Microwave-assisted Raney nickel reduction of bispidinone thioketals to N,N′-dialkylbispidines

Article abstract of DOI:10.1055/s-2006-942394

A series of N,N′-dialkyl-3,7-diazabicyclo[3.3.1]nonanes was prepared by microwave-assisted reduction of a common dithiolane precursor with Raney nickel, using the corresponding alkanol as solvent. The method avoids the use of hydrazine. Georg Thieme Verla

Full text of DOI:10.1055/s-2006-942394

2064
PAPER
Microwave-Assisted Raney Nickel Reduction of Bispidinone Thioketals to
N,N¢-Dialkylbispidines
M
icrowave-Ass
a
iste
d
Rane
u
y Nickel Red
r
uction o
i
f
Bispidinone
TThioketals oom, Helena Grennberg, Adolf Gogoll*
Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, 75123 Uppsala, Sweden
Fax +46(18)4713818; E-mail: Adolf.Gogoll@kemi.uu.se
Received 23 February 2006
converted the N,N¢-dibenzylbispidinone 1 into the thi-
Abstract: A series of N,N¢-dialkyl-3,7-diazabicyclo[3.3.1]nonanes
was prepared by microwave-assisted reduction of a common dithi-
olane precursor with Raney nickel, using the corresponding alkanol
as solvent. The method avoids the use of hydrazine.
olane 2, which was then subjected to reduction
(Scheme 1). Initial studies showed that the reaction was
best carried out in primary alcohol solvent (Table 1). In
addition to the thioacetal reduction, the starting material is
simultaneously debenzylated. This generates a secondary
amine, which is alkylated by the solvent, probably follow-
ing a mechanism that was suggested by Rice and Kohn.13
Key words: alkylations, bicyclic compounds, deoxygenation, de-
sulfurizations, microwave-assisted synthesis
3,7-Diazabicyclo[3.3.1]nonanes (bispidines)1 have a mo-
lecular backbone resembling the alkaloid sparteine. They
are strong Lewis bases which have been used in deproto-
nation reactions,2 and as ligands in various organometallic
complexes,3 e.g., for structural characterization of organic
species.4 Furthermore, they have interesting physiological
properties as antiarrhythmic agents and as opioid receptor
ligands.5
Since this mechanism involves the conversion of the alco-
hol into a carbonyl compound, the reaction is limited to
primary alcohols. It appears to be compatible with alkoxy
groups (Table 1, entries 11 and 12). Surprisingly, 3-furyl-
methanol resulted in partial reduction of only the thiolane,
but not the benzyl groups, thus providing access to 12,
which could not be obtained with benzyl alcohol as sol-
vent. Several other primary alcohols, i.e. (1S,2S,5S)-(–)-
myrtanol, 2-pyridylmethanol, 2-(N,N-dimethylami-
no)ethanol, and allyl alcohol, did not support the reaction.
2-Propanol allowed isolation of a trace amount of product
after HPLC purification. Use of tert-butanol, water or oth-
er non-alcoholic solvents did not yield the desired bispi-
dine products, but resulted in decomposition (t-BuOH,
THF, 1,4-dioxane, acetone, allyl alcohol) or partial recov-
ery of the substrate 2 (H2O, ethan-1,2-diol).
Synthetically, the corresponding ketones, i.e., 3,7-diaza-
bicyclo[3.3.1]nonan-9-ones (bispidinones) are more con-
veniently accessible. Typically, N,N¢-dialkylbispidinones
are obtained via a Mannich reaction with varying yields,
e.g., 85% for N,N¢-dibenzylbispidinone 1,5a and only 3%
yield for N,N¢-dimethylbispidinone.6 Only a few symmet-
ric N,N¢-dialkylbispidines have been reported, prepared in
low to moderate yields by reduction of carbonyl precur-
sors. Reduction of the keto group is almost exclusively
achieved by the Huang-Minlon modification of the
Wolff–Kishner method.7 The yields in this step are gener-
ally fair to good, e.g., N,N¢-dimethylbispidine 3 (60%),6
N,N¢-diisopropylbispidine (38%),2d N,N¢-dibutylbispidine
6 (49%)2b and N,N¢-dibenzylbispidine 12 (94%).8 Howev-
er, the requirement to use hydrazine is a considerable dis-
advantage, since it is highly toxic, flammable, and a
strong mutagen, thus requiring special precautions, or pre-
venting its use entirely. Alternatively, in a few examples,
bispidinones were reduced to the corresponding bis-
pidines via the tosylhydrazone, with varying yields (19%9
to 85%10) for the two steps.
O
S
S
HSCH2CH2SH
Raney-Ni
ROH, MW
p-TsOH⋅H2O
PhH, N2, ∆
Bn
N
N
N
N
N
N
Bn
Bn
R
R
Bn
1
2
3–12
Scheme 1 Synthetic sequence for N,N¢-dialkylbispidines. 3, R =
Me; 4, R = Et; 5, R = Pr; 6, R = Bu; 7, R = i-Bu; 8, R = pentyl; 9, R =
hexyl; 10, R = octyl; 11, R = EtOMe; 12, R = Bn.
With conventional heating at reflux temperature, reaction
times of more than two days were required for the full
consumption of the substrate. Therefore, we turned to mi-
crowave heating. Raney nickel and microwave irradiation
has been used for N-alkylation of anilines with alcohols,14
and for rapid deuterium exchange labeling.15 The amount
of Raney nickel was varied from 10–30 mass equivalents.
Whereas 10 equivalents of Raney nickel occasionally re-
sulted in only partial conversion, 20 equivalents were suf-
ficient, and a further increase to 30 equivalents did not
improve the reaction. Microwave irradiation reduced the
time until full conversion to between 60 minutes and 90
This initiated us to develop an alternative synthetic meth-
od, which avoids the use of hydrazine and only uses
recyclable11 or low-molecular-weight reagents for im-
proved atom efficiency.12 Since it is known that dithioac-
etals can be reductively converted to the corresponding
methylene compound by active Raney nickel catalyst, we
SYNTHESIS 2006, No. 12, pp 2064–2068
x
x.
x
x
.
2
0
0
6
Advanced online publication: 11.05.2006
DOI: 10.1055/s-2006-942394; Art ID: P02206SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Microwave-Assisted Raney Nickel Reduction of Bispidinone Thioketals
2065
Table 1 Synthesis of N,N¢-Dialkylbispidines by Controlled Microwave Heating
Entry
1
Solvent
Temp (°C)
155
Time (min)
Yield (%)a
Purity (%)b
Product
MeOH
120
60
60
90
90
55
60
90
90
90
60
60
61
86
71
84
–
3
4
5
2
EtOH
160
71
3
n-PrOH
160
66
4
i-PrOH
160
traces
55
5
n-BuOH
i-BuOH
160
68
84
–
6
7
6
160
65
7
t-BuOH
160
dec.c
53
8
n-Pentanol
n-Hexanol
n-Octanol
2-Methoxyethanol
160
87
73
92
87
42
8
9
9
160
59
10
11
12
160
58
10
11
11
160
65
2-Methoxyethanol
160
17
(ca 6 equiv) in t-BuOH
13
14
15
16
H2O
155
160
160
160
60
60
90
60
n.r.d
n.r.
–
Ethane-1,2-diol
3-Furylmethanol
Benzyl alcohol
–
53
29
–
12
12
traces
a Determined from 1H NMR spectra of residue after removal of nickel and solvent by addition of a reference compound.
b Calculated as weight% of residue.
c dec.: decomposed.
d n.r.: no reaction, no by-products detected in crude 1H NMR spectrum. Substrate was partly recovered.
chemical shifts were obtained from 1H detected 1H–15N gHMBC17
spectra on a Varian Inova 500 spectrometer. The chemical shift was
referenced to an external standart (0.6 M solution of CH3NO2) in
CDCl3, and is reported relative to liquid NH3. NMR signals were as-
signed from gHSQC,18 gHMBC,17 gNOESY19 and TOCSY20 spec-
tra. IR spectra were recorded on a Perkin–Elmer 1760 FT-IR
spectrometer. Analytical TLC was performed using pre-coated
Merck Silica 60 F254 or Merck neutral aluminum oxide 60 F254
plates, and compound visualization was achieved with UV light
(254 nm), or by developing the plates with a 5% phosphomolybdic
acid solution in ethanol, followed by heating. For column chroma-
tography Matrex silica gel (60 Å, 35–70 mm) or neutral activated g-
Al2O3 (60 mesh) from Strem Chemicals were used. Commercial re-
agents were purchased from Sigma-Aldrich and Cortec. Raney
nickel catalyst was prepared from nickel–aluminum alloy according
to the literature procedure,21 and stored in a freezer after preparation
as a slurry in 99.5% EtOH. Elemental analyses were performed by
Analytische Laboratorien (Prof. Dr. H. Malissa and G. Reuter Gm-
bH, 51789 Lindlar, Germany).
minutes, producing the bispidines in moderate to good
yields.
The microwave-assisted reactions were performed under
single mode irradiation, with monitoring of temperature,
pressure, and irradiation power versus time. During opti-
mization, the reaction temperature was varied between
130 °C and 160 °C, with 160 °C giving the best conver-
sion. Higher temperatures resulted in buildup of excessive
pressure in the reaction vessel (above 20 bars).
Upon prolonged storage, the dialkylbispidines exhibited a
yellowish coloration, presumably due to oxidation.
Broadening of 1H NMR signals indicates the presence of
radicals.16 Therefore, purification and full characteriza-
tion was done after conversion to their p-toluenesulfonate
salts, followed by HPLC on reverse phase with a metha-
nol–water gradient.
Microwave reactions were performed in a Biotage Initiator Sixty
scientific microwave, using heavy-walled glass Emrys process vials
(2–5 mL) sealed with aluminum crimp caps fitted with a septum.
Melting points were determined in open capillaries using a Stuart
Scientific melting point apparatus SMP10 and are uncorrected. 1H
and 13C NMR spectra were recorded at 500 MHz and 125.7 MHz,
respectively, at 25 °C on a Varian Inova 500 spectrometer. Chemi-
cal shifts (for 1H and 13C NMR) were indirectly referenced to TMS
via the residual solvent signal (CDCl3, d = 7.26 and 77.0). 15N NMR
Preparative HPLC was performed on a Gilson HPLC system using
a C-8 preparative column (26 cm × 3 cm) and MeOH–H2O (50–
70%) gradient.
Synthesis 2006, No. 12, 2064–2068 © Thieme Stuttgart · New York

2066
L. Toom et al.
PAPER
3,7-Dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one (1)
This compound was prepared according to a literature procedure
and the spectral data (1H, 13C NMR, IR) were consistent with previ-
ously reported data.5a,8
Purification Method B: After determining the dialkylbispidine
content in the product mixture, p-toluenesulfonic acid monohydrate
(1 equiv) was added to the solution of the crude product in MeOH
(5 mL) and the solution was concentrated and subjected to HPLC on
reverse phase with a MeOH–H2O (50–70%) gradient. The HPLC
purification resulted in 60% separation of an analytically pure prod-
uct in one example (8·p-TsOH; in the other cases the HPLC yields
were not determined).
15N NMR (50.7 MHz, CDCl3): d = 41.5 (Lit5a 39.2).
3,7-Dibenzyl-9,9-(1,3-dithiolan-2-yl)-3,7-diazabicyclo[3.3.1]no-
nane (2)
p-Toluenesulfonic acid monohydrate (14.3 g, 74.9 mmol), 3,7-
dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one (1; 10.0 g, 31.2
mmol) and 1,2-ethanedithiol (35 mL, ca. 90% purity, ca. 375 mmol)
were dissolved in anhyd benzene (300 mL). The orange reaction
mixture was refluxed in a Dean–Stark setup under N2 atmosphere
for 48 h. The reaction mixture was transferred into a 1 L separatory
funnel and washed with 1 M NaOH (100 mL). The aqueous phase
was separated and extracted with CH2Cl2 (50 mL). The combined
organic phases were extracted once more with 1 M NaOH solution
(40 mL) and the aqueous phase was discarded. Benzene and CH2Cl2
were distilled off under normal pressure. Excess of 1,2-ethanedithi-
ol was recovered by vacuum distillation (bp 55 °C). The title prod-
uct was further purified by using a flash chromatography column
packed with neutral alumina and CH2Cl2–pentane–Et3N (5:5:0.2) as
the mobile phase, yielding 2 as slightly yellow oil that was crystal-
lized from acetone (9.2 g, 23.2 mmol, 74% yield); mp 107–108 °C;
Rf = 0.55 (Al2O3, pentane–CH2Cl2–Et3N, 5:5:0.2).
3,7-Dimethyl-7-aza-3-azoniabicyclo[3.3.1]nonane 4-Methyl-
benzenesulfonate (3·p-TsOH)
Mp 144–145 °C.
1H NMR (500 MHz CDCl3): d = 7.79 (AA¢ part of AA¢BB¢, 2 H,
2¢,6¢-CH), 7.15 (BB¢ part of AA¢BB¢, 2 H, 3¢,5¢-CH), 4.07 (br s, 1
H), 3.57 (dm, J = 11.5 Hz, 4 H, 2,4,6,8-CH2-eq), 2.64 (dm, J = 11.5
Hz, 4 H, 2,4,6,8-CH2-ax), 2.62 (s, 6 H, NCH3), 2.34 (s, 3 H,
C6H4CH3), 2.14 (m, 2 H, 1,5-CH), 1.74 (m, 2 H, 9-CH2). The NH
proton appears as part of a broad signal at d = 4.07 ppm together
with H2O.
13C NMR (125.7 MHz, CDCl3): d = 143.6 (C-1¢), 139.3 (C-4¢),
128.6 (3¢,5¢-CH), 125.9 (2¢,6¢-CH), 59.5 (2,4,6,8-CH2), 45.6
(NCH3), 29.8 (9-CH2), 28.5 (1,5-CH), 21.3 (C6H4CH3).
Anal. Calcd for C16H26N2O3S: C, 58.87; H, 8.03; N, 8.58.
Anal. Calcd for C16H26N2O3S + 0.37 H2O: C, 57.69; H, 8.09; N,
8.41. Found: C, 57.69; H, 8.09; N, 8.31.
IR (neat): 2909, 2800, 2768, 1494, 1453, 1275, 1126, 1063, 1019,
854, 748, 727, 698 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.42 (m, 4 H, 2¢,6¢-CH), 7.31 (m,
4 H, 3¢,5¢-CH), 7.24 (m, 2 H, 4¢-CH), 3.53 (s, 4 H, PhCH2), 3.15 (s,
4 H, SCH2), 2.84 (dm, J = 11.2 Hz, 4 H, 2,4,6,8-CH2-ax), 2.76 (dm,
J = 11.2 Hz, 4 H, 2,4,6,8-CH2-eq), 2.13 (m, 2 H, 1,5-CH).
13C NMR (125.7 MHz, CDCl3): d = 138.9 (C-1¢), 128.6 (2¢,6¢-CH),
127.9 (3¢,5¢-CH), 126.5 (C-4¢), 71.8 (C-9), 61.9 (PhCH2), 56.5
(2,4,6,8-CH2), 43.4 (1,5-CH), 37.9 (SCH2).
15N NMR (50.7 MHz, CDCl3): d = 38.4.
3,7-Diethyl-7-aza-3-azoniabicyclo[3.3.1]nonane 4-Methylben-
zenesulfonate (4·p-TsOH)
Mp 122–124 °C.
1H NMR (500 MHz, CDCl3): d = 7.79 (AA¢ part of AA¢BB¢, 2 H,
2¢,6¢-CH), 7.13 (BB¢ part of AA¢BB¢, 2 H, 3¢,5¢-CH), 5.63 (br s, 1
H), 3.57 (dm, J = 11.5 Hz, 4 H, 2,4,6,8-CH2-eq), 2.91 (q, J = 7.2 Hz,
4 H, NCH2CH3), 2.76 (dm, J = 11.5 Hz, 4 H, 2,4,6,8-CH2-ax), 2.33
(s, 3 H, C6H4CH3), 2.19 (m, 2 H, 1,5-CH), 1.81 (m, 2 H, 9-CH2),
1.20 (t, J = 7.2 Hz, 6 H, CH2CH3). The NH proton appears as part
of a broad signal at d = 5.63 ppm together with H2O.
13C NMR (125.7 MHz, CDCl3): d = 144.1 (C-1¢), 138.9 (C-4¢),
128.4 (3¢,5¢-CH), 125.9 (2¢,6¢-CH), 57.1 (2,4,6,8-CH2), 51.9
(CH2CH3), 30.6 (9-CH2), 28.2 (1,5-CH), 21.2 (C6H4CH3), 10.5
(CH2CH3).
Anal. Calcd for C23H28N2S2: C, 69.65; H, 7.12; N, 7.06. Found: C,
69.48; H, 7.10; N, 6.93.
Microwave-Assisted Reduction: General Procedure
3,7-Dibenzyl-9,9-(1,3-dithiolan-2-yl)-3,7-diazabicyclo[3.3.1]no-
nane (2; 50 mg, 0.126 mmol), Raney nickel (1.1 g of the slurry in
the corresponding alcoholic solvent) and the alcohol (2 mL) were
sealed without excluding atmospheric O2 into a MW process vial
with a small magnetic stir bar inside. The MW heating was per-
formed in a Biotage Initiator Sixty MW cavity producing continu-
ous irradiation at 2.45 GHz (Biotage AB, Uppsala, Sweden).
Reaction mixtures were stirred with a magnetic stir bar during the
irradiation. The temperature, pressure and irradiation power were
monitored during the course of the reaction. The average pressure
during the reaction was 3–18 bars. After complete irradiation, the
reaction tube was cooled with high-pressure air. The solution from
the vial was then filtered through a pad of celite, the nickel was
washed with Et2O (6 × 4 mL), allowed to settle, and the Et2O phase
was filtered and combined with the other solution. The combined
solutions were evaporated under vacuum. For exact product quanti-
fication in the residue, an aliquot of 1,4-dimethoxybenzene (98%)
was added as an internal standard and the mixture was subjected to
1H NMR analysis.
Anal. Calcd for C18H30N2O3S: C, 60.98; H, 8.53; N, 7.90. Found: C,
60.63; H, 8.55; N, 7.79.
3,7-Dipropyl-7-aza-3-azoniabicyclo[3.3.1]nonane 4-Methylben-
zenesulfonate (5·p-TsOH)
Mp 103–105 °C.
1H NMR (500 MHz, CDCl3): d = 7.80 (AA¢ part of AA¢BB¢, 2 H,
2¢,6¢-CH), 7.13 (BB¢ part of AA¢BB¢, 2 H, 3¢,5¢-CH), 3.52 (dm, J =
11.5 Hz, 4 H, 2,4,6,8-CH2-eq), 3.25 (br s, 1 H), 2.90 (dm, J = 11.5
Hz, 4 H, 2,4,6,8-CH2-ax), 2.79 (m, 4 H, NCH2CH2), 2.33 (s, 3 H,
C6H4CH3), 2.21 (m, 2 H, 1,5-CH), 1.88 (m, 2 H, 9-CH2), 1.64 (m, 4
H, CH2CH3), 0.92 (t, J = 7.4 Hz, 6 H, CH2CH3). The NH proton ap-
pears as part of a broad signal at d = 3.25 ppm together with H2O.
13C NMR (125.7 MHz, CDCl3): d = 144.1 (C-1¢), 138.8 (C-4¢),
128.4 (3¢,5¢-CH), 126.0 (2¢,6¢-CH), 59.1 (NCH2CH2), 57.9 (2,4,6,8-
CH2), 30.5 (9-CH2), 28.3 (1,5-CH), 21.3 (C6H4CH3), 18.7
(CH2CH3), 11.2 (CH2CH3).
Purification Method A: The product mixture was treated with fine
KOH powder (50 mg) and then purified by bulb-to-bulb vacuum
distillation (ca. 3 × 10–1 mbar), yielding clear oils. However, the dis-
tilled dialkylbispidines exhibited a yellowish coloration, presum-
ably due to oxidation, therefore method B was used to obtain
analytically pure products.
Anal. Calcd for C20H34N2O3S: C, 62.79; H, 8.96; N, 7.32. Found: C,
62.64; H, 9.00; N, 7.27.
3,7-Dibutyl-7-aza-3-azoniabicyclo[3.3.1]nonane 4-Methylben-
zenesulfonate (6·p-TsOH)
Mp 40–43 °C.
Synthesis 2006, No. 12, 2064–2068 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Raney Nickel Reduction of Bispidinone Thioketals
2067
1H NMR (500 MHz, CDCl3): d = 7.80 (AA¢ part of AA¢BB¢, 2 H,
2¢,6¢-CH), 7.13 (BB¢ part of AA¢BB¢, 2 H, 3¢,5¢-CH), 3.74 (br s, 1
H), 3.50 (dm, J = 11.5 Hz, 4 H, 2,4,6,8-CH2-eq), 2.93 (dm, J = 11.5
Hz, 4 H, 2,4,6,8-CH2-ax), 2.83 (m, 4 H, NCH2CH2), 2.33 (s, 3 H,
C6H4CH3), 2.22 (m, 2 H, 1,5-CH), 1.89 (m, 2 H, 9-CH2), 1.57 (m, 4
H, NCH2CH2), 1.32 (m, 4 H, CH2CH3), 0.92 (t, J = 7.3 Hz, 6 H,
CH2CH3). The NH proton appears as part of a broad signal at d =
3.74 ppm together with H2O.
13C NMR (125.7 MHz, CDCl3): d = 144.1 (C-1¢), 138.8 (C-4¢),
128.4 (3¢,5¢-CH), 126.0 (2¢,6¢-CH), 57.9 (2,4,6,8-CH2), 57.2
(NCH2CH2), 30.4 (9-CH2), 28.3 (1,5-CH), 27.4 (NCH2CH2), 21.3
(C6H4CH3), 20.1 (CH2CH3), 13.8 (CH2CH3).
H, CH2), 1.31–1.23 (m, 12 H), 0.87 (m, 6 H, CH2CH3). The NH pro-
ton appears as part of a broad signal at d = 4.49 ppm together with
H2O.
13C NMR (125.7 MHz, CDCl3): d = 144.1 (C-1¢), 138.8 (C-4¢),
128.4 (3¢,5¢-CH), 126.0 (2¢,6¢-CH), 57.9 (2,4,6,8-CH2), 57.5
(NCH2CH2), 31.5 (CH2), 30.4 (9-CH2), 28.3 (1,5-CH), 26.6 (CH2),
25.4 (CH2), 22.5 (CH2), 21.3 (C6H4CH3), 14.0 (CH2CH3).
Anal. Calcd for C26H46N2O3S: C, 66.91; H, 9.93; N, 6.00. Found: C,
66.87; H, 9.97; N, 5.92.
3,7-Dioctyl-7-aza-3-azoniabicyclo[3.3.1]nonane 4-Methylben-
zenesulfonate (10·p-TsOH)
Anal. Calcd for C22H38N2O3S: C, 64.35; H, 9.33; N, 6.82.
Mp 109–110 °C.
Anal. Calcd for C22H38N2O3S + 0.49 H2O: C, 63.00; H, 9.37; N,
6.68. Found: C, 63.00; H, 9.39; N, 6.59.
1H NMR (500 MHz, CDCl3): d = 7.80 (AA¢ part of AA¢BB¢, 2 H,
2¢,6¢-CH), 7.13 (BB¢ part of AA¢BB¢, 2 H, 3¢,5¢-CH), 3.49 (dm, J =
11.5 Hz, 4 H, 2,4,6,8-CH2-eq), 3.04 (br s, 1 H), 2.95 (dm, J = 11.5
Hz, 4 H, 2,4,6,8-CH2-ax), 2.82 (m, 4 H, NCH2CH2), 2.33 (s, 3 H,
C6H4CH3), 2.22 (m, 2 H, 1,5-CH), 1.89 (m, 2 H, 9-CH2), 1.58 (m, 4
H, CH2), 1.32–1.20 (m, 20 H), 0.88 (m, 6 H, CH2CH3). The NH pro-
ton appears as part of a broad signal at d = 3.04 ppm together with
H2O.
13C NMR (125.7 MHz, CDCl3): d = 144.1 (C-1¢), 138.8 (C-4¢),
128.4 (3¢,5¢-CH), 126.0 (2¢,6¢-CH), 57.9 (2,4,6,8-CH2), 57.4
(NCH2CH2), 31.8, 30.3 (9-CH2), 29.4, 29.2, 28.3, 27.0, 25.5, 22.6,
21.2 (C6H4CH3), 14.1 (CH2CH3).
3,7-Diisobutyl-7-aza-3-azoniabicyclo[3.3.1]nonane 4-Methyl-
benzenesulfonate (7·p-TsOH)
Mp 119–121 °C.
1H NMR (500 MHz, CDCl3): d = 7.81 (AA¢ part of AA¢BB¢, 2 H,
2¢,6¢-CH), 7.13 (BB¢ part of AA¢BB¢, 2 H, 3¢,5¢-CH), 3.32 (dm, J =
11.5 Hz, 4 H, 2,4,6,8-CH2), 3.22 (dm, J = 11.5 Hz, 4 H, 2,4,6,8-
CH2), 2.66 (d, J = 7.6 Hz, 4 H, NCH2CHMe2), 2.33 (s, 3 H,
C6H4CH3), 2.29 (m, 2 H, 1,5-CH), 2.02 (m, 2 H, CH2CHMe2), 2.01
(m, 2 H, 9-CH2), 0.95 (d, J = 6.6 Hz, 12 H, CHCH3). NH proton was
not detected.
13C NMR (125.7 MHz, CDCl3): d = 144.1 (C-1¢), 138.8 (C-4¢),
128.5 (3¢,5¢-CH), 126.0 (2¢,6¢-CH), 65.2 (NCH2CHMe2), 58.6
(2,4,6,8-CH2), 29.7 (9-CH2), 28.3 (1,5-CH), 24.2 (CHMe2), 21.3
(C6H4CH3), 20.5 (CHMe2).
Anal. Calcd for C30H54N2O3S: C, 68.92; H, 10.41; N, 5.36. Found:
C, 68.67; H, 10.51; N, 5.19.
3,7-Bis(2-methoxyethyl)-7-aza-3-azoniabicyclo[3.3.1]nonane 4-
Methylbenzenesulfonate (11·p-TsOH)
Mp 87–90 °C.
Anal. Calcd for C22H38N2O3S: C, 64.35; H, 9.33; N, 6.82.
1H NMR (500 MHz, CDCl3): d = 7.79 (AA¢ part of AA¢BB¢, 2 H,
2¢,6¢-CH), 7.14 (BB¢ part of AA¢BB¢, 2 H, 3¢,5¢-CH), 3.64 (m, 4 H,
OCH2), 3.44 (dm, J = 11.4 Hz, 4 H, 2,4,6,8-CH2-eq), 3.37 (s, 6 H,
OCH3), 3.15 (dm, J = 11.4 Hz, 4 H, 2,4,6,8-CH2-ax), 3.07 (m, 4 H,
CH2CH2N), 2.33 (s, 3 H, C6H4CH3), 2.21 (m, 2 H, 1,5-CH), 1.92 (m,
2 H, 9-CH2). NH proton was not detected.
13C NMR (125.7 MHz, CDCl3): d = 144.1 (C-1¢), 139.0 (C-4¢),
128.5 (3¢,5¢-CH), 126.0 (2¢,6¢-CH), 68.1 (OCH2), 58.9 (OCH3), 58.3
(2,4,6,8-CH2), 56.2 (CH2CH2N), 29.7 (9-CH2), 28.3 (1,5-CH), 21.3
(C6H4CH3).
Anal. Calcd for C22H38N2O3S + 0.21 H2O: C, 63.76; H, 9.34; N,
6.76. Found: C, 63.76; H, 9.27; N, 6.64.
3,7-Dipentyl-7-aza-3-azoniabicyclo[3.3.1]nonane 4-Methylben-
zenesulfonate (8·p-TsOH)
Mp 86–87 °C.
1H NMR (500 MHz, CDCl3): d = 7.80 (AA¢ part of AA¢BB¢, 2 H,
2¢,6¢-CH), 7.13 (BB¢ part of AA¢BB¢, 2 H, 3¢,5¢-CH), 3.79 (br s, 1
H), 3.49 (dm, J = 11.5 Hz, 4 H, 2,4,6,8-CH2-eq), 2.93 (dm, J = 11.5
Hz, 4 H, 2,4,6,8-CH2-ax), 2.81 (m, 4 H, NCH2CH2), 2.33 (s, 3 H,
C6H4CH3), 2.21 (m, 2 H, 1,5-CH), 1.88 (m, 2 H, 9-CH2), 1.58 (m, 4
H, CH2), 1.30 (m, 4 H, CH2), 1.24 (m, 4 H, CH2), 0.88 (m, 6 H,
CH2CH3). The NH proton appears as part of a broad signal at d =
3.79 ppm together with H2O.
3,7-Dibenzyl-7-aza-3-azoniabicyclo[3.3.1]nonane 4-Methylben-
zenesulfonate (12·p-TsOH)
Product obtained as an oil.
1H NMR (500 MHz, CDCl3): d = 7.86 (AA¢ part of AA¢BB¢, 2 H,
tosylate 2¢,6¢-CH), 7.46 (m, 4 H, benzyl CH), 7.29 (m, 6 H, benzyl
CH), 7.12 (BB¢ part of AA¢BB¢, 2 H, tosylate 3¢,5¢-CH), 3.99 (s, 4
H, PhCH2), 3.50 (dm, J = 11.4 Hz, 4 H, 2,4,6,8-CH2-eq), 2.70 (dm,
J = 11.4 Hz, 4 H, 2,4,6,8-CH2-ax), 2.32 (s, 3 H, C6H4CH3), 2.10 (m,
2 H, 1,5-CH), 1.77 (m, 2 H, 9-CH2). NH proton was not detected.
13C NMR (125.7 MHz, CDCl3): d = 144.1 (C-1¢), 138.8 (C-4¢),
128.4 (3¢,5¢-CH), 126.0 (2¢,6¢-CH), 57.9 (2,4,6,8-CH2), 57.5
(NCH2CH2), 30.4 (9-CH2), 29.0 (CH2), 28.3 (1,5-CH), 25.1 (CH2),
22.4 (CH2), 21.3 (C6H4CH3), 13.9 (CH2CH3).
Anal. Calcd for C24H42N2O3S: C, 65.71; H, 9.65; N, 6.39.
13C NMR (125.7 MHz, CDCl3): d = 144.1 (tosylate C-1¢), 139.0 (to-
sylate C-4¢), 133.3 (benzyl C-1¢), 130.5 (benzyl 2¢,6¢-CH), 128.7
(benzyl 3¢,5¢-CH), 128.54 (tosylate 3¢,5¢-CH), 128.50 (benzyl 4¢-
CH), 126.1 (tosylate 2¢,6¢-CH), 61.6 (PhCH2), 57.3 (2,4,6,8-CH2),
30.8 (9-CH2), 28.3 (1,5-CH), 21.3 (C6H4CH3).
Anal. Calcd for C24H42N2O3S + 0.32 H2O: C, 64.86; H, 9.67; N,
6.30. Found: C, 64.87; H, 9.77; N, 6.14.
3,7-Dihexyl-7-aza-3-azoniabicyclo[3.3.1]nonane 4-Methylben-
zenesulfonate (9·p-TsOH)
Mp 108–109 °C.
1H NMR (500 MHz, CDCl3): d = 7.80 (AA¢ part of AA¢BB¢, 2 H,
2¢,6¢-CH), 7.13 (BB¢ part of AA¢BB¢, 2 H, 3¢,5¢-CH), 4.49 (br s, 1
H), 3.49 (dm, J = 11.5 Hz, 4 H, 2,4,6,8-CH2-eq), 2.94 (dm, J = 11.5
Hz, 4 H, 2,4,6,8-CH2-ax), 2.81 (m, 4 H, NCH2CH2), 2.33 (s, 3 H,
C6H4CH3), 2.21 (m, 2 H, 1,5-CH), 1.89 (m, 2 H, 9-CH2), 1.57 (m, 4
Acknowledgment
The Swedish Research Council is acknowledged for financial sup-
port.
Synthesis 2006, No. 12, 2064–2068 © Thieme Stuttgart · New York

2068
L. Toom et al.
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Synthesis 2006, No. 12, 2064–2068 © Thieme Stuttgart · New York