Synthesis of morphan derivatives with additional substituents in 8-position

Article abstract of DOI:10.1515/znb-2016-0129

The morphan system (2-azabicyclo[3.3.1]nonane) as a substructure of morphine is of major interest in medicinal chemistry. Herein, the synthesis of morphan derivatives with additional substituents at the propano bridge is reported. In order to avoid the isolation of the smelly and volatile nitrile 6 and the very polar primary amine 9, an efficient one-pot, three-step sequential transformation of the mesylate 5 into amides 10 was developed. The key step of the synthesis was the stereoselective intramolecular opening of the epoxides 11a-d leading to the exo-configured 8-hydroxymorphans 12a-d. The configuration of the exo-configured hydroxymorphan 12d bearing the ?- and s-pharmacophoric 3,4-dichlorophenylacetyl moiety was inverted by oxidation and stereoselective reduction. An X-ray crystal structure analysis of the benzamide 12c confirmed the relative configuration of the hydroxymorphans 12a-d and 14d.

Full text of DOI:10.1515/znb-2016-0129

Z. Naturforsch. 2016; 71(10)b: 1057–1069
Janine Stefaowitz, Dirk Schepmann, Constantin Daniliuc, Susumu Saito
and Bernhard Wünsch*
Synthesis of morphan derivatives with additional
substituents in 8-position
DOI 10.1515/znb-2016-0129
Received May 25, 2016; accepted June 10, 2016
1 Introduction
Abstract: The morphan system (2-azabicyclo[3.3.1]nonane)
The bicyclic morphan system (2-azabicyclo[3.3.1]nonane)
as a substructure of morphine is of major interest in medic-
represents a substructure of the natural product mor-
inal chemistry. Herein, the synthesis of morphan deriva-
phine (Fig. 1), which is isolated from the dried condensed
tives with additional substituents at the propano bridge is
juice of a poppy, Papaver somniferum. The strong anal-
reported. In order to avoid the isolation of the smelly and
gesic effect of morphine is based on the activation of μ-,
volatile nitrile 6 and the very polar primary amine 9, an
κ- and δ-opioid receptors in the central nervous system
efficient one-pot, three-step sequential transformation of
[1]. In order to find novel analgesics, compounds based
the mesylate 5 into amides 10 was developed. The key step
on substructures of morphine were developed includ-
of the synthesis was the stereoselective intramolecular
ing morphinanes (without furan ring), benzomorphans
opening of the epoxides 11a–d leading to the exo-config-
(without cyclohexene ring), morphans (without phenyl
ured 8-hydroxymorphans 12a–d. The configuration of the
ring) and piperidines (only piperidine ring is left) [2]. In
exo-configured hydroxymorphan 12d bearing the κ- and
Fig. 1 morphan 1 exhibiting strong analgesic activity is
σ-pharmacophoric 3,4-dichlorophenylacetyl moiety was
shown exemplarily [3].
inverted by oxidation and stereoselective reduction. An
In addition to strong analgesic activity, morphans are
X-ray crystal structure analysis of the benzamide 12c con-
reported to interact with σ receptors as well. Originally,
firmed the relative configuration of the hydroxymorphans
the σ receptor was regarded as an opioid receptor subtype
12a–d and 14d.
[4], but nowadays the class of σ receptors is accepted to
Keywords: intramolecular epoxide opening; inversion of be an own class of receptors with a characteristic ligand
configuration; morphans; nitrile hydration by Ru/chitin binding profile and a distinct distribution pattern in the
catalyst; X-ray crystal structure.
central nervous system and peripheral tissues [5, 6]. The
σ receptor is subdivided into two subtypes, which are
termed the σ1 and σ2 receptor. The morphan derivative 2
with a benzylidene moiety in 8-position adjacent to the
carbonyl group in 7-position represents one of the most
potent and selective σ2 receptor ligands (Ki(σ2)ꢀ=ꢀ16.5 nm)
known so far [7, 8].
Dedicated to: Professor Gerhard Erker on the occasion of his 70th
birthday.
Due to the promising σ2 affinity of 2 we are interested
in morphan derivatives with additional substituents at
the propano bridge (positions 6–8). Various methods
for the synthesis of the morphan framework have been
reported [9]. However, only few methods led to morphans
with additional substituents at the propano bridge.
The intramolecular aminoselenylation of a cyclohex-
ene derivative [10], the gold-catalyzed intramolecular
hydroamination of a cyclohexadiene derivative [11], the
iodolactamization [12] and the intramolecular epoxide
opening [13] represent the most promising approaches
for the synthesis of morphan derivatives, which allow
the further modification of the substitution pattern of
the propano bridge.
*Corresponding author: Bernhard Wünsch, Institut für
Pharmazeutische und Medizinische Chemie der Universität Münster,
Corrensstraße 48, D-48149 Münster, Germany; and Cells-in-Motion
Cluster of Excellence (EXC 1003 – CiM), Westfälische Wilhelms-
Universität Münster, Germany, Tel.: +49-251-8333311,
Fax: +49-251-8332144, E-mail: wuensch@uni-muenster.de
Janine Stefaowitz and Dirk Schepmann: Institut für Pharmazeutische
und Medizinische Chemie der Universität Münster, Corrensstraße
48, D-48149 Münster, Germany
Constantin Daniliuc: Organisch-Chemisches Institut, Corrensstraße
40, D-48149 Münster, Germany
Susumu Saito: Research Center for Materials Science, Nagoya
University Chikusa, Nagoya 464-8602, Japan
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ꢀJ. Stefaowitz et al.: Synthesis of morphan derivatives with additional substituents in 8-position
OH
O
O
7
8
HO
HO
6
1
CH3
N
CH3
N
2
H3CN
OH
2 (CB 64D): Ki(σ1) = 3061 nM
Ki(σ2) = 16.5 nM
1
Morphine
Fig. 1:ꢀMorphine and morphan derivatives 1 and 2.
In this project we decided to use cyclohexene deriva- the surface of chitin had been developed as a heteroge-
tives (e.g. compounds 7–10) as starting materials. Reac- nous nitrile hydration catalyst [16]. Reaction of nitrile 6
tion of the nitrogen atom in various functional groups of with the Ru-chitin catalyst in an aqueous medium at 120°C
the side chain with the cyclohexene double bond should provided the primary amide 7 in 62% yield.
give the morphan system with an additional substituent
in 8-position of the propano bridge.
The iodolactamization has been reported for the cycli-
zation of unsaturated aliphatic primary amides. For this
purpose, the primary amide is reacted with trimethyl-
silyl triflate to yield an N,O-bis(trimethylsilyl) derivative,
which is treated with I2 to form iodolactams [12, 17, 18].
Although several experiments were performed, starting
2 Synthesis
According to the literature the nitrile 6 [14] was prepared with the primary amide 7 the desired iodolactam could
by LiAlH4 reduction of the aldehyde 3, subsequent con- not be detected.
version of the resulting alcohol 4 into mesylate 5 and SN2
Therefore a bromolactamization reaction of the
reaction of 5 with NaCN (Scheme 1). Working with nitrile N-Boc-amide 8 was envisaged. The N-Boc-amide 8 was
6 was very problematic due to the unpleasant smell of the prepared in 85% yield by deprotonation of the primary
compound, which is increased by its high volatility. More- amide 7 with NaH and subsequent reaction of the anion
over, the high volatility of nitrile 6 has to be taken into with (Boc)2O. According to the method of Yeung and Corey
account during concentration of solutions under reduced [19], the N-Boc-amide was deprotonated with KOtBu and
pressure.
the anion was reacted with N-bromosuccinimide (NBS).
Iodolactamization of primary amide 7 was the first However, all attempts failed to produce the brominated
plan to construct the desired morphan skeleton. For the morphan derivative by bromolactamization of the N-Boc-
transformation of nitriles into primary amides, acid and amide 8.
base catalyzed hydration reactions have been reported
Therefore it was planned to reverse the amide moiety,
[14, 15]. However, the yield after NaOH or H2SO4 catalyzed i.e. to attach the carbonyl moiety at the other side of the
addition of H2O to the nitrile 6 did not exceed 40% despite N atom as shown for the amides 10 (Scheme 2). Thus the
several optimization experiments. Recently, Ru bound at nitrile 6 was reduced with LiAlH4 [20] to yield the primary
amine 9, which was isolated as HCl salt in 76% yield.
Acylation of the primary amine 9 yielded the amide 10.
The benzamide 10c has already been described in the
(c)
(b)
(a)
H
literature [13], the Boc- and Cbz derivatives 10a and 10b
were selected due to the facile removal of these protecting
groups, and the dichlorophenylacetyl moiety of 10d was
introduced since κ-opioid receptor agonists [21, 22] and σ
ligands [22, 23] often contain this substituent. The yield
of the amide 10d was increased to 98% by DCC coupling
of the free amine 9 with 2-(3,4-dichlorophenyl)acetic acid.
In order to avoid the purification and isolation of the
volatile and smelly nitrile 6 and the polar primary amine
9, a one-pot three-step reaction sequence for the syn-
thesis of carbamate 10b and (dichlorophenyl)acetamide
10d starting from mesylate 5 was developed. Mesylate 5
MsO
HO
O
5
4
3
O
(e)
(d)
O
Boc
NC
H2N
N
H
6
7
8
Scheme 1:ꢀSynthesis of 2-(cyclohexen-4-yl)acetamide derivatives.
Reagents and reaction conditions: (a) LiAlH4, THF, 0°C, 90 min, 93%.
(b) MesCl, pyridine, 0°C, 2 h, 90%. (c) NaCN, DMSO, 110–120°C,
90 min, 90%. (d) Ru/chitin, H2O, 120°C, 24 h, 62%. (e) NaH, THF,
r. t., 45 min, then (Boc)2O, THF, r. t., 2.5 d, 85%.
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5
(d)
O
O
(e)
(a)
(b)
O
6
or (c)
R
N
R
N
H
H2N
H
11a−d
10-14
10a−d
9
R
O
OH
OH
a
b
c
d
OtBu
OBn
Ph
(h)
(g)
(f)
O
O
R
O
N
N
N
DCB
R
R
−
CH2
Cl
Cl
14d
13d
DCB =
12a−d
Scheme 2:ꢀSynthesis of diastereomeric hydroxymorphans. Reagents and reaction conditions: (a) LiAlH4, THF, r. t., 12 and 14 h, 76%
(9·HCl). (b) 9·HCl, RC(=O)Cl or (Boc)2O, NEt3, CH2Cl2, r. t., 2–4 h, 57–75% (10a–d), (c) 1. 9·HCl, NaOH, CH2Cl2; then (3,4-dichlorophe-
nyl)acetic acid, DCC, r. t., 3 h, 98%. (d) 1. KCN, 18-crown-6, THF, 85°C, 24 h; 2. LiAlH4, THF, 85°C, 24 h; 3. RC(=O)Cl. NaOH, 85°C, 3 h,
13% (10b), 30% (10d). (e) mCPBA, CHCl3, r. t., 18 h, 48–80%. (f) strong base, THF, 8–38%. (g) Dess-Martin periodinane, CH2Cl2, r. t.,
18 h, 37%. (h) NaBH4, THF, EtOH, r. t., 12 h, 31%. The compounds 12–14 were prepared as racemic mixtures. In the Scheme only one
enantiomer is shown.
was reacted with KCN and 18-crown-6 in boiling THF to
The diastereomeric alcohol 14d was prepared by
yield the nitrile 6. After cooling down, LiAlH4 was added oxidation of the alcohol 12d with Dess–Martin periodi-
to the reaction mixture to prepare the primary amine 9. nane (DMP) [25, 26] to obtain the ketone 13d, which was
The excess of LiAlH4 was destroyed by addition of H2O and reduced diastereoselectively to afford the exo-configured
NaOH. Without any separation benzyl chloroformate or alcohol 14d (Scheme 2).
(dichlorophenyl)acetyl chloride were added to produce
the carbamate 10b and (dichlorophenyl)acetamide 10d in the amide anion from the backside (SN2) and diastereose-
13% and 30% yield over three steps, respectively. lective attack of the carbonyl moiety of 13d by the reducing
Due to diastereoselective opening of the epoxides 11by
As described for the iodolactamization of primary agent also from the less hindered backside, the exo- and
amide 7, the benzamide 10c was reacted with trimthylsilyl endo-configured alcohols 12 and 14d were expected to
trilflate and then with I2. However, as described for 7 the be formed, respectively. However, the assignment of the
formation of a morphan derivative could not be detected. relative configuration of these alcohols by interpretation
1
Therefore, instead of a halolactamization reaction the of the H NMR spectra was difficult due to the existence
opening of epoxides was planned to obtain morphan deriv- of rotational isomers and overlapping signals. The signals
atives with an additional OH moiety in the propano bridge. for characteristic protons in 1-, 3- and 8-position of the
The epoxides 11 were obtained in 48–80% yields after reac- diastereomeric alcohols 12d and 14d and the ketone 13d
tion of the cyclohexene derivatives 10 with m-chloroper- are summarized in Table 1. The broad singlet at 3.72 ppm
benzoic acid (mCPBA) [24]. The benzamide 11c has already and the broad doublet at 4.02 ppm (Jꢀ=ꢀ2.0 Hz) for 8-H of
been reported [13]. According to an HPLC analysis the ratio the rotational isomers of 12d are in good accordance with
of diastereomers of epoxides 11 was 55:45 to 60:40. The an equatorial orientation of this proton with respect to the
diastereomers cis-11d and trans-11d were separated by pre- cyclohexane ring of the bicyclic system. Unfortunately, the
parative HPLC (Agilent® Prep C18 column).
signals for 8-H of the diastereomeric alcohol 14d merge in
The intramolecular opening of the epoxide 11c a multiplet at 3.81–3.95 ppm together with some signals of
(mixture of diastereomers) with KOtBu in boiling THF has the PhCH2C=O moiety.
already been reported by Dolby and Nelson [13]. However,
In order to assign the relative configuration of the
instead of the reported yield of 40%, only 28% of the bicy- alcohols 12 unequivocally, the benzamide 12c was crys-
clic alcohol 12c could be isolated using the same reaction tallized from EtOAc to yield crystals which were suitable
conditions. After careful optimization of each cyclization, for an X-ray crystal structure analysis, (Fig. 2). In this
the hydroxymorphans 12a, 12c and 12d were isolated in structure the OH moiety is exo-oriented. It adopts an axial
25–38% yields, the yield of the Cbz-protected morphan orientation with respect to the cyclohexane ring. The
12b was only 8%.
OH moiety and the N atom of the amide group show an
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Table 1:ꢀ1H NMR signals (δ in ppm) for characteristic protons in 1-, 3- and 8-position of the diastereomeric alcohols 12d and 14d and the
ketone 13d.a
Compd.
ꢁ
1-CH
ꢁ
3-CH2
ꢁ
8-CH
ꢁ
Ratio of rotamers
12d (exo)
ꢃ
ꢃ
ꢃ
ꢃ
3.89, 0.4Hꢃ
4.37, 0.6Hꢃ
4.22, 0.5Hꢃ
4.68, 0.5Hꢃ
4.09, 0.2Hꢃ
4.76, 0.8Hꢃ
3.30ꢁ+ꢁ4.13, 2ꢁ×ꢁ0.4Hꢃ
3.45–3.53, 2ꢁ×ꢁ0.6H ꢃ
3.72, sb, 0.4H
4.02, db, 0.6H
–
ꢃ
ꢃ
ꢃ
ꢃ
60:40
13d
3.99, 0.5H
ꢃ
50:50
80:20
3.41–3.56, 3ꢁ×ꢁ0.5H ꢃ
3.20ꢁ+ꢁ4.26, 2ꢁ×ꢁ0.2Hꢃ
3.47ꢁ+ꢁ3.54, 2ꢁ×ꢁ0.8Hꢃ
14d (endo)ꢃ
3.81–3.95, m, 0.8ꢁ+ꢁ0.2Hꢃ
ꢃ
ꢃ
asb, Singlet broad; db, doublet broad.
were formed as approximately 1:1-mixtures of diastere-
omers. As the (3,4-dichlorophenyl)acetyl moiety repre-
sents an important pharmacophoric element of κ and σ
receptor ligands, the morphan derivative 12d bearing this
substituent was prepared. Moreover, the exo-configured
alcohol 12d was converted into its endo-configured dia-
stereomer 14d by oxidation and stereoselective reduction.
The crystal structure determination of the benzamide 12c
confirms unequivocally the relative configuration of the
morphan derivatives 12a–d and 14d.
4 Experimental
4.1 Chemistry, general methods
Unless otherwise noted, moisture sensitive reactions
were conducted under dry nitrogen. THF was dried with
sodium-benzophenone and was freshly distilled before
use. Water residues in compounds were removed by
lyophilization with a Christ Alpha 1-2 LD Plus appara-
tus. Thin layer chromatography (TLC): Silica gel 60 F254
plates (Merck). Flash chromatography (fc): Silica gel 60,
40–64 μm (Merck); parentheses include: diameter of the
column, eluent, fraction size, Rf value. Melting point:
Melting point apparatus SMP 3 (Stuart Scientific), uncor-
rected. MS: MAT GCQ (Thermo-Finnigan); IR: IR spec-
trophotometer 480Plus FT-ATR-IR (Jasco). NMR spectra:
Agilent 600-MR (600 MHz for 1H, 151 MHz for 13C), Agilent
Fig. 2:ꢀMolecular structure of hydroxymorphan 12c in the crystal.
Displacement ellipsoid are drawn at the 15% probability level,
H atoms as spheres with arbitrary radii.
anti-periplanar orientation with a torsion angle O2–C13–
C12–N1 of –173.3(2)°. The 8-CH2 moiety and the carbonyl
O atom also adopt an anti-periplanar orientation (torsion
angle C8–N1–C1–O1 175.4(3)°).
3 Conclusion
1
13
400-MR spectrometer (400 MHz for H, 101 MHz for C)
For the synthesis of morphan derivatives with additional (Agilent); δ in ppm referred to tetramethylsilane; coupling
substituents at the propano bridge, various methods constants are given with 0.5 Hz resolution.
have been investigated. Bromo- and iodolactamization
of cyclohexene derivatives 7, 8 and 10 failed to yield
8-halo substituted morphans. However, the intramolecu-
4.2 HPLC methods
lar opening of the epoxides 11 provided 8-hydoxy substi-
tuted morphans 12. The yields of the 8-hydroxymorphans HPLC method 1 for the determination of the purity:
12 did not exceed 40%, since the precursor epoxides 11 Merck Hitachi Equipment; UV detector: L-7400;
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autosampler: L-7200; pump: L-7100; degasser: L-7614; 2.04–2.14 (m, 3H, 2-CH2, 5-CH2,), 3.51 (dd, Jꢀ=ꢀ10.5/6.1 Hz,
column: LiChrospher® 60 RP-select B (5 μm), 250–4 mm; 1H, CH2OH), 3.55 (dd, Jꢀ=ꢀ10.5/6.1 Hz, 1H, CH2OH), 5.65–5.71
flow rate: 1.00 mL.min−1; injection volume: 5.0 μL; detec- (m, 2H, CH=CH). A signal for the proton of the OH moiety
13
tion at λꢀ=ꢀ210 nm; room temperature; solvents: A: water is not seen in the spectrum. – C NMR (100 MHz, CDCl3):
with 0.05% (v/v) CF3CO2H; B: CH3CN with 0.05% (v/v) δ (ppm)ꢀ=ꢀ24.8 (1C, C-5), 25.3 (1C, C-6), 28.2 (1C, C-2), 36.5
CF3CO2H: gradient elution: (A%): 0–4 min: 90%, 4–29 (1C, C-1), 68.0 (1C, CH2OH), 126.0 (1C, C-3), 127.3 (1C, C-4). –
min: gradient from 90% to 0%, 29–31 min: 0%, 31–31.5 FT-IR: ν (cm−1)ꢀ=ꢀ3318 (s, v(OH)), 2913 (m, v(CH), alkyl), 1022
min: gradient from 0% to 90%, 31.5–40 min: 90%.
(s, δ(HC=CH)). – Exact mass (APCI): m/zꢀ=ꢀ113.0966 (calcd.
+ +
HPLC method 2 for the determination of the purity of 113.0961 for C7H13O , [M+H] ) [12].
acid labile compounds. Method 2 corresponds to method
1, but the solvents A and B did not contain CF3CO2H.
HPLC method 3 for the separation of diastereomeric 4.3.2 [(Cyclohex-3-en-1-yl)methyl] methanesulfonate (5)
epoxides 11: Merck Hitachi Equipment; UV detector:
Dionex UItiMate 3000 RS variable wavelength; autosam- Under N2, at 0°C the alcohol 4 (2.50 g, 22.3 mmol) was
pler Dionex UltiMate 3000 autosampler; Dionex UltiMate added dropwise to a solution of methanesulfonyl chlo-
3000 pump; degasser; data transfer: D-line; data acqui- ride (2.59 mL, 33.4 mmol) in pyridine (15 mL). After stir-
sition: Chromeleon7; column: Phenomenex Gemini 5 μm, ring for 2 h at 0°C, conc. HCl was added (pH 1–2) and the
C18, 110 A, 250–4 mm; flow rate 1.00 mL.min−1; injection mixture was extracted with Et2O (3ꢀ×ꢀ50 mL). The com-
volume 5.0 μL, detection at λꢀ=ꢀ254 nm; room temperature; bined organic layers were washed with aq. NaHCO3 solu-
elution solvents: method 3a: water-CH3CN 50:50; method tion and H2O, dried (Na2SO4) and concentrated in vacuo.
3b: water-CH3CN 60:40; method 3c: water-CH3CN 70:30.
The residue was purified by Kugelrohr distillation. Color-
HPLC method 4 for the preparative separation of dias- less oil, b. p. 150°C at 2.4 mbar, yield 3.82 g (90%). Rfꢀ=ꢀ0.49
tereomeric epoxides cis-11d and trans-11d: Merck Hitachi (EtOAc:C6H12 50:50). C8H14O3S (190.1). – 1H NMR (400 MHz,
Equipment; UV detector L-7400; autosampler L-7200; CDCl3): δ (ppm)ꢀ=ꢀ1.33–1.39 (m, 1H, 6-CH2), 1.77–1.84 (m,
pump L-7150; interface D7000; degasser; data trans- 2H, 1-CH, 6-CH2), 2.02–2.18 (m, 4H, 2-CH2, 5-CH2,), 3.00 (s,
fer: D-line; data acquisition: HSM-software LACHrom; 3H, SO3CH3), 4.11 (d, Jꢀ=ꢀ6.6 Hz, 2H, CH2O), 5.62–5.71 (m,
13
column: Agilent Prep C18, 10 μm, 21.2ꢀ×ꢀ250 mm; flow 2H, CH=CH). – C NMR (100 MHz, CDCl3): δ (ppm)ꢀ=ꢀ24.4
rate 20.0 mL min−1; injection volume 400 μL, detection (1C, C-5), 25.1 (1C, C-6), 27.9 (1C, C-2), 33.7(1C, C-1), 37.6 (1C,
at λꢀ=ꢀ210 nm; room temperature; elution solvent: water- SO3CH3), 74.2 (1C, CH2O), 125.25 (1C, C-3), 127.4 (1C, C-4). –
CH3CN 70:30.
FT-IR: ν (cm−1)ꢀ=ꢀ2916 (m, v, C–H, alkyl), 1350 (s, ν, -SO2-),
1145 (s, ν, -SO2O-), 937 (s, δ, HC=CH). – Exact mass (APCI):
+
+
m/zꢀ=ꢀ191.0746 (calcd. 191.0736 for C8H15O3S , [M+H] ) [12].
4.3 Synthetic procedures
4.3.1 (Cyclohex-3-en-1-yl)methanol (4)
4.3.3 2-(Cyclohex-3-en-1-yl)acetonitrile (6)
Under N2, at 0°C a solution of cyclohex-3-ene-1-carbalde- Mesylate 5 (8.20 g, 43.1 mmol) dissolved in DMSO (5 mL)
hyde (3, 6.58 g, 7.0 mL, 59.7 mmol) in THF (5 mL) was was added to a solution of NaCN (3.17 g, 64.8 mmol) in
added to a mixture of LiAlH4 (2.49 g, 65.7 mmol) in THF (20 DMSO (30 mL) at 85°C and the mixture was heated to
mL). During the addition the temperature was kept below 110–120°C for 90 min. The mixture was extracted with
20°C. After 90 min stirring at 0°C, the mixture was care- Et2O (3ꢀ×ꢀ50ꢀmL). The combined extracts were washed with
fully treated with THF-H2O 4:1 until gas production was saturated NaCl solution, dried (Na2SO4) and concentrated
ceased. Under cooling, H2SO4 (15% aqueous solution) was in vacuo. The crude yellow oil was purified by Kugelrohr
added until the precipitate was dissolved. The solution distillation. Colorless oil, b. p. 140°C at 5.6 mbar, yield
was extracted with Et2O (3ꢀ×ꢀ50 mL). The combined organic 4.70 g (90%). Rfꢀ=ꢀ0.61 (EtOAc:C6H12 50:50). C8H11N (121.2).
1
layers were washed with aq. NaHCO3 solution, dried – H NMR (400 MHz, CDCl3): δ (ppm)ꢀ=ꢀ1.39–1.49 (m, 1H,
(Na2SO4) and evaporated in vacuo. The crude product was 6-CH2), 1.78–1.88 (m, 2H, 1-CH, 6-CH2), 1.95–2.05 (m, 2H,
purified by Kugelrohr distillation. Colorless oil, b. p. 110°C 2-CH2), 2.18–2.26 (m, 2H, 5-CH2), 2.33 (dd, Jꢀ=ꢀ1.2/0.4 Hz, 2H,
13
at 5.8 mbar, yield 6.23 g (93%). Rfꢀ=ꢀ0.45 (EtOAc:C6H12 50:50). CH2CN), 5.60–5.71 (m, 2H, CH=CH). – C NMR (100 MHz,
C7H12O (112.2). – 1H NMR (400 MHz, CDCl3): δ (ppm)ꢀ=ꢀ1.28– CDCl3): δ (ppm)ꢀ=ꢀ23.8 (1C, CH2CN), 24.4 (1C, C-5), 27.9
1.32 (m, 1H, 6-CH2), 1.68–1.84 (m, 3H, 1-CH, 2-CH2, 6-CH2), (1C, C-1), 30.8 (1C, C-2), 30.9 (1C, C-6), 118.9 (1C, CH2CN),
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1062ꢀ ꢀJ. Stefaowitz et al.: Synthesis of morphan derivatives with additional substituents in 8-position
124.9 (1C, C-3), 127.0 (1C, C-4). – FT-IR: ν (cm−1)ꢀ=ꢀ2916 (m, solution. The organic layer was separated and the water
v, C–H, alkyl), 2245 (m, ν, -C≡N), 1045 (s, δ, HC=CH), 655 layer was extracted with CH2Cl2 (3ꢀ×ꢀ20 mL). The com-
(m, δ, HC=CH). – Exact mass (APCI): m/zꢀ=ꢀ122.0987 (calcd. bined organic layers were dried (Na2SO4), the solvent
+
+
122.0964 for C8H12N , [M+H] ) [12].
was removed in vacuo and the residue was purified by
flash column chromatography (EtOAc-C6H12 5:95, Øꢀ=ꢀ2.5
cm, Vꢀ=ꢀ10 mL). Colorless solid, m. p. 47°C, yield 0.14 g
(85%). Rfꢀ=ꢀ0.84 (EtOAc:C6H12 10:90). C13H21NO3 (239.3).
4.3.4 2-(Cyclohex-3-en-1-yl)acetamide (7)
1
– H NMR (600 MHz, CDCl3): δ (ppm)ꢀ=ꢀ1.29–1.37 (m,
A mixture of RuCl3·3H2O (11.2 mg) and chitin (495 mg, 0.79 1H, 6-CH2), 1.53 (s, 9H, C(CH3)3), 1.71–1.85 (m, 2H, 5-CH2,
mmol) in H2O (30 mL) was heated to 50°C for 30 min. The 6-CH2), 2.04–2.10 (m, 2H, 2-CH2), 2.13–2.23 (m, 2H, 1-CH,
mixture was concentrated under reduced pressure. The 5-CH2), 2.78 (d, Jꢀ=ꢀ6.6 Hz, 2H, CH2CO), 5.60–5.69 (m, 2H,
dark gray solid was dried in vacuo overnight. Under Ar, CH=CH). – 13C NMR (150 MHz, CDCl3): δ (ppm)ꢀ=ꢀ24.9
a Schlenk tube was charged with RuCl3/chitin (505.5 mg, (1C, C-2), 27.8 (3C, C(CH3)3), 28.7 (1C, C-6), 30.0 (1C, C-1),
0.05 mmol Ru) and degassed H2O (15 mL). A 1 m NaOAc 31.5 (1C, C-5), 43.3 (1C, CH2CO), 84.7 (1C, C(CH3)3), 126.1
solution (3.50 mL) and later 0.16 m NaBH4 aq. (3.00 mL) (1C, C-3), 127.0 (1C, C-4), 149.8 (1C, O=C–OtBu), 173.6 (1C,
were added dropwise. The mixture was stirred for 3.5 h CH2C=O). – FT-IR: ν (cm−1)ꢀ=ꢀ2982 (m, v, C–H, alkyl), 2920
at r. t. The solution was removed with a needle and Ar (m, v, C–H, alkyl), 1744 (s, v, C=O), 1115 (s, v, C–O). – LC/
pressure. The activated catalyst was washed twice for MS ((+)-ESI): tRꢀ=ꢀ7.3 min, m/zꢀ=ꢀ249.1592 (calcd. 240.1594
+
3 h with degassed H2O (7 mL) and dried in vacuo for 2 h. for C13H22NO3, [M+H ])
Degassed H2O (7 mL) and the nitrile 6 (182 mg, 1.5 mmol)
were added. The mixture was shaken at 120°C for 84 h.
The catalyst was filtered off and washed with methanol 4.3.6 2-(Cyclohex-3-en-1-yl)ethan-1-amine
(5ꢀ×ꢀ10 mL). The solvent was removed in vacuo and the
residue was purified by flash column chromatography
hydrochloride (9·HCl)
(CH2Cl2-CH3OH 80:10, Øꢀ=ꢀ3 cm, Vꢀ=ꢀ10 mL). Colorless solid, Under N2 at 0°C, a solution of the nitrile 6 (1.00 g, 8.25
m. p. 140°C, yield 130 mg (62%). Rfꢀ=ꢀ0.32 (CH2Cl2-acetone mmol) in THF (2 mL) was added to a mixture of LiAlH4
1
50:50). C8H13NO (139.2). – H NMR (600 MHz, CDCl3): δ (0.63 g, 16.50 mmol) in THF (10 mL). During the addition
(ppm)ꢀ=ꢀ1.27–1.35 (m, 1H, 6-CH2), 1.70–1.76 (m, 1H, 6-CH2), the temperature was kept below 20°C. After 12 h stir-
1.77–1.82 (m, 1H, 2-CH2), 2.01–2.12 (m, 3H, 1-CH, 5-CH2) 2.14– ring at r. t., the mixture was treated with H2O under ice
2.21 (m, 3H, 2-CH2, CH2CO), 5.60–5.69 (m, 2H, CH=CH). – 13C cooling until gas production was ceased. NaOH solution
NMR (150 MHz, CDCl3): δ (ppm)ꢀ=ꢀ24.9 (1C, C-5), 28.6 (1C, (50%) was added until the precipitate was dissolved and
C-1), 31.1 (1C, C-6), 31.5 (1C, C-2), 42.9 (1C, CH2CO), 125.9 (1C, two phases were formed. The organic layer was separated
C-3), 127.0 (1C, C-4), 175.0 (1C, C=O). – FT-IR: ν (cm−1)ꢀ=ꢀ3344 and the water layer was extracted with Et2O (3ꢀ×ꢀ30 mL).
(s, ν, CONH), 3170 (s, ν, CONH), 1624 (s, v, C=O), 648 (s, The combined organic layers were dried (Na2SO4) and
δ, HC=CH). – Exact mass (APCI): m/zꢀ=ꢀ140.1075 (calcd. the solvent was removed in vacuo. The crude oil was dis-
+
+
140.1070 for C8H14NO , [M+H] ) [17].
solved in Et2O (2 mL) and HCl in Et2O (1 m) was added.
The resulting colorless solid (9·HCl) was washed with
Et2O and dried in vacuo. Colorless solid, m. p. 160–166°C
(decomposition), yield 1.02 g (76%). Rfꢀ=ꢀ0.47 (CH3OH-
CH2Cl2 10:90ꢀ+ꢀ10% N,N-dimethylethylamine). C8H16ClN
4.3.5 tert-Butyl N-[(cyclohex-3-en-1-yl)acetyl]
carbamate (8)
1
(161.7). – H NMR (400 MHz, DMSO): δ (ppm)ꢀ=ꢀ1.17
NaH (0.40 g, 60% dispersion in mineral oil, 10 mmol) (ddt, Jꢀ=ꢀ15.7/10.2/7.8 Hz, 1H, 6-CH2), 1.49–1.72 (m, 5H,
was washed in a strong nitrogen stream three times with 1-CH, 2-CH2, 6-CH2, CHCH2CH2NH2), 1.98–2.10 (m, 3H,
THF (10 mL) to remove the mineral oil. The remaining 5-CH2, 2-CH2), 2.81 (dd, Jꢀ=ꢀ8.3/7.1 Hz, 2H, CHCH2CH2NH2),
+
13
NaH was suspended in THF (8 mL) and at 0°C acetamide 5.60–5.67 (m, 2H, CH=CH), 7.80 (bs, 2H, NH3 ). – C NMR
7 (0.10 g, 0.72 mmol) dissolved in THF (2 mL) was added (100 MHz, DMSO): δ (ppm)ꢀ=ꢀ24.3 (1C, C-5), 27.9 (1C, C-6),
over 30 min. The mixture was warmed to r. t. and stirred 30.2 (1C, C-1), 30.9 (1C, C-2), 33.6 (1C, CHCH2CH2NH2),
for 45 min. At 0°C di-tert-butyl dicarbonate (0.31 g, 36.8 (1C, CHCH2CH2NH2), 126.0 (1C, C-3), 126.8 (1C, C-4).
+
1.44 mmol) was added dropwise. After complete addi- – FT-IR: ν (cm−1)ꢀ=ꢀ2916 (s, v, NH3 ), 1462 (s, δ, C–H), 652
tion, the mixture was stirred for 2.5 d at r. t. The mixture (s, δ, HC=CH). – Exact mass (APCI): m/zꢀ=ꢀ126.1282 (calcd.
+
+
was treated with THF-H2O (3:1) and later with 1% NH4Cl 126.1277 for C8H16N , [M+H] ).
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J. Stefaowitz et al.: Synthesis of morphan derivatives with additional substituents in 8-positionꢂ
ꢂ1063
4.3.7 tert-Butyl N-[2-(cyclohex-3-en-1-yl)ethyl]
was heated to 85°C for 24 h. After cooling to 0°C, LiAlH4
(0.66 g, 17.35 mmol) was added. The mixture was heated to
85°C for 24 h. At 0°C the mixture was carefully treated with
carbamate (10a)
Under N2, a mixture of the amine hydrochloride 9·HCl H2O until gas production had ceased. Then NaOH solution
(0.15 g, 1.20 mmol) and NEt3 (0.3 mL, 2.40 mmol) in dry (50%) was added until the precipitate was dissolved and
CH2Cl2 (2 mL) was added dropwise to a solution of di- two layers were formed. Benzyl chloroformate (4.48 mL,
tert-butyl dicarbonate (0.39 mL, 1.80 mmol) in dry CH2Cl2 5.38 g, 31.54 mmol) was added and the mixture was heated
(5 mL). After stirring for 4 h at r. t., the mixture was treated to 85°C for 3 h. After cooling to r. t., the organic layer was
with H2O (10 mL). The organic layer was separated and the removed and the aqueous layer was extracted with CH2Cl2
aqueous layer was extracted with CH2Cl2 (2ꢀ×ꢀ30 mL). The (3ꢀ×ꢀ200 mL). The combined organic layers were washed
combined organic layers were washed with aq. NaHCO3 with aq. NaHCO3 solution and with saturated NaCl solu-
solution and with saturated NaCl solution, dried (Na2SO4) tion, dried (Na2SO4) and concentrated in vacuo. The crude
and concentrated in vacuo. The crude oil was purified by yellow oil was purified by flash column chromatography
flash column chromatography (EtOAc-C6H12ꢀ=ꢀ10:90, Øꢀ=ꢀ3 (EtOAc-C6H12ꢀ=ꢀ5:95, Øꢀ=ꢀ3 cm, Vꢀ=ꢀ7 mL). Yellow oil, yield:
cm, Vꢀ=ꢀ10 mL). Colorless oil, yield 0.18 g (67%). Rfꢀ=ꢀ0.57 0.52 g (13%). Rfꢀ=ꢀ0.35 (EtOAc:C6H12 40:60). C16H21NO2 (259.3).
1
(EtOAc:C6H12 20:80). C13H23NO2 (225.3). – 1H NMR (400 MHz, – H NMR (400 MHZ, CDCl3): δ (ppm)ꢀ=ꢀ1.19–1.31 (m, 1H,
CDCl3): δ (ppm)ꢀ=ꢀ1.18–1.28 (m, 1H, 6-CH2), 1.29–1.48 (m, 6-CH2), 1.43–1.53 (m, 2H, CHCH2CH2NH), 1.56–1.77 (m,3H,
11H, CHCH2CH2NH, C(CH3)3), 1.55–1.76 (m, 3H, 1-CH, 2-CH2, 1-CH, 2-CH2, 6-CH2), 2.00–2.14 (m, 3H, 2-CH2, 5-CH2), 3.25 (t,
6-CH2), 1.99–2.13 (m, 3H, 2-CH2, 5-CH2), 3.17 (q, Jꢀ=ꢀ6.2 Hz, Jꢀ=ꢀ7.2 Hz, 2H, CHCH2CH2NH), 4.71 (bs, 1H, NH), 5.09 (s, 2H,
2H, CHCH2CH2NH), 4.50 (bs, 1H, NH), 5.60–5.68 (m, 2H, CH2O), 5.61–5.69 (m, 2H CH=CH), 7.31–7.39 (m, 5H, CHarom.). –
13
CH=CH). – C NMR (100 MHz, CDCl3): δ (ppm)ꢀ=ꢀ25.2 (1C, 13C NMR (100 MHz, CDCl3): δ (ppm)ꢀ=ꢀ25.1 (1C, C-5), 28.8 (1C,
C-5), 28.6 (3C, C(CH3)3), 28.8 (1C, C-6), 31.2 (1C, C-1), 31.7 C-6), 31.1 (1C, C-1), 31.7 (1C, C-2), 36.8 (1C, CHCH2CH2NH),
(1C, C-2), 36.8 (1C, CHCH2CH2NH), 38.5 (1C, CHCH2CH2N), 39.1 (1C, CHCH2CH2NH), 66.7 (1C, CH2O), 126.3 (1C, C-3),
79.2 (1C, C(CH3)3), 126.3 (1C, C-3), 127.2 (1C, C-4), 156.1 (1C, 127.2 (1C, C-4), 128.2 (2 C, C-2arom., C-6arom.), 128.5 (3C, C-3arom.
,
C=O). – FT-IR: ν (cm−1)ꢀ=ꢀ2974 (m, v, C–H, alkyl), 2913 (m, C-4arom., C-5arom.), 136.7 (1C, C-1arom.), 156.5 (1C, C=O). – FT-IR:
v, C–H, alkyl), 1690 (s, v, C=O), 1512 (s, δ, N–H), 1169 (s, ν (cm−1)ꢀ=ꢀ3329 (m, v, NH), 2978 (m, v, C–H, alkyl), 2909 (m,
v, C–O). – LC/MS ((+)-ESI): tRꢀ=ꢀ6.5–6.6 min, m/zꢀ=ꢀ226.1793 v, C–H, alkyl), 1694 (s, v, C=O), 1524 (s, δ, N–H), 1246 (s,
+
+
(calcd. 226.1802 for C13H24NO2 , [M+H ]).
v, C–O), 732 (m, γ, C–H, mono-substituted arom.), 694 (m,
γ, C–H, mono-substituted arom.). – Exact mass (APCI):
m/zꢀ=ꢀ260.1655 (calcd. 260.1645 for C16H22NO2 , [M+H ]). –
Purity (HPLC, method 1): 78.7%, tRꢀ=ꢀ22.9 min.
+
+
4.3.8 Benzyl N-[2-(cyclohex-3-en-1-yl)ethyl]carbamate
(10b)
Method A – Acylation of primary amine hydrochloride 4.3.9 N-[2-(Cyclohex-3-en-1-yl)ethyl]benzamide (10c)
9·HCl: Under N2, a solution of the amine hydrochloride
9·HCl (0.23 g, 1.42 mmol) and NEt3 (0.29 g, 0.40 mL, 2.85 Under N2, a mixture of the amine hydrochloride 9·HCl
mmol) in CH2Cl2 (2 mL) was added dropwise to a mixture (0.50 g, 3.99 mmol) and NEt3 (1.10 mL, 7.98 mmol) in
of benzyl chloroformate (0.36 g, 0.27 mL, 2.13 mmol) in CH2Cl2 (2 mL) was added dropwise to a solution of benzoyl
CH2Cl2 (5 mL). After stirring for 2 h at r. t., a saturated chloride (0.92 mL, 7.98 mmol) in CH2Cl2 (5 mL) [13]. After
NaHCO3 solution was added. The organic layer was sep- stirring for 3 h at room temperature, the mixture was
arated and the aqueous layer was extracted with CH2Cl2 treated with H2O (10 mL). The organic layer was sepa-
(2ꢀ×ꢀ20 mL). The combined extracts were washed with aq. rated and the aqueous layer was extracted with CH2Cl2
NaHCO3 solution and with saturated NaCl solution, dried (2ꢀ×ꢀ30 mL). The combined organic layers were washed
(Na2SO4) and concentrated in vacuo. The crude yellow oil with aq. NaHCO3 solution and with saturated NaCl solu-
was purified by flash column chromatography (EtOAc- tion, dried (Na2SO4) and concentrated in vacuo. The crude
C6H12ꢀ=ꢀ5:95, Øꢀ=ꢀ3 cm, Vꢀ=ꢀ7 mL). Yellow oil, yield: 0.23 g yellow oil was purified by flash column chromatography
(62%).
(EtOAc-C6H12 20:80ꢀ→ꢀ30:70, Øꢀ=ꢀ3 cm, Vꢀ=ꢀ10 mL). Color-
Method B – one-pot three-step procedure starting less solid, m. p. 81–83°C, yield 0.68 g (75%). Rfꢀ=ꢀ0.51
with mesylate 5: Under N2, mesylate 5 (3.00 g, 15.77 mmol) (EtOAc:C6H12 50:50). C15H19NO (229.3). – 1H NMR (400 MHz,
was added to a mixture of KCN (2.05 g, 31.54 mmol) and CDCl3): δ (ppm)ꢀ=ꢀ1.26–1.32 (m, 1H, 6-CH2), 1.55–1.80 (m,
18-crown-6 (4.18 g, 15.77 mmol) in THF (75 mL). The mixture 5H, 1-CH, 2-CH2, 6-CH2, CHCH2CH2NH), 2.04–2.07 (m, 2H,
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1064ꢀ ꢀJ. Stefaowitz et al.: Synthesis of morphan derivatives with additional substituents in 8-position
5-CH2), 2.13–2.18 (m, 1H, 2-CH2), 3.51 (td, Jꢀ=ꢀ7.3/5.2 Hz, 2H, was heated to 85°C for 24 h. After cooling to 0°C, LiAlH4 (0.66
CHCH2CH2NH), 5.53–5.68 (m, 2H, CH=CH), 6.19 (bs, 1H, g, 19.0 mmol) was added. The mixture was heated to 85°C
NH), 7.39–7.43 (m, 2H, 3-CHarom., 5-CHarom.), 7.47–7.50 (m, 1H, for 24 h. At 0°C the mixture was carefully treated with H2O
4-CHarom.), 7.75 (dd, Jꢀ=ꢀ7.1/1.4 Hz, 2H, 2-CHarom., 6-CHarom.). – until gas production was ceased. NaOH solution (50%) was
13C NMR (100 MHz, CDCl3): δ (ppm)ꢀ=ꢀ25.1 (1C, C-5), 28.8 (1C, added until the precipitate was dissolved and two layers
C-6), 31.4 (1C, C-1), 31.8 (1C, C-2), 36.4 (1C, CHCH2CH2NH), were formed. 2-(3,4-Dichlorophenyl)acetyl chloride (5.30 g,
38.1 (1C, CHCH2CH2N), 126.2 (1C, C-3), 127.0 (2C, C-2arom.
,
17.4 mmol) was added and the mixture was heated to 85°C
C-6arom.), 127.2 (1C, C-4), 128.7 (2C, C-3arom., C-5arom.), 131.5 for 3 h. After cooling to r. t., the organic layer was removed
(1C, C-4arom.), 134.9 (1C, C-1arom.), 167.7 (1C, C=O). – FT-IR: ν and the aqueous layer was extracted with CH2Cl2 (3ꢀ×ꢀ200
(cm−1)ꢀ=ꢀ2913 (m, v, C–H, alkyl), 1636 (s, v, C=O), 1539 (s, δ, mL). The combined organic layers were dried (Na2SO4) and
N–H), 700 (m, γ, C–H, mono-substituted arom.), 652 (m, concentrated in vacuo. The crude product was purified via
γ, C–H, mono-substituted arom.). – Exact mass (APCI): flash column chromatography (EtOAc-C6H12ꢀ=ꢀ30:70, Øꢀ=ꢀ5
+
+
m/zꢀ=ꢀ230.1550 (calcd. 230.1539 for C15H20NO , [M+H ]). – cm, Vꢀ=ꢀ10 mL). Colorless solid, yield 1.50 g (30%).
Purity (HPLC, method 1): 93.4%, tRꢀ=ꢀ20.73 min.
M. p. 75°C. Rfꢀ=ꢀ0.49 (EtOAc:C6H12 50:50). C16H19Cl2NO
1
(312.2). – H NMR (400 MHz, CDCl3): δ (ppm)ꢀ=ꢀ1.17–1.28
(m, 1H, 6-CH2), 1.39–1.58 (m, 3H, 1-CH, CHCH2CH2NH),
1.61–1.73 (m, 2H, 6-CH2, 2-CH2), 1.99–2.11 (m, 3H, 2-CH2,
5-CH2), 3.28 (td, Jꢀ=ꢀ7.4/5.7 Hz, 2H, CHCH2CH2NH), 3.48 (s,
2H, CH2CO), 5.45 (bs, 1H, NH), 5.59–5.67 (m, 2H, CH=CH),
4.3.10 N-[2-(Cyclohex-3-en-1-yl)ethyl]-2-(3,4-
dichlorophenyl)acetamide (10d)
Method A – Acylation of primary amine hydrochloride 7.11 (dd, Jꢀ=ꢀ8.2/2.1 Hz, 1H, 6-CHarom.), 7.36 (d, Jꢀ=ꢀ2.1 Hz,
13
9·HCl: Under N2, a mixture of amine hydrochloride 9·HCl 1H, 2-CHarom.), 7.40 (d, Jꢀ=ꢀ8.2 Hz, 1H, 5-CHarom.). – C NMR
(0.30 g, 2.39 mmol) and NEt3 (0.66 mL, 0.48 g, 4.79 mmol) (100 MHz, CDCl3): δ (ppm)ꢀ=ꢀ25.1 (1C, C-5), 28.8 (1C, C-6),
in dry CH2Cl2 (5 mL) was added dropwise to a solution 31.4 (1C, C-1), 31.7 (1C, C-2), 36.2 (1C, CHCH2CH2NH), 37.9
of 2-(3,4-dichlorophenyl)acetyl chloride (0.64 g, 2.88 (1C, CHCH2CH2NH), 42.8 (1C, CH2C=O), 126.1 (1C, C-4),
mmol) in dry CH2Cl2 (5 mL). After stirring at r. t. for 2 h, 127.2 (1C, C-3), 128.8 (1C, C-6arom.), 130.9 (1C, C-5arom.), 131.4
the mixture was treated with H2O (10 mL). The organic (1C, C-2arom.), 131.7 (1C, C-3arom.), 133.0 (1C, C-4arom.), 135.2
layer was separated and the aqueous layer was extracted (1C, C-1arom.), 169.8 (1C, C=O). – FT-IR: ν (cm−1)ꢀ=ꢀ3283 (w,
with CH2Cl2 (2ꢀ×ꢀ30 mL). The combined organic layers were v, N–H), 2978 (m, v, C–H, alkyl), 2912 (m, v, C–H, alkyl),
washed with aq. NaHCO3 solution and with saturated NaCl 1639 (s, v, C=O), 1551 (s, δ, N–H). – Exact mass (APCI):
solution, dried (Na2SO4) and concentrated in vacuo. The m/zꢀ=ꢀ312.0929 (calcd. 312.0916 for C16H2035Cl2NO , [M+H ]).
crude oil was purified via flash column chromatography – Purity (HPLC, method 1): 97.5%, tRꢀ=ꢀ23.3 min.
(EtOAc-C6H12ꢀ=ꢀ30:70, Øꢀ=ꢀ3 cm, Vꢀ=ꢀ10 mL). Colorless solid,
+
+
yield: 0.41 g (57%).
Method B – Acylation of primary amine 9 using a cou- 4.3.11 tert-Butyl N-[2-(7-oxabicyclo[4.1.0]heptan-3-yl)
pling reagent; Amine hydrochloride 9·HCl was dissolved
in NaOH and the amine 9 was extracted with Et2O. The
ethyl]carbamate (11a)
solvent was removed in vacuo to afford the amine 9. A Cyclohexene 10a (0.18 g, 0.79 mmol) was dissolved in
mixture of amine 9 (2.00 g, 15.9 mmol), (3,4-dichlorophe- CHCl3 (4 mL) and the solution was added to a suspension
nyl)acetic acid (6.48 g, 31.9 mmol) and DCC (6.58 g, 31.9 of m-chloroperbenzoic acid (0.36 g, 1.59 mmol) in CHCl3 (6
mmol) in dry CH2Cl2 (40 mL) was stirred at r. t. for 3 h. A sat- mL). Themixturewasstirredatr. t. for18h. AK2CO3 solution
urated solution of NaHCO3 was added and the precipitate (1 g K2CO3 in 100 mL of H2O) was added and the layers were
was filtered off. The resulting layers were separated and separated. The aqueous layer was extracted with CH2Cl2
the aqueous layer was extracted with CH2Cl2 (3ꢀ×ꢀ50 mL). (3ꢀ×ꢀ30 mL) and the combined organic layers were washed
The combined organic layers were dried (Na2SO4) and the with aq. NaHCO3 solution and saturated NaCl solution.
solvent was removed in vacuo. The crude oil was purified The combined organic layers were dried (Na2SO4) and the
via flash column chromatography (EtOAc-C6H12ꢀ=ꢀ30:70, solvent was removed in vacuo. The crude oil was purified
Øꢀ=ꢀ5 cm, Vꢀ=ꢀ10 mL). Colorless solid, yield 4.88 g (98%).
by column chromatography (EtOAc-C6H12ꢀ=ꢀ10:90ꢀ→ꢀ30:70,
Method C – one-pot three-step procedure starting Øꢀ=ꢀ2.5 cm, Vꢀ=ꢀ10 mL). Colorless oil, yield 0.11 g (57%).
1
with mesylate 5: Under N2, mesylate 5 (3.00 g, 15.8 mmol) Rfꢀ=ꢀ0.57 (EtOAc-C6H12 50:50). C13H23NO3 (241.3). – H NMR
was added to a mixture of KCN (2.05 g, 31.5 mmol) and (600 MHz, CDCl3): δ (ppm)ꢀ=ꢀ0.92 (2× td, Jꢀ=ꢀ11.5/6.4 Hz,
18-crown-6 (4.17 g, 15.8 mmol) in THF (45 mL). The mixture 0.5H, 4-CH2), 1.13–1.18 (m, 0.5H, 4-CH2), 1.30–1.55 (m, 14H,
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ꢂ1065
2-CH2, 3-CH, 4-CH2, C(CH3)3, CHCH2), 1.70 (m, 0.5H, 5-CH2), 4.3.13 N-[2-(7-Oxabicyclo[4.1.0]heptan-3-yl)ethyl]
1.83 (2× dd, Jꢀ=ꢀ11.5/6.4 Hz, 0.5H, 5-CH2), 1.97–2.01 (m, 0.5H,
5-CH2), 2.03–2.08 (m, 0.5H, 2-CH2), 2.11–2.18 (m, 1H, 2-CH2,
benzamide (11c)
5-CH2), 3.03 (m, 4H, 1-CH, 6-CH, CH2NH), 4.46 (bs, 1H, NH). Cyclohexene 10c (0.25 g, 1.10 mmol) was dissolved in CHCl3
13
– C NMR (150 MHz, CDCl3): δ (ppm)ꢀ=ꢀ23.7 (1C, C-5), 24.5 (4 mL) and the solution was added to a suspension of
(1C, C-4), 26.3 (1C, C-5), 27.1 (1C, C-3), 27.2 (1C, C-4), 28.7 (3C, m-chloroperbenzoic acid (50%, 0.56 g, 2.20 mmol) in CHCl3
C(CH3)3), 30.4 (1C, C-3), 30.7 (1C, C-2), 31.8 (1C, C-2), 36.5 (6 mL) [13]. The mixture was stirred at r. t. for 18 h. A K2CO3
(1C, CHCH2), 37.2 (1C, CHCH2), 38.2 (1C, CH2NH), 38.3 (1C, solution (1 g K2CO3 in 100 mL of H2O) was added and the
CH2NH), 51.8 (1C, C-6), 52.0 (1C, C-6), 52.6 (1C, C-1), 53.1 (1C, layers were separated. The aqueous layer was extracted with
C-1), 79.3 (2× 1C, C(CH3)3), 166.0 (2× 1C, NHC=O). – FT-IR: ν CH2Cl2 (3ꢀ×ꢀ30 mL) and the combined organic extracts were
(cm−1)ꢀ=ꢀ2978 (m, v, C–H, alkyl), 1694 (s, v, C=O), 1169 (s, washed with aq. NaHCO3 solution and saturated NaCl solu-
ν, C–O). – LC/MS ((+)-ESI): tRꢀ=ꢀ5.3–5.4 min, m/zꢀ=ꢀ242.1747 tion. The combined organic layers were dried (Na2SO4) and
+
+
(calcd. 242.1751 for C13H24NO3 , [M+H ]).
the solvent was removed in vacuo. The crude oil was puri-
fied by flash column chromatography (EtOAc-C6H12ꢀ=ꢀ85:15,
Øꢀ=ꢀ2.5 cm, Vꢀ=ꢀ10 mL). Colorless solid, m. p. 56°C, yield
0.27 g (80%). Rfꢀ=ꢀ0.21 (EtOAc-C6H12 50:50). C15H19NO2
(245.3). – 1H NMR (400 MHz, CDCl3): δ (ppm)ꢀ=ꢀ0.92–1.02 (m,
0.5H, 4-CH2), 1.13–1.75 (m, 6H, 2-CH2, 3-CH, 4-CH2, 5-CH2,
4.3.12 Benzyl N-[2-(7-oxabicyclo[4.1.0]heptan-3-yl)
ethyl]carbamate (11b)
Cyclohexene 10b (0.37 g, 1.43 mmol) was dissolved in CHCH2CH2NH), 1.81–1.90 (m, 0.5H, 5-CH2), 1.98–2.05 (m,
CHCl3 (4 mL) and the solution was added to a suspension 0.5H, 5-CH2), 2.09–2.23 (m, 1.5H, 2-CH2, 5-CH2), 3.12–3.18
of m-chloroperbenzoic acid (0.64 g, 2.86 mmol) in CHCl3 (m, 2H, 1-CH, 6-CH), 3.39–3.53 (m, 2H, CHCH2CH2NH), 6.11
(6 mL). The mixture was stirred at r. t. for 18 h. A K2CO3 (bs, 1H, NH), 7.40–7.51 (m, 3H, 3-CHarom., 4-CHarom., 5-CHarom.),
solution (1 g K2CO3 in 100 mL of H2O) was added and the 7.73–7.75 (m, 2H, 2-CHarom., 6-CHarom.). Ratio of diastereomers
13
layers were separated. The aqueous layer was extracted 40:60 (HPLC method 3a). – C NMR (100 MHz, CDCl3): δ
with CH2Cl2 (3ꢀ×ꢀ30 mL) and the combined organic extracts (ppm)ꢀ=ꢀ23.5 (1C, C-5), 24.5 (1C, C-4), 25.2 (1C, C-5), 27.1 (1C,
were washed with aq. NaHCO3 solution and saturated C-4), 27.5 (1C, C-3), 30.6 (1C, C-3), 30.7 (1C, C-2), 31.8 (1C, C-2),
NaCl solution. The combined organic layers were dried 36.1 (1C, CHCH2CH2NH), 37.8 (1C, CHCH2CH2NH), 51.8 (1C,
(Na2SO4) and the solvent was removed in vacuo. The crude C-6), 52.0 (1C, C-6), 52.6 (1C, C-1), 53.1 (1C, C-1), 126.9 (2C,
oil was purified by flash column chromatography (EtOAc- C-2arom., C-6arom.), 128.7 (2C, C-3arom., C-5arom.), 131.5 (1C, C-4arom.),
C6H12ꢀ=ꢀ20:80, Øꢀ=ꢀ3 cm, Vꢀ=ꢀ10 mL). Yellow oil, yield 0.19 g 134.8 (1C, C-1arom.), 167.7 (1C, C=O). – FT-IR: ν (cm−1)ꢀ=ꢀ2978 (m,
(48%). Rfꢀ=ꢀ0.55 (EtOAc:C6H12 50:50). C16H21NO3 (275.3). – 1H v, C–H, alkyl), 1639 (m, v, C=O), 1543 (s, δ, N–H), 710 (m, γ,
NMR (400 MHz, CDCl3): δ (ppm)ꢀ=ꢀ0.92 (2× td, Jꢀ=ꢀ11.5/6.4 C–H, mono-substituted arom.), 695 (m, γ, C–H, mono-sub-
Hz, 0.5H, 4-CH2), 1.08–1.52 (m, 5.5H, 3-CH, 2-CH2, 4-CH2, stituted arom.). – Exact mass (APCI): m/zꢀ=ꢀ246.1490 (calcd.
+
+
CHCH2CH2NH), 1.70 (2× dt, Jꢀ=ꢀ13.4/4.1ꢀHz, 0.5H, 5-CH2), 1.83 246.1489 for C15H20NO2 , [M+H ]). – Purity (HPLC, method 2):
(2× dd, Jꢀ=ꢀ11.5/6.4 Hz, 0.5H, 5-CH2), 1.95–2.18 (m, 2H, 2-CH2, 96%, tRꢀ=ꢀ16.93 min.
5-CH2), 3.10–3.22 (m, 4H, CHCH2CH2NH,1-CH, 6-CH), 4.73
(bs, 1H, NH), 5.08 (s, 2H, OCH2), 7.30–7.35 (m, 5H, CHarom.).
Ratio of diastereomers 45: 55 (HPLC method 3c). – 13C NMR 4.3.14 N-[2-((1RS,3SR,6SR)-7-Oxabicyclo[4.1.0]
(100 MHz, CDCl3): δ (ppm)ꢀ=ꢀ23.5 (1C, C-5), 24.4 (1C, C-4),
25.2 (1C, C-5), 27.0 (1C, C-3), 27.1 (1C, C-4), 30.2 (1C, C-3), 30.6
(1C, C-2), 31.7 (1C, C-2), 36.4 (1C, CHCH2CH2NH), 37.1 (1C,
CHCH2CH2NH), 38.7 (2× 1C, CHCH2CH2N), 51.7 (1C, C-1), 51.9
(1C, C-1), 52.6 (1C, C-6), 53.0 (1C, C-6), 66.8 (2× 1C, OCH2),
heptan-3-yl)ethyl]-2-(3,4-dichloro-phenyl)
acetamide (cis-11d) and N-[2-((1RS,3RS,6SR)-
7-Oxabicyclo[4.1.0]-heptan-3-yl)ethyl]-2-(3,4-
dichlorophenyl)-acetamide (trans-11d)
128.2(2C,C-2arom.,C-6arom.),128.6(3C,C-3arom.,C-4arom.,C-5arom.), Cyclohexene 10d (1.5 g, 4.80 mmol) dissolved in CHCl3
136.7 (1C, C-1arom.), 156.5 (1C, C=O). – FT-IR: ν (cm−1)ꢀ=ꢀ3340 (5 mL), was added to a mixture of m-chloroperbenzoic acid
(w, v, N–H), 2924 (m, v, C–H, alkyl), 1701(s, v, C=O), 1528 (s, (50%, 2.15 g, 9.61 mmol) in CHCl3 (10 mL). The mixture was
δ, N–H), 1242 (s, v, C–O), 737 (s, γ, C–H, mono-substituted stirred at r. t. for 18 h. A K2CO3 solution (1 g K2CO3 in 100 mL
arom.), 698 (s, γ, C–H, mono-substituted arom.). – LC/MS of H2O) was added and the layers were separated. The
((+)-ESI): tRꢀ=ꢀ5.5–5.6 min, m/zꢀ=ꢀ276.1602 (calcd. 276.1594 aqueous layer was extracted with CH2Cl2 (3ꢀ×ꢀ50 mL) and
+
+
for C16H22NO3 , [M+H ]). – Purity (HPLC, method 2): 66%, the combined extracts were washed with NaHCO3 solu-
tRꢀ=ꢀ19.70 min.
tion and saturated NaCl solution. The combined organic
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1066ꢀ ꢀJ. Stefaowitz et al.: Synthesis of morphan derivatives with additional substituents in 8-position
layers were dried (Na2SO4) and the solvent was removed in (1C, C-5arom.), 131.6 (1C, C-4arom.), 132.9 (1C, C-3arom.), 135.2 (1C,
vacuo. The crude oil was purified by flash column chroma- C-1arom.), 169.7 (1C, C=O). – FT-IR: ν (cm−1)ꢀ=ꢀ3291(w, v, N–H),
tography (EtOAc-C6H12ꢀ=ꢀ40:60, Øꢀ=ꢀ6 cm, Vꢀ=ꢀ10 mL) to give 2924 (m, v, C–H, alkyl), 1643 (s, v, C=O), 1523 (s, ν, C=O).
a 40:60 mixture of diastereomers (HPLC method 3b) as a – LC/MS ((+)-ESI): tRꢀ=ꢀ5.8 min, m/zꢀ=ꢀ328.0869 (calcd.
+
+
colorless solid, m. p. 80°C, yield 0.90 g (57%). The dias- 328.0866 for C16H2035Cl2NO2 , [M+H ]). – Purity (HPLC,
tereomers were separated by preparative HPLC, method 4. method 2): 95%, tRꢀ=ꢀ20.18 min.
After separation, the solvents were removed in vacuo and
the products were lyophilized.
cis-11d (fraction 1: tRꢀ=ꢀ59.37 min): Colorless oil. 4.3.15 tert-Butyl (1RS,5SR,8RS)-8-hydroxy-2-
1
Rfꢀ=ꢀ0.33 (EtOAc-C6H12 70:30). C16H19Cl2NO2 (328.2). – H
NMR(600MHz, CDCl3):δ(ppm)ꢀ=ꢀ1.09(ddd, Jꢀ=ꢀ12.3/4.3/2.3
azabicyclo[3.3.1]nonane-2-carboxylate (12a)
Hz, 0.5H, 4-CH2), 1.13 (ddd, Jꢀ=ꢀ12.3/4.3/2.3 Hz, 0.5H, Under N2, the epoxide 11a (0.10 g, 0.41 mmol) was dis-
4-CH2), 1.18–1.35 (m, 4H, 3-CH2, 4-CH2, CHCH2CH2NH), solved in THF (6 mL) and a solution of LiHMDS in THF
1.40 (dd, Jꢀ=ꢀ11.1/2.4 Hz, 0.5H, 2-CH2), 1.43 (dd, Jꢀ=ꢀ11.1/2.4 (1 m, 0.6 mL) was added dropwise at 0°C. After stirring
Hz, 0.5H, 2-CH2), 1.64–1.73 (m, 1H, 5-CH2), 2.00 (ddd, for 24 h at r. t., H2O (10 mL) was added. The organic layer
Jꢀ=ꢀ7.7/3.9/1.9 Hz, 0.5H, 2-CH2), 2.03 (ddd, Jꢀ=ꢀ7.7/3.9/1.9 Hz, was separated and the aqueous layer was extracted with
0.5H, 2-CH2), 2.10 (dq, Jꢀ=ꢀ4.3/2.3 Hz, 0.5H, 5-CH2), 2.12 CH2Cl2 (3ꢀ×ꢀ20 mL). The combined organic layers were
(dt, Jꢀ=ꢀ4.5/2.3 Hz, 0.5H, 5-CH2), 3.09 (td, Jꢀ=ꢀ4.5/1.9 Hz, dried (Na2SO4), the solvent was removed in vacuo and the
1H, 1-CH), 3.12 (dq, Jꢀ=ꢀ3.9/1.9 Hz, 1H, 6-CH), 3.19–3.26 (m, residue was purified by flash column chromatography
2H, CHCH2CH2NH), 3.46 (s, 2H, CH2CO), 5.46 (bs, 1H, NH), (EtOAc-C6H12ꢀ=ꢀ60:40, Øꢀ=ꢀ2.5 cm, Vꢀ=ꢀ10 mL). Colorless oil,
7.10 (dd, Jꢀ=ꢀ8.2/1.5 Hz, 0.5H, 6-CHarom.), 7.11 (dd, Jꢀ=ꢀ8.2/1.5 yield 0.25 g (25%). Rfꢀ=ꢀ0.27 (EtOAc:C6H12 50:50). C13H23NO3
1
Hz, 0.5H, 6-CHarom.), 7.36 (d, Jꢀ=ꢀ1.5 Hz, 0.5H, 2-CHarom.), (241.2). – H NMR (400 MHz, CDCl3): δ (ppm)ꢀ=ꢀ0.86–0.99
7.37 (d, Jꢀ=ꢀ1.5 Hz, 0.5H, 2-CHarom.), 7.40 (d, Jꢀ=ꢀ8.2 Hz, (m, 0.5H, 4-CH2), 1.08–1.55 (m, 14.5H, 4-CH2, 5-CH, 6-CH2,
0.5H, 5-CHarom.), 7.41 (d, Jꢀ=ꢀ8.2 Hz, 0.5H, 5-CHarom.). – 13C 7-CH2, 9-CH2, OC(CH3)3), 1.65–1.75 (m, 0.5H, 7-CH2), 1.78–
NMR (150 MHz, CDCl3): δ (ppm)ꢀ=ꢀ24.4 (1C, C-4), 25.2 (1C, 1.88 (m, 0.5H, 9-CH2), 1.94–2.18 (m, 2H, 9-CH2, 7-CH2), 3.09–
C-5), 30.5 (1C, C-3), 30.6 (1C, C-2), 36.6 (1C, CHCH2CH2NH), 3.16 (m, 2H, 8-CH, 1-CH), 3.21–3.26 (m, 1H, 3-CH2), 3.62–3.68
37.6 (1C, CHCH2CH2NH), 42.9 (1C, CH2C=O), 51.7 (1C, C-1), (m, 1H, 3-CH2). – 13C NMR (100 MHz, CDCl3): δ (ppm)ꢀ=ꢀ23.5
52.5 (1C, C-6), 128.8 (1C, C-6arom.), 130.9 (1C, C-5arom.), 131.2 (1C, C-9), 23.4 (1C, C-9), 24.4 (1C, C-6), 24.5 (1C, C-6), 25.2
(1C, C-2arom.), 131.6 (1C, C-4arom.), 133.0 (1C, C-3arom.), 135.3 (1C, C-7), 25.3 (1C, C-7), 26.9 (1C, C-4), 27.1 (1C, C-4), 27.4 (1C,
(1C, C-1arom.), 169.7 (1C, C=O). – FT-IR: ν (cm−1)ꢀ=ꢀ3291(w, v, C-5), 27.7 (1C, C-5), 28.3 (3C, C(CH3)3), 30.5 (1C, C-9), 30.6
N–H), 2924 (m, v, C–H, alkyl), 1643 (s, v, C=O). – LC/MS (1C, C-9), 30.7 (1C, C-5), 30.8 (1C, C-5), 31.8 (1C, C-7), 35.6
((+)-ESI): tRꢀ=ꢀ5.8 min, m/zꢀ=ꢀ328.0879 (calcd. 328.0866 for (1C, C-6), 36.1 (1C, C-6), 36.2 (1C, C-4), 36.7 (1C, C-4), 38.2
+
+
C16H2035Cl2NO2 , [M+H ]). – Purity (HPLC, method 2): 86%, (1C, C-3), 38.3 (1C, C-3), 42.0 (1C, C-3), 42.2 (C-3), 51.8 (1C,
tRꢀ=ꢀ20.01 min. C-1), 51.9 (1C, C-1), 52.7 (1C, C-8), 53.0 (1C, C-8), 82.9 (1C,
trans-11d (fraction 2, tRꢀ=ꢀ66.31 min): Yellow solid, C(CH3)3), 83.0 (1C, C(CH3)3), 155.0 (1C, NCO2C(CH3)3), 155.3
m. p. 101°C. Rfꢀ=ꢀ0.33 (EtOAc-C6H12 70:30). C16H19Cl2NO2 (1C, NCO2C(CH3)3). – FT-IR: ν (cm−1)ꢀ=ꢀ3333 (s, v, O–H), 2925
1
(328.2). – H NMR (600 MHz, CDCl3): δ (ppm)ꢀ=ꢀ0.89–0.99 (m, v, C–H, alkyl), 1709 (s, v, C=O), 1165 (s, v, C–O, alcohol).
(m, 1H, 4-CH2), 1.31–1.36 (m, 3H, 5-CH2, CHCH2CH2NH), – Exact mass (APCI): m/zꢀ=ꢀ242.1725 (calcd. 242.1751 for
+
+
1.43–1.48 (m, 2H, 3-CH, 4-CH2), 1.79 (dd, Jꢀ=ꢀ11.6/6.5 C13H24NO3 , [M+H ]).
Hz, 0.5H, 2-CH2), 1.82 (dd, Jꢀ=ꢀ11.6/6.5 Hz, 0.5H, 2-CH2),
1.96 (ddd, Jꢀ=ꢀ6.6/5.0/2.4ꢀHz, 0.5H, 2-CH2), 1.99 (ddd,
Jꢀ=ꢀ6.6/5.0/2.4 Hz, 0.5H, 2-CH2), 2.11 (dt, Jꢀ=ꢀ3.8/1.9 Hz, 0.5H, 4.3.16 Benzyl (1RS,5SR,8RS)-8-hydroxy-2-
5-CH2), 2.13 (dt, Jꢀ=ꢀ3.8/1.9 Hz, 0.5H, 5-CH2), 3.11 (bt, Jꢀ=ꢀ4.5
Hz, 1H, 1-CH), 3.14 (dt, Jꢀ=ꢀ3.8/1.8 Hz, 1H, 6-CH), 3.22 (2× td,
azabicyclo[3.3.1]nonane-2-carboxylate (12b)
Jꢀ=ꢀ7.3/3.3 Hz, 2H, CHCH2CH2NH), 3.46 (s, 2H, CH2C=O), 5.49 Under N2, the epoxide 11b (0.10 g, 0.69 mmol) was dis-
(bs, 1H, NH), 7.10 (dd, Jꢀ=ꢀ8.2/2.2ꢀHz, 1H, 6-CHarom.), 7.36 (d, solved in THF (6 mL) and a solution of NaHMDS in THF
Jꢀ=ꢀ2.2 Hz, 1H, 2-CHarom.), 7.40 (d, Jꢀ=ꢀ8.2Hz, 1H, 5-CHarom.). – (1 m, 1.38 mL, 1.38 mmol) was added dropwise at 0°C. After
13C NMR (150 MHz, CDCl3): δ (ppm)ꢀ=ꢀ23.5 (1C, C-2), 27.0 (1C, stirring for 72 h at r. t., H2O (10 mL) was added. The organic
C-4), 27.4 (1C, C-3), 31.8 (1C, C-5), 35.9 (1C, CHCH2CH2NH), layer was separated and the aqueous layer was extracted
37.6 (1C, CHCH2CH2NH), 42.8 (1C, CH2CO), 51.9 (1C, C-1), with CH2Cl2 (3ꢀ×ꢀ20 mL). The combined organic extracts
53.0 (1C, C-6), 128.8 (1C, C-6arom.), 130.9 (1C, C-2arom.), 131.4 were dried (Na2SO4) and the solvent was removed in vacuo.
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J. Stefaowitz et al.: Synthesis of morphan derivatives with additional substituents in 8-positionꢂ
ꢂ1067
The crude yellow oil was purified via flash column chro- (2C, C-2benzoyl, C-6benzoyl), 126.7 (2C, C-2benzoyl, C-6benzoyl), 128.6
matography (EtOAc-C6H12ꢀ=ꢀ30:70, Øꢀ=ꢀ2.5 cm, Vꢀ=ꢀ10 mL). (2C, (2C, C-3
, C-5benzoyl), 128.7 (1C, C-4benzoyl), 129.5
benzoyl
Colorless oil, yield 8.70 mg (9%). Rfꢀ=ꢀ0.46 (EtOAc-C6H12 (3C, C-3
, C-4benzoyl, C-5benzoyl), 136.9 (1C, C-1benzoyl), 137.2
benzoyl
1
2:8). C16H21NO3 (275.2). – H NMR (400 MHz, CDCl3): δ (1C, C-1benzoyl), 171.9 (1C, C=O), 172.5 (1C, C=O). – FT-IR: ν
(ppm)ꢀ=ꢀ1.33–1.95 (m, 9H, 4-CH2, 5-CH, 6-CH2, 7-CH2, 9-CH2), (cm−1)ꢀ=ꢀ3337 (s, v, O–H), 2920 (m, v, C–H, alkyl), 1593 (s,
3.12–3.24 (m, 2H, 8-CH, 3-CH2), 3.46–3.55 (m, 0.5H, 3-CH2), v, C=O), 1427 (s, δ, O–H), 703 (m, δ, C–H, mono-substi-
3.64–3.70 (m, 0.5H, 3-CH2), 4.28 (bdd, Jꢀ=ꢀ23.8/2.7 Hz, tuted arom.), 633(m, δ, C–H, mono-substituted arom.).
0.5H, 1-CH), 4.88 (bdd, Jꢀ=ꢀ27.0/2.5 Hz, 0.5H, 1-CH), 5.08– – Exact mass (APCI): m/zꢀ=ꢀ246.1495 (calcd. 246.1489 for
13
+
+
5.23 (m, 2H, CH2CO), 7.28–7.43 (m, 5H, CHarom.). – C NMR C15H20NO2 , [M+H ]). – Purity (HPLC, method 1): 97%,
(100 MHz, CDCl3): δ (ppm)ꢀ=ꢀ24.0 (1C, C-5), 24.2 (1C, C-5), tRꢀ=ꢀ15.83 min.
24.7 (1C, C-6), 25.3 (1C, C-6), 26.4 (1C, C-7), 27.6 (1C, C-9),
28.2 (1C, C-9), 36.4 (1C, C-4), 37.2 (1C, C-4), 38.7 (1C, C-3),
40.1 (1C, C-3), 49.1 (1C, C-1), 52.0 (1C, C-8), 53.1 (1C, C-8), 4.3.18 2-(3,4-Dichlorophenyl)-1-[(1RS,5SR,8RS)-8-hydroxy-
67.2 (1C, CH2C=O), 67.4 (1C, CH2C=O), 70.0 (1C, C-1), 128.0
(2C, C-2arom., C-6arom.), 128.1 (2C, C-2arom., C-6arom.), 128.5 (3C,
2-azabicyclo[3.3.1]nonan-2-yl]-ethan-1-one (12d)
C-3arom., C-4arom., C-5arom.), 128.6 (3C, C-3arom., C-4arom., C-5arom.), Under N2, the epoxide 11b (410 mg, 1.25 mmol) was dis-
155.7 (1C, C-1arom.), 156.3 (1C, C-1arom.), 207.1 (1C, C=O). – solved in THF (6 mL) and a solution of NaHMDS in THF
FT-IR: ν (cm−1)ꢀ=ꢀ3345 (s, v, O–H), 2978 (m, v, C–H, alkyl), (1 m, 2.49 mL, 2.50 mmol) was added dropwise at 0°C.
2928 (m, v, C–H, alkyl), 1693 (s, v, C=O), 1242 (s, v, C–O, After stirring for 72 h at r. t., H2O (10 mL) was added. The
alcohol), 729 (m, δ, C–H, mono-substituted arom.), 693 organic layer was separated and the aqueous layer was
(m, δ, C–H, mono-substituted arom.). – LC/MS ((+)-ESI): extracted with CH2Cl2 (3ꢀ×ꢀ20 mL). The combined organic
tRꢀ=ꢀXX min (supply XX), m/zꢀ=ꢀ276.1602 (calcd. 276.1594 for extracts were dried (Na2SO4) and the solvent was removed
+
+
C16H22NO3 , [M+H ]).
in vacuo. The crude oil was purified via flash column chro-
matography (CH2Cl2-acetoneꢀ=ꢀ80:20, Øꢀ=ꢀ2.5 cm, Vꢀ=ꢀ10
mL). Colorless solid, m. p. 92°C, yield 154 mg (38%).
1
4.3.17 [(1RS,5SR,8RS)-8-Hydroxy-2-azabicyclo[3.3.1]
Rfꢀ=ꢀ0.46 (CH2Cl2-acetone 50:50). C16H19Cl2NO2 (328.2). – H
nonan-2-yl]phenylmethan-1-one (12c)
NMR (400 MHz, CDCl3): δ (ppm)ꢀ=ꢀ1.36–1.42 (m, 1H, 7-CH2),
1.45–1.78 (m, 4H, 4-CH2, 6-CH2, 9-CH2), 1.85–2.04 (m, 3H,
Under N2, the epoxide 11c (180 mg, 0.73 mmol) was dis- 4-CH2, 5-CH, 7-CH2), 2.11–2.19 (m, 1H, 6-CH2, 9-CH2), 3.30
solved in THF (6 mL) and a solution of KOtBu in THF (1 m, (ddd, Jꢀ=ꢀ14.6/11.5/6.7 Hz, 0.4H, 3-CH2), 3.45–3.53 (m, 1.2H,
1.47 mL, 1.47 mmol) was added dropwise at 0°C. After 3-CH2), 3.62–3.73 (m, 2H, CH2CO), 3.72 (bs, 0.4H, 8-CH),
stirring for 24 h under reflux conditions, H2O (10 mL) 3.89 (bd, Jꢀ=ꢀ2.5 Hz, 0.4H, 1-CH), 4.02 (bd, Jꢀ=ꢀ2.0 Hz,
was added [13]. The organic layer was separated and 0.6H, 8-CH), 4.13 (2× dd, Jꢀ=ꢀ8.2/2.2 Hz, 0.4H, 3-CH2), 4.37
the aqueous layer was extracted with CH2Cl2 (3ꢀ×ꢀ20 mL). (bd, Jꢀ=ꢀ3.6 Hz, 0.6H, 1-CH), 7.07 (dd, Jꢀ=ꢀ8.4/2.2 Hz, 0.5H,
The combined organic extracts were dried (Na2SO4) and 6-CHarom.), 7.11 (dd, Jꢀ=ꢀ8.4/2.2 Hz, 0.5H, 6-CHarom.), 7.35 (d,
the solvent was removed in vacuo. The crude yellow oil Jꢀ=ꢀ2.2 Hz, 1H, 2-CHarom.), 7.38 (d, Jꢀ=ꢀ8.4Hz, 0.5H, 5-CHarom.),
was purified by flash column chromatography (EtOAc- 7.39 (d, Jꢀ=ꢀ8.4Hz, 0.5H, 5-CHarom.). A signal for the proton
13
C6H12ꢀ=ꢀ90:10, Øꢀ=ꢀ2.5 cm, Vꢀ=ꢀ20 mL). Colorless powder, of the OH moiety is not seen in the spectrum. – C NMR
m. p. 195–196°C, yield 40.8 mg (26%). Rfꢀ=ꢀ0.25 (EtOAc- (100 MHz, CDCl3): δ (ppm)ꢀ=ꢀ24.1, (1C, C-5), 24.8 (2C, C-5,
1
C6H12 80:20). C15H19NO2 (245.3). – H NMR (400 MHz, C-9), 25.3 (1C, C-9), 26.0 (1C, C-7), 26.5 (1C, C-6), 26.8 (1C,
CDCl3): δ (ppm)ꢀ=ꢀ1.43 (bd, Jꢀ=ꢀ7.7 Hz, 0.6H, 7-CH2), 1.52– C-6), 28.3 (1C, C-4), 28.6 (1C, C-7), 29.0 (1C, C-4), 39.3 (1C,
1.76 (m, 3.6H, 4-CH2, 6-CH2, 7-CH2, 9-CH2), 1.81–2.09 (m, C-3), 39.7 (1C, CH2C=O), 40.7 (1C, CH2C=O), 42.0 (1C, C-3),
5.2H, 4-CH2, 5-CH, 6-CH2, 7-CH2, 9-CH2), 2.22 (bd, J =13.5 50.9 (1C, C-1), 53.0 (1C, C-1), 66.3 (1C, C-8), 69.1 (1C, C-8),
Hz, 0.6H, 9-CH2), 3.37–3.56 (m, 1.6H, 3-CH2), 3.80 (bs, 128.5 (1C, C-6arom.), 128.6 (1C, C-6arom.), 128.9 (1C, C-4arom.),
0.8H, 1-CH, 8-CH), 4.21 (bs, 0.6H, 8-CH), 4.35 (dd, 0.4H, 130.6 (1C, C-5arom.), 130.7 (1C, C-5arom.), 130.9 (1C, C-2arom.),
Jꢀ=ꢀ14.7/8.1 Hz, 3-CH2), 4.55 (bs, 0.6H, 1-CH), 7.33–7.41 (m, 131.0 (1C, C-2arom.), 131.1(1C, C-3arom.), 135.3 (1C, C-1arom.), 170.4
5H, CHbenzoyl). – 13C NMR (100 MHz, CDCl3): δ (ppm)ꢀ=ꢀ24.4 (1C, C=O). – FT-IR: ν (cm−1)ꢀ=ꢀ3325 (s, v, O–H), 2924 (m, v,
(1C, C-5), 24.7 (1C, C-9), 25.4 (1C, C-5), 25.6 (1C, C-9), 26.2 C–H, alkyl), 1624 (s, v, C=O), 1412 (s, δ, O–H). – LC/MS ((+)-
(1C, C-7), 26.5 (1C, C-6), 27.2 (1C,C-7), 28.7 (1C, C-4), 29.2 ESI): tRꢀ=ꢀ5.7–5.8 min, m/zꢀ=ꢀ328.0878 (calcd. 328.0866 for
+
+
(1C, C-6), 29.3 (1C, C-3), 39.6 (1C, C-4), 44.0 (1C, C-3), 51.1 C16H2035Cl2NO2 , [M+H ]). – Purity (HPLC, method 1): 70.9%,
(1C, C-1), 54.2 (1C, C-1), 66.4 (1C, C-8), 69.0 (1C, C-8), 126.3 tRꢀ=ꢀ19.93 min.
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ꢀꢀꢀꢁ
1068ꢀ ꢀJ. Stefaowitz et al.: Synthesis of morphan derivatives with additional substituents in 8-position
(3ꢀ×ꢀ30 mL). The combined organic layers were dried
(Na2SO4) and the solvent was removed in vacuo. The
crude product was purified by flash column chromatog-
4.3.19 (1RS,5SR)-2-[2-(3,4-Dichlorophenyl)acetyl]-2-
azabicyclo[3.3.1]nonan-8-one (13d)
Dess-Martin periodinane (260 mg, 0.61 mmol) was added raphy (EtOAc-C6H12ꢀ=ꢀ9:1, Øꢀ=ꢀ2.5 cm, Vꢀ=ꢀ10 mL). Color-
to a solution of bicyclic alcohol 12d (100 mg, 0.30 mmol) less solid, m. p. 179–181°C, yield 11.6 mg (31%). Rfꢀ=ꢀ0.21
1
in CH2Cl2 (10 mL). After 18 h stirring at r. t., the mixture (EtOAc-C6H12 9:1). C16H19Cl2NO2 (314.2). – H NMR (600
was treated with aq. NaHCO3 solution. The layers were MHz, CDCl3): δ (ppm)ꢀ=ꢀ1.55–189 (m, 7H, 4-CH2, 6-CH2,
separated and the aqueous layer was extracted with 7-CH2, 9-CH2), 1.94–2.02 (m, 2H, 4-CH2, 5-CH, 9-CH2), 3.20
CH2Cl2 (3ꢀ×ꢀ30 mL). The combined organic extracts were (td, Jꢀ=ꢀ12.9/4.8 Hz, 0.2H, 3-CH2), 3.47 (dt, Jꢀ=ꢀ13.1/7.0 Hz,
washed with saturated NaCl solution and dried (Na2SO4). 0.8H, 3-CH2), 3.54 (dt, Jꢀ=ꢀ13.1/6.9ꢀHz, 0.8H, 3-CH2), 3.72
The solvent was removed in vacuo. The crude product (s, 1.6 H, CH2CO), 3.81–3.95 (m, 1.4 H, 8-CH, CH2CO), 4.09
was purified by flash column chromatography (EtOAc- (bs, 0.2H, 1-CH), 4.26 (dd, Jꢀ=ꢀ14.1/8.3 Hz, 0.2H, 3-CH2),
C6H12ꢀ=ꢀ60:40, Øꢀ=ꢀ2.5 cm, Vꢀ=ꢀ10 mL). Colorless oil, yield 4.76 (s, 0.8H, 1-CH), 7.11 (dd, Jꢀ=ꢀ8.2/1.6 Hz, 1H, 6-CHarom.),
40 mg (37%). Rfꢀ=ꢀ0.41 (EtOAc:C6H12 80:20). C16H17Cl2NO2 7.35 (d, Jꢀ=ꢀ1.6 Hz, 1H, 2-CHarom.), 7.40 (d, Jꢀ=ꢀ8.2 Hz, 1H,
1
(326.2). – H NMR (400 MHz, CDCl3): δ (ppm)ꢀ=ꢀ1.61–1.66 5-CHarom.). A signal for the proton of the OH moiety is
13
(m, 0.5H, 6-CH2), 1.75–1.80 (m, 0.5H, 6-CH2), 1.82–1.87 not seen in the spectrum. – C NMR (150 MHz, CDCl3):
(m, 0.5H, 4-CH2), 1.92–2.14 (m, 4.5H, 4-CH2, 6-CH2, 7-CH2), δ (ppm)ꢀ=ꢀ23.4 (1C, C-5), 24.5 (1C, C-5), 27.9 (1C, C-7), 28.2
2.23–2.28 (m, 1H, 5-CH), 2.36 (ddd, Jꢀ=ꢀ14.9/7.1/4.5 Hz, 0.5H, (1C, C-4), 29.0 (1C, C-7), 29.1 (1C, C-4), 29.7 (1C, C-9), 29.8
9-CH2), 2.47–2.55 (m, 1H, 9-CH2), 2.65 (ddd, Jꢀ=ꢀ16.4/11.1/8.2 (1C, C-6), 31.4 (1C, C-9), 32.2 (1C, C-6), 39.9 (1C, CH2C=O),
Hz, 0.5H, 9-CH2), 3.41–3.56 (m, 1.5H, 3-CH2), 3.63–3.71 (m, 40.8 (1C, CH2C=O), 40.9 (1C, C-3), 42.4 (1C, C-3), 51.9 (1C,
2H, CH2CO), 3.99 (ddd, Jꢀ=ꢀ14.5/7.1/4.8 Hz, 0.5H, 3-CH2), C-1), 53.4 (1C, C-1), 72.2 (1C, C-8), 74.0 (1C, C-8), 128.6 (1C,
4.22 (bt, Jꢀ=ꢀ2.9 Hz, 0.5 H, 1-CH), 4.68 (bs, 0.5H, 1-CH), 7.08 C-6arom.), 129.0 (1C, C-6arom.), 130.4 (1C, C-2arom.), 130.7 (1C,
(dd, Jꢀ=ꢀ8.2/2.1 Hz, 0.5H, 6-CHarom.), 7.12 (dd, Jꢀ=ꢀ8.2/2.1 Hz, C-2arom.), 130.8 (1C, C-3arom.), 131.2 (2C, C-3arom., C-5arom.),
0.5H, 6-CHarom.), 7.34 (d, Jꢀ=ꢀ2.1 Hz, 1H, 2-CHarom.), 7.38 (d, 131.4 (1C, C-5arom.), 132.4 (1C, C-4arom.), 132.7 (1C, C-4arom.),
13
Jꢀ=ꢀ8.2 Hz, 1H, 5-CHarom.). – C NMR (100 MHz, CDCl3): δ 134.9 (1C, C-1arom.),136.7 (1C, C-1arom.), 172.1 (1C, C=O), 173.9
(ppm)ꢀ=ꢀ23.7 (2× 1C, C-5), 28.9 (1C, C-4), 30.1 (1C, C-4), 30.4 (1C, C=O). – FT-IR: ν (cm−1)ꢀ=ꢀ3379 (s, v, O–H), 2978 (m,
(1C, C-6), 30.8 (1C, C-6), 31.3 (1C, C-7), 32.4 (1C, C-7), 35.9 v, C–H, alkyl), 2928 (m, v, C–H, alkyl), 1608 (s, v, C=O),
(1C, C-9), 37.2 (1C, C-9), 37.9 (1C, C-3), 39.8 (1C, CH2C=O), 1443 (m, δ, O–H), 1069 (m, γ, C–H). – Purity (HPLC,
40.3 (1C, CH2C=O), 40.7 (1C, C-3), 57.9 (1C, C-1), 59.7 (1C, method 1): 93.5%, tRꢀ=ꢀ20.52 min.
C-1), 128.3 (1C, C-6arom.), 128.9 (1C, C-6arom.), 130.5 (1C,
C-5arom.), 130.7 (1C, C-5arom.), 130.9 (1C, C-3arom.), 131.1 (1C,
C-3arom.), 131.3 (1C, C-2arom.), 131.4 (1C, C-2arom.), 132.6 (1C, 4.4 X-ray crystal structure analysis of 12c
C-4arom.), 132.8 (1C, C-4arom.), 134.8 (1C, C-1arom.), 135.1 (1C,
C-1arom.), 169.6 (1C, C=O), 171.1 (1C, C=O), 208.7 (1C, C-8), Recrystallization of 12c from EtOAc gave colorless single
210.0 (1C, C-8). – FT-IR: ν (cm−1)ꢀ=ꢀ2928 (m, v, C–H, alkyl), crystals suitable for X-ray diffraction. Tꢀ=ꢀ223(2) K, Nonius
1717 (m, v, C=O of ketone), 1639 (m, v, C=O of amide), 1030 Kappa CCD diffractometer, CuKα radiation, λꢀ=ꢀ1.54178
(m, γ, C–H). – LC/MS ((+)-ESI): tRꢀ=ꢀ5.8 min, m/zꢀ=ꢀ326.0701 Å, ω and ϕ scans; an empirical absorption correction
(calcd. 326.0709 for C16H1835Cl2NO2 , [M+H ]). – Purity was applied (0.874ꢀꢁ≤ꢁꢀTꢀꢁ≤ꢁꢀ0.973). The hydrogen atom posi-
+
+
(HPLC, method 1): 88.8%, tRꢀ=ꢀ20.33 min.
tions were calculated and refined as riding atoms. Flack
(x) parameter refined to –0.45(44). Programs used: data
collection, collect [27]; data reduction Denzo-SMN [28];
absorption correction, Denzo [29]; structure solution
shelxs-97 [30]; structure refinement shelxs-97 [31] and
graphics, xp [32].
4.3.20 2-(3,4-Dichlorophenyl)-1-[(1RS,5SR,8SR)-8-
hydroxy-2-azabicyclo[3.3.1]nonan-2-yl]-ethan-1-
one (14d)
Table 2 summarizes the crystal data and numbers per-
The ketone 13d (37.0 mg, 0.11 mmol) was dissolved in THF tinent to data collection and structure refinement.
(6 mL) and EtOH (2ꢀmL). NaBH4 (43.0 mg, 1.13 mmol) was
CCDC 1480173 (12c) contains the supplementary crys-
added and the mixture was stirred at r. t. for 12 h. Then 2 tallographicdataforthispaper. Thesedatacanbeobtained
m HCl and CH2Cl2 (10 mL) were added and the layers were free of charge from The Cambridge Crystallographic Data
separated. The aqueous layer was extracted with CH2Cl2 Centre via www.ccdc.cam.ac.uk/data_request/cif.
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ꢁꢀꢀꢀ
J. Stefaowitz et al.: Synthesis of morphan derivatives with additional substituents in 8-positionꢂ
ꢂ1069
Table 2:ꢀCrystal structure data for 12c.
[6] T. Maurice, T. P. Su, Pharmacol. Ther. 2009, 124, 195.
[7] C. M. Bertha, M. V. Mattson, J. L. Flippen-Anderson,
R. B. Rothman, H. Xu, X.-Y. Cha, K. Becketts, K. C. Rice, J. Med.
Chem. 1994, 37, 3163.
[8] K. W. Crawford, W. D. Bowen, Cancer. Res. 2002, 62, 3133.
[9] J. Bonjoch, F. Diaba, B. Bredshaw, Synthesis 2011, 7, 993.
[10] M. E. Hediger, Bioorg. Med. Chem. 2004, 12, 4995.
[11] M.-C. P. Yeh, H.-F. Pai, Z.-J. Lin, B.-R. Lee, Tetrahedron 2009, 65,
4789.
[12] G. Karig, A. Fuchs, A. Büsing, T. Brandstetter, S. Scherer, J. W.
Bats, A. Eschenmoser, G. Quinkert, Helv. Chim. Acta 2000, 83,
1049.
[13] L. J. Dolby, S. J. Nelson, J. Org. Chem. 1973, 38, 2882.
[14] W. Bauer, K.-H. Büchel, H. Döpp, T. Eicher, J. Falbe,
C. J. Grundmann, H. Hagemann, M. Hanack, D. Klamann,
H.-G. Korth, R. P. Kreher, C. Kropf, G. Krüger, K. Kühlein,
R. Mayer, H. Pielartzik, M. Regitz, D. Schumann, G. Simchen,
R. Sustmann, Houben-Weyl Methods in Organic Chemistry, Vol.
E5, Georg Thieme Verlag Stuttgart, 1985, p. 262.
[15] F. Becke, H. Fleig, P. Päßler, Liebigs Ann. Chem. 1971, 749,
198.
[16] A. Matsuoka, T. Isogawa, Y. Morioka, B. R. Knappett, A. E. H.
Wheatley, S. Saito, H. Naka, R. Soc. Chem. Adv. 2014, 5, 12152.
[17] S. Knapp, K. E. Rodriques, A. T. Levorse, R. M. Ornaf,
Tetrahedron Lett. 1985, 26, 1803.
Formula
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
C15H19NO2
245.31
0.20ꢁ×ꢁ0.12ꢁ×ꢁ0.04
Monoclinic
Cc
Mr
Crystal size, mm3
Crystal system
Space group
a, Å
b, Å
c, Å
5.9182(8)
18.9640(14)
11.2060(20)
97.460(15)
1247.0(3)
4
β, deg
V, Å3
Z
D
calcd, g cm−3
1.307
F(000), e
528
μ(CuKα), mm−1
((sinθ)/λ)max, Å−1
Refl. measured
Refl. unique/Rint
Param. refined
0.7
0.60
5158
1071/0.052
164
R(F) / wR(F2)a (all refl.)ꢃ
0.1048
x(Flack)
ꢃ
ꢃ
ꢃ
–0.45(44)
1.060
GoF (F2)b
Δρfin (max/min), e Å−3
0.205/–0.169
aR1ꢁ=ꢁ||Fo|ꢁ–ꢁ|Fc||/Σ|Fo|, wR2ꢁ=ꢁ[Σw(Fo2ꢁ–ꢁFc2)2/Σw(Fo )2]1/2
,
2
[18] S. Knapp, A. T. Levorse, J. Org. Chem. 1988, 53, 4006.
[19] Y.-Y. Yeung, E. J. Corey, Tetrahedron Lett. 2007, 48, 7567.
[20] B. Wünsch, C. Geiger in Houbel-Weyl, Science of Synthesis, Vol.
40a, (Eds.: D. Enders, E. Schaumann), Georg Thieme Verlag,
Stuttgart, 2009, pp. 23–64.
wꢁ=ꢁ[σ2(Fo )ꢁ+ꢁ(AP)2ꢁ+ꢁBP]−1, where Pꢁ=ꢁ(Max(Fo , 0)ꢁ+ꢁ2Fc2)/3;
2
2
b GoFꢁ=ꢁ[Σw(Fo2ꢁ–ꢁFc2)2/(nobsꢁ–ꢁnparam)]1/2
.
[21] C. Bourgeois, E. Werfel, F. Galla, K. Lehmkuhl, H. Torres-Gómez,
D. Schepmann, B. Kögel, T. Christoph, W. Straßburger,
W. Englberger, M. Soeberdt, S. Hüwel, H.-J. Galla, B. Wünsch
J. Med. Chem. 2014, 57, 6845.
[22] B. R. de Costa, W. D. Bowen, S. B. Hellewell, C. George,
R. B. Rothman, A. A. Reid, J. M. Walker, A. E. Jacobson,
K. C. Rice, J. Med. Chem. 1989, 32, 1996.
[23] L. Radesca, W. D. Bowen, L. Di Paolo, B. R. de Costa, J. Med.
Chem. 1991, 34, 3058.
[24] R. N. McDonald, R. N. Steppel, J. E. Dorsey, Org. Synth., Coll.
1988, 6, 276B.
[25] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
[26] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277.
[27] R. W. W. Hooft, collect, Bruker Analytical X-ray Instruments
Inc., Delft (The Netherlands) 2008.
[28] Z. Otwinowski, W. Minor in Methods in Enzymology, Vol. 276,
Macromolecular Crystallography, Part A (Eds.: C. W. Carter Jr,
R. M. Sweet), Academic Press, New York, 1997, pp. 307.
[29] Z. Otwinowski, D. Borek, W. Majewski, W. Minor, Acta Crystallogr.
2003, A59, 228–234.
Acknowledgments: This work was performed within the
framework of the International Research Training Group
‘Complex Functional Systems in Chemistry: Design, Syn-
thesis and Applications’ in collaboration with the Uni-
versity of Nagoya. Financial support of this project by
the IRTG Münster-Nagoya and the Deutsche Forschun-
gsgemeinschaft is gratefully acknowledged. This work
was partially supported by JSPS Core-to-Core Program, A.
Advanced Research Network.
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