (s, 3 H,
CH3), 1.18–1.15 (m, 1 H, CHH), 1.05 (s, 3 H, CH3).
13C NMR (90.6 MHz, CDCl3): d = 176.3 (s, CO), 155.7 (s, Car),
154.2 (s, Car), 151.4 (d, CHar), 149.2 (d, CHar), 139.5 (d, CHar),
136.9 (d, CHar), 123.7 (d, CHar), 121.2 (d, CHar), 120.9 (s, Car),
120.3 (d, CHar), 100.3 (s, C≡CAr), 77.2 (s, C≡CAr), 52.6 (t, NCH2),
51.4 (t, CH2), 48.4 (t, CH2), 44.3 (t, CH2), 38.5 (s, Cal), 33.7 (q,
CH3), 31.1 (s, Cal), 30.7 (s, Cal), 29.9 (q, CH3), 25.6 (q, CH3).
IR: 3311, 2957, 2920, 1653, 1598, 1538, 1494, 1404, 1244, 1198,
1096, 969, 936, 920 cm–1.
MS (EI, 70 eV): m/z (%) = 359 (10) [M+], 277 (100), [(M –
C6H10)+], 236 (8), 199 (28), 183 (16), 152 (14), 83 (15), 77 (21), 57
(26).
HRMS (EI): m/z calcd for C23H25N3O [M+]: 359.1998; found:
359.1995.
1H NMR (360 MHz, CDCl3): d = 8.09 (s, 2 H, CHar), 5.61 (br s, 1 H,
NH), 4.53 (t, 3J = 9.7 Hz, 4 H, C=NCH2), 4.10 (t, 3J = 9.7 Hz, 4 H,
OCH2), 3.39 (ddd, 2J = 12.0 Hz, 3J = 2.9 Hz, 4J = 1.3 Hz, 1 H,
NCHH), 3.21 (d, 2J = 12.0 Hz, 1 H, NCHH), 2.24 (td, 2J = 13.5 Hz,
2
4
4J = 1.9 Hz, 1 H, CHH), 1.98 (td, J = 13.8 Hz, J = 1.9 Hz, 1 H,
CHH), 1.82 (td, 2J = 13.0 Hz, 4J = 1.9 Hz, 1 H, CHH), 1.36 (s, 3 H,
CH3), 1.36 (dd, 2J = 13.8 Hz, 4J = 1.3 Hz, 1 H, CHH), 1.23 (d,
2J = 13.0 Hz, 1 H, CHH), 1.18 (d, 2J = 13.5 Hz, 1 H, CHH), 1.18 (s,
3 H, CH3), 1.05 (s, 3 H, CH3).
Bis(2,2¢-bipyridine)[(1S,5R,7S)-7-(2,2¢-bipyridin-5-ylethynyl)-
1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-one]ruthenium(II)
Bis(hexafluorophosphate) (17)
13C NMR (90.6 MHz, CDCl3): d = 176.0 (s, C=O), 163.2 (s, C=N),
146.6 (s, Car), 134.0 (s, Car), 127.4 (d, Car), 103.4 (s, C≡CAr), 76.7
(s, C≡CAr), 68.4 (t, OCH2), 54.9 (t, C=NCH2), 52.6 (t, CH2), 51.0
(t, CH2), 48.1 (t, CH2), 44.2 (t, CH2), 38.4 (s, Cal), 33.5 (q, CH3),
31.2 (s, Cal), 30.6 (s, Cal), 29.7 (q, CH3), 25.5 (q, CH3).
MS (EI, 70 eV): m/z (%) = 420 (10) [M+], 364 (5), 282 (10), 277
(28), 183 (8), 167 (31), 149 (68), 113 (10), 71 (20), 44 (100)
[C2H4O+].
A suspension of bipyridine 16 (20.0 mg, 55.6 mmol, 1.10 equiv) and
[(bpy)2RuCl2]34 (26.3 mg, 50.6 mmol, 1.00 equiv) in a mixture of
EtOH (2.5 mL) and H2O (5 mL) was degassed by purging with ar-
gon for 5 min and then heated to reflux for 16 h. After cooling to r.t.,
the solvents were removed in vacuo and the residue was dissolved
in MeOH (1.5 mL). Upon addition of KPF6 (5.30 mg, 288 mmol,
5.69 equiv) a red solid precipitated, which was isolated by filtration
and washed with H2O (2 × 2 mL). After drying in vacuo 50.6 mg
20
(94%) of ruthenium complex 17 was obtained as a red solid; [a]D
–1.0 (c = 0.1, MeOH).
HRMS (EI): m/z calcd for C24H28N4O3 [M+]: 420.2162; found:
420.2161.
IR: 2953, 2120, 1648, 1606, 1460, 1441, 1242, 1111, 824, 767, 718,
679 cm–1.
{(1R,5S,7R)-7-[2-(2,6-Bis(4,5-dihydrooxazol-2-yl)pyridin-4-
yl]ethynyl)-1,3,5-trimethyl-3-azabicyclo[3.3.1]nonan-2-
one}(2,6-dicarboxylate-pyridine)ruthenium(II) (19)
Due to the chirality of the octahedrally coordinated ruthenium metal
center, complex 17 was obtained as a 1:1 mixture of two diastereo-
isomers. As a result there are two sets of signals in the NMR spectra.
1H NMR (360 MHz, CD3CN): d = 8.53–8.41 (m, 6 H, CHar), 8.10–
7.95 (m, 6 H, CHar), 7.84–7.52 (m, 6 H, CHar), 7.45–7.36 (m, 5 H,
CHar), 5.60 (br s, 0.5 H, NH), 5.47 (br s, 0.5 H, NH), 3.15–2.99 (m,
2 H, NCH2), 1.90–1.68 (m, 3 H, CHH), 1.34–1.23 (m, 2 H, CHH),
1.21–1.15 (m, 4 H, CHH, CH3), 1.02–1.01 (m, 3 H, CH3), 0.98–0.96
(m, 3 H, CH3).
13C NMR (90.6 MHz, CDCl3): d = 176.1 (s, CO), 157.9 (s, Car),
157.6 (s, Car), 156.1 (s, Car), 156.0 (s, Car), 153.0–152.4 (d, CHar),
140.4–140.3 (d, CHar), 138.7 (d, CHar), 133.0 (d, CHar), 132.7–
132.5 (d, CHar), 129.7–129.6 (d, CHar), 128.5 (d, CHar), 125.7–
125.1 (d, CHar), 124.6–124.5 (d, CHar), 106.2 (s, C≡CAr), 106.0 (s,
C≡CAr), 75.7 (s, C≡CAr), 53.0 (t, NCH2), 51.0 (t, NCH2), 48.9 (t,
CH2), 48.7 (t, CH2), 44.3 (t, CH2), 38.9 (s, Cal), 33.2 (q, CH3), 32.5
(s, Cal), 32.0 (s, Cal), 31.7 (s, Cal), 31.7 (s, Cal), 31.0 (s, Cal), 29.7 (q,
CH3), 25.7 (q, CH3).
A solution of dipicolinic acid (16.7 mg, 100 mmol, 1.00 equiv) and
NaOH (8.0 mg, 200 mmol, 2.00 equiv) in MeOH (6.7 mL) and H2O
(6.7 mL) was degassed for 10 min by purging with argon and then
added to a solution of pybox ligand 18 (42.0 mg, 100 mmol,
1.00 equiv) and [dichloro(p-cymene)ruthenium(II)]2 (30.6 mg,
50.0 mmol, 0.50 equiv) in anhyd MeOH (6.7 mL). The mixture was
heated to 65 °C for 1 h. After cooling to r.t., the mixture was diluted
with CH2Cl2 (100 mL) and H2O (100 mL). The layers were separat-
ed and the aqueous layer was extracted with CH2Cl2 (100 mL). The
combined organic layers were dried (Na2SO4) and the solvent was
removed in vacuo. The crude product was purified by flash chroma-
tography (SiO2, 2 × 15 cm, CH2Cl2–MeOH, 15:1 → 12:1) to yield
40.0 mg (58%) of the ruthenium complex 19 as a deep-purple solid;
Rf = 0.10 (CH2Cl2–MeOH, 15:1) [UV, KMnO4].
IR: 3453, 2967, 2953, 1644, 1633, 1622, 1490, 1456, 1397, 1320,
1271, 1029 cm–1.
1H NMR (360 MHz, CDCl3): d = 8.33 (d, 3J = 7.7 Hz, 2 H, CHar),
HRMS (+ESI): m/z calcd for C43H41F6N7OPRu [(M – PF6)+]:
918.2058; found: 918.2063; m/z calcd for C43H41N7ORu [(M – 2
PF6)2+]: 386.6208; found: 386.6203.
8.10 (t, 3J = 7.7 Hz, 1 H, CHar), 7.93 (s, 2 H, CHar), 5.45 (br s, 1 H,
3
2
NH), 4.63 (t, J = 9.6 Hz, 4 H, OCH2), 3.37 (d, J = 11.8 Hz, 1 H,
3
2
NHH), 3.34 (t, J = 9,6 Hz, 4 H, C=NCH2), 3.22 (d, J = 11.8 Hz,
1 H, NHH), 2.31 (td, 2J = 13.5 Hz, 4J = 1.9 Hz, 1 H, CHH), 2.03 (td,
2J = 14.0 Hz, 4J = 1.9 Hz, 1 H, CHH), 1.85 (td, 2J = 12.7 Hz,
UV-Vis (MeOH): lmax (e) = 450 (8738), 288 (55 340), 245 nm
(20 388).
Synthesis 2011, No. 6, 961–971 © Thieme Stuttgart · New York

PAPER
Ruthenium Complexes
969
2
4J = 1.9 Hz, 1 H, CHH), 1.40 (s, 3 H, CH3), 1.37 (d, J = 14.0 Hz,
3J = 8.4 Hz, 3J = 7.3 Hz, 4J = 1.4 Hz, 1 H, H-6), 7.41 (d,
2
3
1 H, CHH), 1.27 (d, J = 12.7 Hz, 1 H, CHH), 1.24 (s, 3 H, CH3),
3J = 16.4 Hz, 1 H, =CH), 7.37 (virt. t, J = ~7.6 Hz, 2 H, Ph-m-
1.23 (d, 2J = 13.5 Hz, 1 H, CHH), 1.06 (s, 3 H, CH3).
CH), 7.31 (dd, 3J = 8.4 Hz, J = 1.1 Hz, 1 H, H-5), 7.27 (tt,
4
4
3J = 7.3 Hz, J = 1.3 Hz, 1 H, Ph-p-CH), 7.24 (ddd, 3J = 8.4 Hz,
13C NMR (90.6 MHz, CDCl3): d = 176.3 (s, C=O), 171.6 (s, CO2),
168.0 (s, C=N), 150.3 (s, Car), 146.6 (s, Car), 135.1 (d, Car), 127.2 (d,
Car), 126.1 (d, Car), 122.1 (s, Car), 103.0 (s, C≡CAr), 77.9 (s,
C≡CAr), 71.4 (t, OCH2), 52.6 (t, CH2), 51.0 (t, CH2), 50.8 (t,
C=NCH2), 48.4 (t, CH2), 44.2 (t, CH2), 38.6 (s, Cal), 33.0 (q, CH3),
31.4 (s, Cal), 30.8 (s, Cal), 29.8 (q, CH3), 25.5 (q, CH3).
3J = 7.3 Hz, 4J = 1.1 Hz, 1 H, H-7), 3.75 (s, 3 H, CH3).
13C NMR (90.6 MHz, CDCl3): d = 161.5 (s, C-2), 139.0 (s, C-8a),
137.4 (s, Ph-i-C), 133.2 (d, C-4), 131.7 (d, =CH), 130.0 (d, C-6),
129.0 (s, C-3), 128.6 (d, Ph-m-CH, C-8), 127.8 (d, Ph-p-CH), 126.8
(d, Ph-o-CH), 123.5 (d, =CH), 122.2 (d, C-7), 120.7 (s, C-4a), 113.8
(d, C-5), 29.7 (q, CH3).
MS (ESI): m/z (%) = 688 (100) [(M + H)+].
MS (EI, 70 eV): m/z (%) = 261 (98) [M+], 260 (100) [(M – H)+], 246
(E)-3-Styrylquinolin-2-one (21)
(15) [(M – CH3)+], 232 (12), 217 (14), 184 (26) [(M – C6H5)+], 130
+
To a deaerated solution of Pd(OAc)2 (11.0 mg, 50.0 mmol, 0.10
equiv) and Ph3P (59.0 mg, 225 mmol, 0.45 equiv) in THF (3 mL)
were added 3-bromoquinolin-2(1H)-one29 (112 mg, 500 mmol,
1.00 equiv), (E)-styrylboronic acid30 (222 mg, 1.50 mmol,
3.00 equiv) and NaOH (200 mg, 5.00 mmol, 10.0 equiv) and the re-
action mixture was heated to 120 °C for 16 h. After cooling to r.t.,
the mixture was diluted with CH2Cl2 (100 mL) and H2O (20 mL).
The layers were separated and the aqueous layer was extracted with
CH2Cl2 (2 × 100 mL). The combined organic layers were dried
(Na2SO4), filtered, and the solvents were removed in vacuo. The
crude product was purified by flash chromatography (SiO2,
2 × 20 cm, CH2Cl2–MeOH, 60:1 → 30:1) to yield 108 mg (87%) of
quinolone 21 as a yellow solid; mp 248 °C; Rf = 0.41 (CH2Cl2–
MeOH, 20:1) [UV, KMnO4].
(7), 77 (2) [C6H5 ].
HRMS (EI): m/z calcd for C18H15NO [M+]: 261.1154; found:
261.1151.
(3-Phenyloxiran-2-yl)quinolin-2(1H)-one (23)
Ruthenium complex 19 (0.6 mg, 1.00 mmol, 0.05 equiv) was added
to a solution of quinolone 22 (4.95 mg, 20.0 mmol, 1.00 equiv) in
toluene (0.5 mL) and the deep-red solution was stirred for 5 min at
r.t. Subsequently, bis(acetoxy)iodobenzene (22.3 mg, 60.0 mmol,
3.00 equiv) was added and the resulting brown suspension was
stirred at r.t. for 6 days. The reaction mixture was purified directly
by flash chromatography (SiO2, 1.0 × 10 cm, CH2Cl2–
MeOH, 70:1 → 30:1) to yield 4.00 mg (76%) of oxirane 23 as a col-
orless solid; mp 204 °C; Rf = 0.46 (CH2Cl2–MeOH, 20:1) [UV,
KMnO4].
IR: 3162, 3005, 2877, 1647, 1558, 1496, 1255, 971, 887, 746, 728,
685 cm–1.
HPLC (AD-H, hexane–i-PrOH, 90:10, 1 mL/min): tR = 22.3 min;
tR = 33.0 min (major enantiomer).
IR: 3010, 2851, 1658, 1573, 1498, 1433, 1263, 1220, 867, 749 cm–1.
1H NMR (500 MHz, CDCl3): d = 10.78 (br s, 1 H, NH), 7.98 (s,
1 H, H-4), 7.64 (d, 2J = 16.4 Hz, 1 H, =CH), 7.62–7.59 (m, 3 H, Ph-
o-CH, H-8), 7.52 (ddd, J = 8.4 Hz, 3J = 7.2 Hz, J = 1.4 Hz, 1 H,
3
4
1H NMR (250 MHz, DMSO-d6): d = 12.01 (br s, 1 H, NH), 7.81 (s,
1 H, H-4), 7.75 (dd, 3J = 8.3 Hz, 4J = 1.2 Hz, 1 H, H-8), 7.52 (ddd,
3J = 8.4 Hz, 3J = 7.2 Hz, 4J = 1.2 Hz, 1 H, H-6), 7.44–7.39 (m, 5 H,
H-6), 7.41 (d, J = 16.4 Hz, 1 H, =CH), 7.40 (virt. t, 3J = ~7.4 Hz,
2
2 H, Ph-m-CH), 7.32 (d, 3J = 8.4 Hz, 1 H, H-5), 7.29 (tt,
3J = 7.4 Hz, 4J = 1.4 Hz, 1 H, Ph-p-CH), 7.23 (ddd, J = 8.0 Hz,
3
4
HAr), 7.36 (d, 3J = 8.4 Hz, J = 1.2 Hz, 1 H, H-5), 7.22 (ddd,
3J = 7.2 Hz, 4J = 1.2 Hz, 1 H, H-7).
3J = 8.3 Hz,3J = 7.2 Hz,4J = 1.2 Hz,1 H, H-7), 4.16 (d, 3J = 1.9 Hz,
13C NMR (90.6 MHz, CDCl3): d = 162.7 (s, C-2), 137.4 (s, C-8a),
137.2 (s, Ph-i-C), 134.9 (d, C-4), 132.2 (d, =CH), 130.1 (d, C-6),
129.1 (s, C-3), 128.7 (d, Ph-m-CH), 128.0 (d, C-8), 127.8 (d, Ph-p-
CH), 126.9 (d, Ph-o-CH), 123.0 (d, =CH), 122.8 (d, C-7), 120.4 (s,
C-4a), 115.1 (d, C-5).
1 H, oxirane-CH), 4.03 (d, 3J = 1.9 Hz, 1 H, oxirane-CH).
13C NMR (62.9 MHz, DMSO-d6): d = 161.2 (s, C-2), 137.9 (s, C-
8a), 136.7 (s, Ph-i-C), 133.7 (d, C-4), 130.2 (d, C-6), 128.8 (s, C-3),
128.4 (d, C-m-CH), 128.4 (d, Ph-p-CH), 128.0 (d, C-8), 125.8 (d,
Ph-o-CH), 122.0 (d, C-7), 118.7 (s, C-4a), 114.9 (d, C-5), 61.4 (d,
oxirane-CH), 57.9 (d, oxirane-CH).
MS (EI, 70 eV): m/z (%) = 247 (100) [M+], 246 (95) [(M – H)+], 228
(21), 217 (15), 202 (46), 170 (11) [(M – C6H5)+], 123 (9), 77 (13)
MS (EI, 70 eV): m/z (%) = 263 (54) [M+], 247 (22) [(M – O)+], 234
+
[C6H5 ], 44 (19).
(42), 218 (16), 172 (100) [(M – C6H5N)+], 129 (60), 91 (22)
HRMS (EI): m/z calcd for C17H13NO [M+]: 247.0997; found:
247.0999; m/z calcd for C17H12NO [(M – H)+]: 246.0919; found:
246.0919.
+
[C6H5N+], 77 (20) [C6H5 ], 44 (62).
HRMS (EI): m/z calcd for C17H13NO2 [M+]: 263.0946; found:
263.0946.
(E)-1-Methyl-3-styrylquinolin-2-one (22)
1-Methyl-(3-phenyloxiran-2-yl)quinolin-2(1H)-one (24)
Oxirane 24 was prepared in full analogy to oxirane 23 and was ob-
tained in 87% yield as a yellow solid; mp 138 °C; Rf = 0.47 (P–
EtOAc, 1:1) [UV, KMnO4].
NaH (60% suspension in mineral oil, 10.0 mg, 237 mmol,
1.50 equiv) was added to a solution of quinolone 21 (39.0 mg,
158 mmol, 1.00 equiv) in THF (2 mL) and the resulting suspension
was stirred for 30 min. MeI (20.0 mL, 316 mmol, 2.00 equiv) was
added and the reaction mixture was stirred at r.t. for 2 h. Sat. aq
NH4Cl (10 mL) was added and the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(Na2SO4), filtered, and the solvents were removed in vacuo. The
crude product was purified by flash chromatography (SiO2,
1.0 × 10 cm, P–EtOAc, 9:1) to yield 34.0 mg (82%) of the quino-
lone 22 as a yellow solid; mp 138 °C; Rf = 0.65 (P–EtOAc, 1:1)
[UV, KMnO4].
HPLC: (AD-H, hexane–i-PrOH, 90:10, 1 mL/min): tR = 30.1 min;
tR = 35.5 min.
IR: 3034, 2924, 1647, 1594, 1499, 1462, 1378, 1296, 1220, 752,
700 cm–1.
1H NMR (360 MHz, CDCl3): d = 7.71 (s, 1 H, H-4), 7.61 (dd,
3J = 8.1 Hz, 4J = 1.4 Hz, 1 H, H-8), 7.52 (ddd, 3J = 8.2 Hz,
3J = 7.3 Hz, 4J = 1.4 Hz, 1 H, H-6), 7.39–7.31 (m, 6 H, CHar), 7.27
3
4
(ddd, 3J = 8.1 Hz, J = 7.3 Hz, J = 1.0 Hz, 1 H, H-7), 4.31 (d,
IR: 3035, 2918, 1637, 1590, 1498, 1458, 1415, 1230, 1233, 975,
749, 732, 690 cm–1.
3J = 1.9 Hz, 1 H, oxirane-CH), 3.79 (d, J = 1.9 Hz, 1 H, oxirane-
3
CH), 3.76 (s, 3 H, CH3).
1H NMR (360 MHz, CDCl3): d = 7.85 (s, 1 H, H-4), 7.89–7.55 (m,
3
3 H, Ph-o-CH, H-8), 7.54 (d, J = 16.4 Hz, 1 H, =CH), 7.51 (ddd,
Synthesis 2011, No. 6, 961–971 © Thieme Stuttgart · New York

970
F. Voss et al.
PAPER
13C NMR (90.6 MHz, CDCl3): d = 161.6 (s, C-2), 139.3 (s, C-8a),
136.6 (s, Ph-i-C), 133.0 (d, C-4), 130.5 (d, C-6), 129.1 (s, C-3),
129.0 (d, C-8), 128.5 (d, Ph-m-CH, Ph-p-CH), 125.9 (d, Ph-o-CH),
122.4 (d, C-7), 120.2 (s, C-4a), 114.1 (d, C-5), 63.1 (d, oxirane-CH),
58.5 (d, oxirane-CH), 29.4 (q, CH3).
MS (EI, 70 eV): m/z (%) = 293 (28) [M+], 278 (10), 265 (9) [(M –
CO)+], 172 (23) [(M – C8H9O)+], 152 (15), 145 (67) [C9H7NO+],
135 (44) [C8H7O2 ] 121 (100) [C8H9O+], 77 (22), 57 (24), 43 (30).
+
HRMS (EI): m/z calcd for C18H15NO3 [M+]: 293.1052; found:
293.1053.
(E)-3-(4-Methoxystyryl)quinolin-2(1H)-one (25)
2H-Benzo[e][1,4]thiazin-3-one-1-oxide (28)
A Schlenk flask was charged with 3-bromoquinolin-2(1H)-one29
(200 mg, 901 mmol, 1.00 equiv), (E)-(4-methoxystyryl)boronic
acid (206 mg, 1.16 mmol, 1.29 equiv), Na2CO3 (478 mg, 4.47
mmol, 5.00 equiv), and [Pd(dppf)Cl2] (66.0 mg, 89.3 mmol,
0.10 equiv) in a mixture of previously degassed DMF (15 mL) and
H2O (3 mL). The reaction mixture was degassed under argon by
three freeze-pump-thaw cycles and was then heated to 100 °C for
2 h. After cooling to r.t., EtOAc (100 mL) and H2O (50 mL) were
added and the layers were separated. The organic layer was washed
with brine (50 mL), dried (Na2SO4), filtered, and the solvent was re-
moved in vacuo. The crude product was purified by flash chroma-
tography (SiO2, 2.0 × 17 cm, CH2Cl2–EtOAc–MeOH, 100:0:0 →
100:10:1) to yield 166 mg (67%) of quinolone 25 as a yellow solid;
mp 258 °C; Rf = 0.69 (EtOAc–MeOH, 95:5) [UV/KMnO4].
Ruthenium complex 19 (1.80 mg, 3.00 mmol, 0.10 equiv) was add-
ed to a solution of sulfide 27 (4.96 mg, 30.0 mmol, 1.00 equiv) in
toluene (0.75 mL) and the deep-red solution was stirred for 5 min at
–25 °C. Subsequently, iodosobenzene (13.2 mg, 60.0 mmol,
2.00 equiv) was added and the resulting brown suspension was
stirred at –25 °C for 96 h. The reaction mixture was purified directly
by flash chromatography (SiO2, 1 × 10 cm, EtOAc–MeOH, 95:5) to
yield 4.3 mg (80%, 12% ee) of sulfoxide 28 as a colorless solid.
The analytical data for compound 28 were in agreement with the lit-
erature data.6b
Acknowledgment
Our research was supported by the Deutsche Forschungsgemein-
schaft (Schwerpunktprogramm 1179 Organokatalyse) and by the
Fonds der Chemischen Industrie (Ph.D. scholarship to Fl.V.).
IR: 2838, 1652, 1599, 1560, 1509, 1433, 1327, 1255, 1174, 1106,
1030, 954, 758 cm–1.
1H NMR (360 MHz, DMSO-d6): d = 11.91 (br s, 1 H, NH), 8.14 (s,
1 H, H-4), 7.69–7.64 (m, 2 H, =CH, H-8), 7.53 (d, 3J = 8.8 Hz, 2 H,
An-m-CH), 7.46 (ddd, 3J = 8.5 Hz, 3J = 7.2 Hz, 4J = 1.4 Hz, 1 H, H-
6), 7.30 (d, 3J = 8.5 Hz, 1 H, H-5), 7.20–7.15 (m, 2 H, H-7, =CH),
6.96 (d, 3J = 8.8 Hz, 2 H, An-o-CH), 3.78 (s, 3 H, OCH3).
13C NMR (90.6 MHz, DMSO-d6): d = 161.1 (s, C-2), 159.1 (s, An-
C–OCH3), 137.5 (s, C-8a), 134.0 (d, =CH), 130.7 (d, = CH), 129.7
(d, CHar), 129.6 (s, Car), 128.4 (s, Car), 127.8 (d, An-m-CH), 127.5
(d, CHar), 121.9 (d, CHar), 121.1 (d, CHar), 119.5 (s, C-4a), 114.7 (d,
C-8), 114.2 (d, An-o-CH), 55.1 (q, OCH3).
MS (EI, 70 eV): m/z (%) = 277 (100) [M+], 262 (30) [(M – CH3)+],
233 (10), 220 (14), 131 (17), 57 (24), 44 (86).
HRMS (EI): m/z calcd for C18H15NO2 [M+]: 277.1105; found:
277.1101.
References
(1) Current address: Novartis Pharma AG, Novartis Campus,
4056 Basel, Switzerland.
(2) Current address: Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena,
CA 91125, USA.
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3-[3-(4-Methoxyphenyl)oxirane-2-yl]quinolin-2(1H)-one (26)
Ruthenium complex 19 (2.50 mg, 3.61 mmol, 0.10 equiv) was add-
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toluene (0.72 mL) and the deep-red solution was stirred for 5 min at
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HPLC (AS-H, 250 × 4.6 mm, hexane–i-PrOH, 80:20, 1 mL/
min): tR = 15.7 min, 27.0 min (major enantiomer).
IR: 3147, 1645, 1614, 1593, 1515, 1230, 1256, 1181, 1155, 1113,
1066, 1023, 970, 750 cm–1.
1H NMR (360 MHz, CDCl3): d = 11.97 (br s, 1 H, NH), 8.05 (s, 1 H,
H-4), 7.84 (d, 3J = 8.7 Hz, 1 H, H-8), 7.64–7.60 (m, 2 H, H-5, H-7),
7.37–7.32 (m, 1 H, H-6), 7.30 (d, 3J = 8.7 Hz, 2 H, An-m-CH), 6.87
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Synthesis 2011, No. 6, 961–971 © Thieme Stuttgart · New York