Formation of 3-azabicyclo[3.3.1]non-3-enes: Imino amides vs. imino alkenes

Article abstract of DOI:10.1007/s00706-014-1185-x

An effective method for synthesising alkaloid-like compounds containing the 3-azabicyclo[3.3.1]non-3-ene core structure was successfully carried out in a stereoselective manner via the bridged-Ritter reactions. Important optically active 6-alkyl(aryl)amido-4-alkyl(aryl)-2,2,6-trimethyl-3-azabicyclo[3.3.1]non- 3-enes (imino amides) and 4-alkyl(aryl)-2,2,6-trimethyl-3-azabicyclo[3.3.1]nona- 3,6-dienes (imino alkenes) were obtained in one step from (-)-β-pinene and the respective nitriles in the presence of concentrated H₂SO ₄. The relative compositions of these products were controlled by varying the reaction conditions. Kinetic studies were conducted to enable a mechanistic understanding of the reaction pathways. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-014-1185-x

Monatsh Chem (2014) 145:983–992
DOI 10.1007/s00706-014-1185-x
ORIGINAL PAPER
Formation of 3-azabicyclo[3.3.1]non-3-enes: imino amides
vs. imino alkenes
•
Alison T. Ung Steven G. Williams Alexander Angeloski
•
•
•
Jason Ashmore Unnikrishnan Kuzhiumparambil
•
•
Mohan Bhadbhade Roger Bishop
Received: 24 November 2013 / Accepted: 13 February 2014 / Published online: 13 March 2014
Ó Springer-Verlag Wien 2014
Abstract An effective method for synthesising alkaloid-
like compounds containing the 3-azabicyclo[3.3.1]non-3-
ene core structure was successfully carried out in a stereo-
selective manner via the bridged-Ritter reactions.
Important optically active 6-alkyl(aryl)amido-4-alky-
l(aryl)-2,2,6-trimethyl-3-azabicyclo[3.3.1]non-3-enes
(imino amides) and 4-alkyl(aryl)-2,2,6-trimethyl-3-azabi-
cyclo[3.3.1]nona-3,6-dienes (imino alkenes) were obtained
in one step from (-)-b-pinene and the respective nitriles in
the presence of concentrated H2SO4. The relative compo-
sitions of these products were controlled by varying the
reaction conditions. Kinetic studies were conducted to
enable a mechanistic understanding of the reaction
pathways.
Introduction
A typical Ritter reaction comprises the reaction of a car-
benium ion (usually generated in situ) with a nitrile, and
then quenching with water affords an amide product, as
shown in Scheme 1. In its widest terms, however, the Ritter
reaction is considerably more than this. It encompasses all
reactions of a carbenium ion with a nitrile group, followed
by subsequent event(s). When viewed in this light, it is
seen to be one of the more versatile reactions in organic
synthesis [1–9].
One fascinating variant is the bridged-Ritter reaction,
examples of which are illustrated in Scheme 2. In such
instances, the nitrile reagent essentially clips across a
cyclic precursor in a transannular process to yield a cyclic
imine (Schiff base) product [10, 11].
Keywords Bridged-Ritter reactions ꢀ
Stereoselective reactions ꢀ Alkaloid-like compounds ꢀ
Terpenes ꢀ Kinetic studies
Our earlier work on bridged-Ritter reactions [11–17]
clearly established that multi-cyclic imines, such as 2 and 4
chemical scaffolds, can be obtained in a single step from
inexpensive starting materials (Scheme 2). For instance,
some of these (like 4) are 3-azabicyclo[3.3.1]non-3-enes,
nitrogen-containing molecules that are highly reminiscent
of the natural alkaloid derivatives. For this reason, we refer
to these compounds as alkaloid-like compounds. The
uniqueness of these cyclic compounds lies in their struc-
tural similarity to that of the bioactive but rare Aristotelia
alkaloids (five species are known so far) [18–20]. The
3-azabicyclo[3.3.1]nonane structure can be found in the
core structure of known bioactive alkaloids such as (?)-
aristolone, (?)-aristoteline, (-)-serratoline, and (?)-ari-
stelone (Fig. 1).
A. T. Ung (&) ꢀ S. G. Williams ꢀ A. Angeloski ꢀ J. Ashmore ꢀ
U. Kuzhiumparambil
School of Chemistry and Forensic Science, University of
Technology, P.O. Box 123, Broadway, Sydney,
NSW 2007, Australia
e-mail: Alison.Ung@uts.edu.au
M. Bhadbhade
Mark Wainwright Analytical Centre, University of New South
Wales, Sydney 2052, Australia
Elegant examples of asymmetric bridged-Ritter reac-
tions were demonstrated by Marschoff [21–23], where (?)-
limonene underwent a bridged-Ritter reaction with CH3CN
in the presence of HClO4 to produce an optically active
R. Bishop
School of Chemistry, University of New South Wales,
Sydney 2052, Australia
123

984
A. T. Ung et al.
Scheme 1
Scheme 3
dependent reactive intermediates and products, monitored
by GC/MS analyses.
Scheme 2
Results and discussion
Synthesis of chiral cyclic-imines from (-)-b-pinene
and CH3CN
The use of (-)-b-pinene as the starting material was
investigated in our bridged-Ritter reactions. When (-)-b-
pinene was treated with acetonitrile, in the presence of
concentrated H2SO4 [12], optically active imino amide
(?)-5 and imino alkene (?)-6 were obtained in the ratio of
2.78:1 (Scheme 3). Compound (?)-5 was obtained in 64 %
yield under concentrated H2SO4 conditions. This is an
improvement of the isolated yield in comparison to the
reaction of (-)-b-pinene with CH3CN, using HClO4 as the
protic acid, where the yields were reported to be only
between 12 and 36 % [27]. The assignment of configura-
tion of (?)-5 was deducted on the grounds of chemical path
stereospecificity [25] to be (1S,5S,6S) with the expected
(1R,5R,6R)-6-acetamido-2,2,4,6-tetramethy-3-azabicyclo
[3.3.1]non-3-ene. The absolute stereochemistry of this
compound was confirmed by X-ray analysis [24] with the
25
reported specific optical rotation ½aꢁD = -144.1° (c = 1.3,
CHCl3) [25, 26]. Similar asymmetric bridged-Ritter pro-
cesses also occurred using a variety of other terpenoid
substrates [26].
25
specific rotation of ½aꢁD = ?144.1°, based on the specific
As part of our alkaloid-like drug discovery program, we
aim to develop feasible synthetic pathways that allow quick
access to alkaloid-like chemical scaffolds that can be used
to produce a library of alkaloid-like compounds for drug
discovery.
rotation of the corresponding opposite enantiomer [26].
The optical purity of (?)-5 was directly determined from
25
its observed rotation (½aꢁD = ?108°) to be 75 % e.e.
Imino alkene (?)-6 was also obtained under this study in
which concentrated H2SO4 was used as an alternative to
toxic mercury nitrate as previously reported by Delpech
et al. [27, 28] for the synthesis of ( )-6 from (-)-a-pinene.
In this article, we describe the detailed stereospecific
synthesis of chiral 3-azabicyclo[3.3.1]non-3-enes via the
bridged-Ritter reaction conditions, starting from (-)-b-
pinene with acetonitrile, chloroacetonitrile, and benzoni-
trile. We further explore the selectivity outcome of the
products under different reaction conditions and investigate
the reaction mechanisms based on the study of time-
1
The H NMR spectrum reveals the alkene proton (H-7)
at 5.35 ppm as a complex tdd. The C-6 methyl group
appears at 1.80 ppm as a ddd. The 13C NMR spectrum
showed two quaternary signals at 167.0 and 134.5, which
Fig. 1 Structures of bioactive
Aristotelia alkaloids
123

Formation of 3-azabicyclo[3.3.1]non-3-enes
985
Scheme 4
Table 1 Summary of product composition of polar bridging Ritter
reactions
Reaction conditions
Composition/%
Fig. 2 ORTEP diagram of the structure of compound 7, showing the
relative stereochemistry of the compound
(?)-5
(?)-6
7
a
65
51
22
11
10
4
molecules, and they are in the centrosymmetric space
group C2/c. This indicates compound 7 is indeed a racemic
mixture. The relative stereochemistry of 7 is shown in
Fig. 2.
b
are due to the imine carbon (C-4) and the alkene carbon (C-
Under Ritter reaction conditions, Carman et al. [31]
reported the formation of ( )-exo-N-isobornylacetamide 7
from the reaction of (?)-camphene with CH3CN in the
presence of H2SO4/acetic acid. The racemic formation was
further confirmed by Hanzawa et al. [35] on the reaction of
chiral (-)-isobornyl acetate with benzonitrile to give the
racemic ( )-exo-N-isobornylbenzamide. The racemisation
was explained by the isobornyl carbocation intermediate
that underwent the 6,2-hydride shift to form two equal
carbocations.
6), respectively. The optical rotation of compound (?)-6
25
was found to be ½aꢁD = ?9.1° (c = 0.95, CHCl3).
Polar solvents, such as acetic acid, were reported to
increase the yields in Ritter reactions as they could increase
the nucleophilicity of the nitrile and the stability of the
carbenium ion [29, 30]. The polar reaction conditions
reported by Bishop et al. [11] were adopted for the reaction
of (-)-b-pinene and acetonitrile in two attempted methods
(a and b). The conditions and outcome for each reaction
are summarised in Scheme 4 and Table 1.
In our case, the formation of compound 7 was unex-
pected, and its optical rotation contradicts the X-ray
analysis. The mechanism in Scheme 5 has been proposed
to explain the formation of ( )-7. The carbenium ion
A underwent intermolecular cyclisation to give isobornyl
carbocation B, which underwent the 6,2-hydride shift to
form the minor carbocation intermediate C, in a lower
proportion than that of B. Both intermediates underwent
The results of these reaction conditions in method a and
b revealed the formation of (?)-5 and (?)-6 in the ratios of
2.95:1 and 5:1. This clearly indicates that the use of acetic
acid only provided a modest increase of (?)-5 over (?)-6
in method a. In the case of method b, although the for-
mation of (?)-5 has somewhat improved over that of (?)-
6. However, the downside was the reduction of the overall
yields of the products. In attempts to optimise the forma-
tion of (?)-5, we also observed the formation of an
unexpected isobornylacetamide 7 in both method a and b,
in 10 and 4 % yields, respectively (Table 1).
Scheme 5
The HRMS of 7 reveals the exact mass of 196.16593,
which corresponds to C12H22NO ([M ? H]?). NMR
spectral data of 7 are in agreement to those previously
reported in the literature [31]. The optical rotation of
25
compound 7 was found to be ½aꢁD = ?20.3° (c = 0.47,
CHCl3). Forster [32, 33] reported the specific optical
rotation of (-)-exo-N-isobornylacetamide [(-)-7] to be
25
½aꢁD = -19.5°. This stereochemical outcome was con-
firmed by the work by Zhou et al. [34]. On the basis of the
optical rotation of compound 7, one would infer that this
compound is the (?)-exo-N-isobornylacetamide. The X-ray
analysis has revealed that the structure contained two
123

986
A. T. Ung et al.
found in (?)-6. 13C NMR analysis confirms all the carbons
required. The specific rotation of compound (?)-10 was
Scheme 6
25
found to be ½aꢁD = ?49.1° (c = 0.57, CHCl3).
It is suggested that (?)-10 was the rearranged product of
9 (Scheme 6). The presence of both compounds was ini-
tially observed in the 1H NMR spectrum of the crude
mixture. The same sample was further monitored by
1
obtaining its H NMR spectra over a period of time. The
1
last H NMR spectrum was only shown to contain (?)-10.
This finding suggests that compound 9 formed in the initial
step of the bridged-Ritter reaction. It then underwent
double-bond migration over time to form the less con-
strained (?)-10 [36].
The identity of isobornyl chloroacetamide 11 was con-
firmed by spectral analysis. The 1H NMR spectrum
revealed the presence of the new CH2 group as a doublet at
4.04 ppm that was correlated to the 13C peak at 42.9 ppm
by HSQC. It also shows H-2 at 3.89 ppm as a complex td.
The two methyl groups at C-70 appear as two singlets at
0.84 and 0.95 ppm, respectively. The third methyl at C-10
was also observed at 0.84 ppm. The low specific optical
nucleophilic addition with CH3CN and then quenching
with water afforded racemic mixture of 7.
The bridging Ritter reaction between (-)-b-pinene
and chloroacetonitrile
When (-)-b-pinene was treated with chloroacetonitrile,
under concentrated H2SO4 conditions, optically active
imino amide (?)-8, imino alkene (?)-10, and the isobor-
nylamide 11 were obtained (Scheme 6). The three
compounds were isolated by silica column chromatography
to give (?)-8, (?)-10, and 11 in the yields 31, 23, and
19 %, respectively.
25
rotation of 11 (½aꢁD = ?1.4°) suggests that racemisation
may also occur in the formation of compound 11, in a
similar manner to that of compound 7 (Scheme 5).
In contrast to its counterpart compound 7, compound 11
was formed without the use of acetic acid. Despite this, the
behaviour of the carbenium ion in chloroacetonitrile
allowed for a much larger mole ratio of 11 to form in
contrast to 7.
The specific rotation of compound (?)-8 was found to
25
be ½aꢁD = ?90.8° (c = 1.06, CHCl3). The 1H NMR
spectrum revealed the presence of the two new CH2
groups; the group at C-40 appears as two separate doublets
at 4.18 and 4.03 ppm, while the chloroacetamide group
(COCH2Cl) as a broad singlet at 4.02 ppm. The carbons of
these were also observed in the 13C spectrum at both 49.8
and 43.1 ppm, respectively. Other characteristic features of
8 were also observed, such as the three CH3 groups at 31.2,
26.5, and 25.9 ppm.
Bridged Ritter reaction of (-)-b-pinene and PhCN
The reaction of (-)-b-pinene with PhCN under our reac-
tion conditions provided the imino amide (?)-12 and imino
alkene (?)-13. The outcome of the reaction revealed that
(?)-12 and (?)-13 were the major and minor products, in
42 and 24 % yields, respectively (Scheme 7).
The ratio of (?)-12 and (?)-13 was reversed by varying
the reaction conditions. The cyclic imino alkene (?)-13
was obtained as the major product (74 %) over the cyclic
imino amide (?)-12 (14 %) when the reaction mixture was
left to stand at room temperature overnight without stirring,
allowing the PhCN to diffuse slowly into the aqueous layer
where the reaction took place. Beside (?)-12 and (?)-13,
Structure of compound (?)-10 was fully characterised
1
by spectral analysis. The H NMR spectrum showed the
two terminal alkene protons (CH2-60) to appear as two
distinct singlets at 4.86 and 4.78 ppm. These two reso-
nances were confirmed to correlate to the same C-60 by
HSQC. It is noteworthy that the H-5 appears at 3.36 ppm,
further downfield than the corresponding proton (2.5 ppm)
Scheme 7
123

Formation of 3-azabicyclo[3.3.1]non-3-enes
987
there was also a small trace of compound 14 with molec-
ular mass of m/z = 257 as detected by GC/MS of the crude
product. Due to its small quantity, it was not possible to
isolate compound 14 for a full analysis, after a few
attempts had been made.
Scheme 8
Kinetic studies
Kinetic studies were undertaken to understand the reaction
mechanisms for the formation of (?)-12, (?)-13 by
investigating the rate at which intermediates and products
formed over time. The reaction was monitored by direct
removal of reaction aliquots at a time interval; these were
then quenched with water and followed by GC–MS ana-
lysis. Figure 3 shows the composition of products (?)-12
and (?)-13, and the intermediate 14 (molecular weight of
257), in each of the GC/MS samples at specific times.
Atthe30-minmark, the studiesshow theamountof(?)-12
was 17 % and almost equal to that of 14 (16 %), while the
concentration of (?)-13 was at the lowest (4 %). The com-
position of (?)-12 and (?)-13 increases almost in a linear
fashion at a similar rate, while that of compound 14 propor-
tionally decreased. The presence of intermediate alcohol 14
in the reaction mixture has provided a plausible reaction
pathway, which suggests that the reaction proceeded through
the intermediate E as shown in Scheme 7. Intermediate
E came about via the nucleophilic addition of A to give the
intermediate D. D further underwent intramolecular cycli-
sation to form the carbenium ion E from which the three
compounds (?)-12, (?)-13, and 14 were derived. This was
evidenced by (1) the composition of (?)-12, (?)-13, and 14
over the reaction time at 0 °C at the 30-min mark (4:1:4) and
(2) the eventual increase in concentration of (?)-12 and (?)-
13, corresponding to the decrease of 14. The formation of 14
dominated at low temperature. In contrast, at room temper-
ature, the major products were eventually (?)-12 and (?)-13.
The data suggest that the transformationof E into14 becomes
reversible at moderate temperature, and the rate-determining
step (k1) is the reaction of E with another mole of PhCN to
form F and eventually (?)-12 (Scheme 8).
Conclusions
This study has led to a better understanding of the chemistry
involved in the bridged-Ritter reaction and products that
formed. The significance of the bridged-Ritter reaction con-
ditions was determined. It was concluded that (1) a single
enantiomer of either cyclic imine amide or imine alkene can
be obtained in one step from the reaction of (-)-b-pinene and
a nitrile and (2) the yields and the ratios of these products
depend on the reaction conditions. It was observed that the
stronger acidic conditions provide the highest yields. With
more polar conditions, the yields were compromised while
allowing for the formation of unexpected the isonorbornyl
derivatives. The kinetic studies have allowed a proposed
mechanism for the reaction to being uncovered.
Experimental
Reagents and analytical grade solvents were purchased
from commercial sources. Progress of reactions was
Fig. 3 Reaction profile showing the composition of (?)-12, (?)-13,
and 14 at specific times
123

988
A. T. Ung et al.
N-((1S,5S,6S)-2,2,4,6-Tetramethyl-3-azabicyclo[3.3.1]-
monitored by TLC analysis, performed on aluminium-
backed Merck 60 GF254 silica gel or Merck 60 GF254
neutral alumina gel with UV detection at 254 nm and/or
Dragendorff’s reagent. Compounds were purified by col-
umn chromatography using Merck flash either neutral
alumina or silica gel (40–63 lm). Purity of compounds was
non-3-en-6-yl)acetamide (5, C14H24N2O)
A green wax (1.106 g, 4.67 mmol, 64 % yield); Rf = 0.73
(neutral
alumina,
10 %
ethyl
acetate/hexane);
25
ꢀ
½aꢁD = ?108.0° (c = 1, CH2Cl2); IR (film): m = 3,295,
3,073, 2,969, 2,935, 1,644, 1,544, 1,460, 1,372, 1,289,
1,210, 1,168, 1,110, 1,037, 894, 752, 665 cm-1; 1H NMR:
d = 5.32 (br s, 1H, NH), 3.17 (br d, J = 2.0 Hz, 1H, H-5),
2.09 (s, 3H, CH3-40), 1.99 (s, 3H, COCH3), 1.81 (ddd,
J = 2.0, 2.0, 11.0 Hz, 1H, Ha-9), 1.75 (dd, J = 2.0,
2.0 Hz, 1H, H-1), 1.71 (ddd, J = 2.5, 14.0 Hz, 1H, Ha-
8), 1.57 (ddd, J = 4.0, 6.0, 10 Hz, 1H, Hb-9), 1.54 (dd,
J = 4.5, 8.5 Hz, 1H, Ha-7), 1.47 (s, 3H, CH3-60), 1.44 (dd,
J = 4.5, 7.5 Hz, 1H, Hb-7), 1.40 (ddd, J = 4.5, 7.5,
10.0 Hz, 1H, Hb-8), 1.28 (s, 3H, CH3-20), 1.15 (s, 3H, CH3-
20) ppm; 13C NMR: d = 169.8 (C=O), 166.7 (C-4), 60.4
(C-6), 57.0 (C-2), 55.7 (CH-1), 40.3 (CH-5), 33.2 (CH2-7),
31.7 (CH3-40), 29.8 (CH3-60), 24.6 (COCH3), 24.6 (CH2-9),
24.1 (CH2-8), 21.1 (CH3-20), 14.2 (CH3-20) ppm; GC–MS
(EI): Rt = 17.18 min, m/z (%) = 236 (60, M?), 221 (25),
177 (70), 136 (68); HR-ESI–MS: [M ? H]? found
237.19780, C14H25N2O requires 237.19669.
1
1
determined by H NMR and GC/MS. H and 13C NMR
spectra were recorded on an Agilent 500-MHz spectrom-
eter (500 MHz 1H, 125 MHz 13C) in deuterated chloroform
(CDCl3), unless otherwise specified. NMR assignments
1
were based on COSY, HSQC, and DEPT experiments. H
and 13C NMR assignments are based on the numbering
system used on the systematic name. Gas chromatographer/
mass spectrometer (GC/MS) analysis was carried out on an
Agilent 6890 series gas chromatographer coupled to an
Agilent 5973 network MS (EI) mass spectrometer. Sepa-
ration was achieved on
a Zebron ZB-5mS (5 %
polysilphenylene, 95 % polydimethylsiloxane) capillary
column (30 m 9 0.25 mm 9 0.25 lm). Helium was used
as the carrier gas at a flow rate of 1.2 cm3 min-1. The
injection was done by three front inlet washes, three
samples pumps, and three post washes. The injection port
was in split mode, with a split flow rate of 1.7 cm3 min-1
.
(1S,5S)-2,2,4,6-Tetramethyl-3-azabicyclo[3.3.1]nona-3,6-
diene (6, C12H19N)
The mass spectrometer was operated from 50 to 290 amu,
in positive mode, and a solvent delay of 2 min was applied.
The following temperature program was used: 50 °C
maintained for 2 min, then ramped at 10 °C min-1 to
290 °C and held for 4 min. High-resolution mass spectra
were obtained on an Agilent 6510 Accurate Mass Q-TOF
Mass Spectrometer, equipped with an ESI source.
A yellow oil (0.311 g, 1.76 mmol, 23 % yield); Rf = 0.61
(silica, 50 % ethyl acetate/hexane, trace amount of Et3N);
25
½aꢁD = ?9.07° (c = 0.95, CHCl3); IR (film): mꢀ = 2,965,
2,926, 2,870, 1,665, 1,454, 1,359, 1,330, 1,296, 1,253,
1,054, 1,035, 1,018, 884, 821, 799 cm-1 1H NMR:
;
d = 5.35 (tdd, J = 1.5, 2.5, 3.0 Hz, 1H, H-7), 2.50 (br s,
1H, H-5), 2.22 (ddd, J = 1.5, 2.5, 3.0 Hz, 1H, Ha-8), 2.18
(ddd, J = 2.5, 5.0, 7.5 Hz, 1H, Hb-8), 2.04 (s, 3H, CH3-40),
1.86-1.85 (m, 2H, Ha-9, H-1), 1.80 (ddd, 1.5, 2.5, 5.0 Hz,
3H, CH3-60), 1.56 (ddd, J = 2.5, 5.0, 11.5 Hz, 1H, Hb-9),
1.20 (s, 3H, CH3-20), 1.15 (s, 3H, CH3-20) ppm; 13C NMR:
d = 167.0 (C-4), 134.5 (C-6), 122.2 (CH-7), 58.5 (C-2),
40.4 (CH-5), 33.4 (CH-1), 31.8 (CH3-40), 28.9 (CH2-8),
28.2 (CH3-6), 28.0 (CH3-20), 25.5 (CH2-9), 23.9 (CH3-20)
ppm; GC–MS (EI): Rt = 10.95 min, m/z (%) = 177 (15,
M?), 136 (35); HR-ESI–MS: [M ? H]? found 178.15790,
C12H20N requires 178.15903.
Bridged Ritter reaction of (-)-b-pinene with CH3CN
Sulfuric acid (18 M, 4.2 cm3, 78.7 mmol) was stirred at 0 °C
in a flask fitted with a reflux condenser and a drying tube. To
the reaction flask was added 21 cm3 acetonitrile (0.4 mol). A
solution of 1.0 g (-)-b-pinene (1.15 cm3, 7.34 mmol) in
5 cm3 benzene was added drop-wise, via the condenser, into
the reaction mixture. A further 0.5 cm3 of benzene was used
to wash all traces of (-)-b-pinene into the reaction flask. The
mixture was stirred at 0 °C for 30 min and then at room
temperature for 24 h. Water (30 cm3) was added into the
reactionmixtureandstirredfor30 min. Theresultingmixture
was washed with light petroleum ether, and then the aqueous
layer was basified with 2 M solution of sodium hydroxide to
pH [ 10. The aqueous layer was extracted with chloroform
(40 cm3 9 3). The combined extracts were washed with
50 cm3 water, dried over anhydrous Na2CO3, and filtered.
The solvent was removed under reduced pressure to yield
green viscous oil as the crude product. The crude product was
purified by silica column chromatography using gradient
elution from hexane to ethyl acetate/hexane (1:1) to provide
(?)-5, (?)-6 in 64 and 23 % yields, respectively.
Bridged-Ritter reaction of (-)-b-pinene with CH3CN
in acetic acid
Method a: Sulfuric acid (18 M, 4.5 cm3) was diluted with
0.5 cm3 water and stirred in a flask fitted with a reflux
condenser and a drying tube at room temperature. To the
reaction flask, 21 cm3 acetonitrile (0.40 mol) was added. A
solution of 1.0 g (-)-b-pinene (1.15 cm3, 7.34 mmol) in
5 cm3 glacial acetic acid was added drop-wise, via the
condenser, into the reaction mixture. A further 0.5 cm3 of
123

Formation of 3-azabicyclo[3.3.1]non-3-enes
989
acetic acid was used to wash all traces of (-)-b-pinene into
the reaction flask. The reaction was then heated to *50 °C
for 24 h. The reaction mixture was worked up by the
addition of 20 cm3 water and then basified with 4 M NaOH
until pH was[10. The reaction mixture was worked up to
give the crude product (1.857 g) and purified as previously
described to give 1.121 g 5 (65 %), 0.295 g 6 (22 %), and
0.146 g 7 (10 %). Compound 7 was further purified by
recrystallization from hexane to give pale yellow crystals.
Method b: (-)-b-pinene (1.46 g, 10.7 mmol) was added
to a stirred mixture of 1.5 cm3 98 % sulfuric acid, 10 cm3
acetonitrile, and 15 cm3 glacial acetic acid at 0 °C. The
reaction was stirred for 30 min at 0 °C and then overnight
at room temperature. The reaction was then worked up to
give the crude product (2.174 g), purified as previously
described to give 1.292 g 5 (51 %), 0.22 g 6 (11 %), and
0.086 g 7 (4 %).
30 cm3 water. The mixture was then basified with 2 M
NaOH (until pH [ 10). The aqueous layer was washed
with petroleum spirits (2 9 50 cm3) to remove any
remaining pinene before extraction with CHCl3
(2 9 15 cm3) and drying with Na2SO4.
Within the petroleum spirits fraction, crystals that
formed were filtered to give pure (?)-8 (0.704 g). Petro-
leum spirits was removed from the filtrate to give a crude
mixture (0.390 g) that was analysed by GC/MS to be
mainly (?)-10 and 11 with small quantities of (?)-8
remaining. The chloroform extraction was also analysed by
GC/MS after the solvent had been removed via reduced
pressure to show it contained mainly 8, with small quan-
tities of (?)-10 and 11. The two crudes were therefore
combined and purified via separation on an alumina col-
umn using a mobile phase of 15 % EtOAc and 85 %
petroleum spirits. Elution from the column was monitored
by TLC, using the same mobile phase, developed in I2(g)
atmosphere. This resulted in isolation of a further 8
(0.306 g), as well as 0.511 g 10 and 0.468 g 11.
N-((1S,2S,4S)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl)-
acetamide (7, C12H21NO)
A pale yellow solid (58.2 mg, 0.298 mmol, 4 %); m.p.:
2-Chloro-N-[(1S,5S,6S)-4-(chloromethyl)-2,2,6-trimethyl-
3-azabicyclo[3.3.1]non-3-en-6-yl]acetamide
(8, C14H22Cl2N2O)
125 °C; Rf = 0.68 (silica, 50 % ethyl acetate/hexane);
25
ꢀ
½aꢁD = ?20.3° (c = 0.47, CHCl3); IR (film): m = 3,314,
2,955, 2,875, 1,651, 1,547, 1,461, 1,372, 1,330,
1,291 cm-1 1H NMR: d = 5.35 (br s, 1H, NH), 3.90
;
A pale orange solid (1.011 g, 3.32 mmol, 31 %); m.p.:
152 °C; Rf = 0.18 (1.5:8.5 EtOAc/petroleum spirits);
(ddd, J = 4.5, 4.5, 9.0 Hz, 1H, H-2), 1.96 (s, 3H,
NCOCH3), 1.86 (dd, J = 9.0, 13.0 Hz, 1H, H-3), 1.73
(dd, J = 4.0, 8.0 Hz, 1H, H-4), 1.70 (dddd, J = 4.0, 8.0,
12.0, 13.5 Hz, 1H, H-5), 1.56 (ddd, J = 4.5, 12.0, 13.0 Hz,
1H, H-3), 1.53 (ddd, J = 4.0, 8.5, 8.5 Hz, 1H, H-6), 1.23
(ddd, J = 4.0, 9.0, 13.5 Hz, H-6), 1.15 (ddd, J = 4.0, 9.5,
13.5 Hz, H-5), 0.90 (s, 3H, CH3-10), 0.83 (s, 3H, CH3-70),
0.82 (s, 3H, CH3-70) ppm; 13C NMR: d = 169.2 (C=O),
56.8 (CH-2), 48.4 (C-7), 47.10 (C-1), 44.9 (CH-4), 39.2
(CH2-3), 36.0 (CH2-6), 27.0 (CH2-5), 23.6 (COCH3), 20.3
(CH3-10), 20.3 (CH3-70), 11.7 (CH3-70) ppm; GC–MS (EI):
Rt = 14.19 min, m/z (%) = 195 (30, M?), 180 (10), 136
(40); HR-ESI–MS: [M ? H]? found 196.16593,
C12H22NO requires 196.16567.
25
ꢀ
½aꢁD = ?90.8° (c = 1.06, CHCl3); IR (neat): m = 3,280,
3,098, 2,974, 2,953, 2,898, 2,872, 1,683, 1,653, 1,573,
1,459, 1,432, 1,343, 1,262, 1,107, 972, 890, 806, 725, 706,
1
692, 660 cm-1; H NMR: d = 6.55 (s, 1H, NH), 4.18 (d,
J = 11.0 Hz, H1, H-4a’) 4.03 (d, J = 11.0 Hz, H1, H-4b’),
4.02 (br s, 2H, COCH2Cl), 3.41 (br s, 1H, H-5), 1.87
(br m, 1H, H-9a), 1.84-1.81 (m, 1H, H-8a), 1.76-1.70 (m,
3H, H-8b, H-9b, H-1), 1.60 (tt, J = 4.0, 14.0 Hz, H, H-7a),
1.46 (s, 3H, CH3-60), 1.35 (td, J = 5.0, 14.0 Hz, H-7b),
1.32 (s, 3H, CH3-20), 1.19 (s, 3H, CH3-20) ppm; 13C NMR:
d = 165.0 (C=O), 164.4 (C = N, C-4), 59.2 (C-6), 56.1 (C,
C-2), 49.8 (CH2, C-40), 43.1 (CH2, COCH2Cl), 36.9 (CH,
C-5), 34.0 (CH, C-1), 32.3 (CH2, C-7), 31.2 (CH3, C-20),
26.5 (CH3, C-60), 25.9 (CH3, C-20), 24.6 (CH2, C-9), 24.4
(CH2, C-8) ppm; GC–MS (EI): Rt = 20.43 min, m/z
(%) = 304, 289 (11), 269 (100), 211 (13), 176 (23); HR-
ESI–MS: [M ? H]? found 305.11109, C14H23Cl2N2O
requires 305.11092.
Bridging Ritter reaction between (-)-b-pinene
and chloroacetonitrile
Sulfuric acid (18 M, 4.2 cm3, 78.7 mmol) was stirred in a
flask fitted with a reflux condenser and a drying tube at
0 °C. To the reaction flask, 25 cm3 chloroacetonitrile
(0.40 mol) was added. A solution of 1.0 g (-)-b-pinene
(1.15 cm3, 7.34 mmol) in 5 cm3 benzene was added drop-
wise into the reaction mixture, via the condenser. A further
0.50 cm3 of benzene was used to wash all traces of (-)-b-
pinene into the reaction flask. After 30 min the reaction
was allowed to reach room temperature and left to run for
2.5 h. The reaction was then quenched by the addition of
(1S,5S)-4-(Chloromethyl)-2,2-dimethyl-6-methylene-3-
azabicyclo[3.3.1]non-3-ene (10, C12H18ClN)
A dark brown oily substance (0.511 g, 2.42 mmol, 23 %);
25
Rf = 0.75 (1.5:8.5 EtOAc/petroleum spirits); ½aꢁD = ?49.1°
ꢀ
(c = 0.57, CHCl3); IR (neat): m = 2,970, 2,935, 2,872,
2,209, 1,562, 1,460, 1,382, 1,262, 1,141, 909, 810 cm-1
;
1H NMR: d = 4.86 (s, 1H, H-6a0), 4.78 (s, 1H, H-6b0), 4.13
(d, J = 12.0 Hz, 1H, H-4a0), 4.04 (d, J = 12.0 Hz, 1H,
H-4b0), 3.36 (br s, 1H, H-5), 2.27–2.25 (m, 2H, CH2-8),
123

990
A. T. Ung et al.
2.01–1.88 (m, 1H, H-7a), 1.82 (s, 3H, CH3-20), 1.77 (1H, H1),
1.73–1.63 (1H, H-7b), 1.58–1.53 (2H, CH2-9), 1.25 (s, 3H,
CH3-20) ppm; 13C NMR: d = 164.5 (C-4), 122.3 (C-6), 110.5
(CH2, C-60), 60.2 (C-2), 45.0 (CH2, C-40), 41.5 (CH, C-5),
35.3 (CH, C-1), 30.9(CH3, C-20), 29.7 (CH2, C-9), 28.7 (CH2,
C-8), 25.0 (CH2, C-7), 23.5 (CH3, C-20) ppm; GC–MS (EI):
Rt = 13.02 min, m/z (%) = 211, 196 (6), 176 (100), 93 (44);
HR-ESI–MS: [M ? H]? found 212.11262, C12H19ClN
requires 212.11278.
The reaction was repeated, and after at 0 °C for 30 min,
the reaction was further stirred at RT for 24 h. After the
usual workup and purification, the reaction gave 1.03 g
(?)-12 (42 %) and 0.39 g (?)-13 (24 %).
N-((1S,5S,6S)-2,2,6-Trimethyl-4-phenyl-3-azabicyclo-
[3.3.1]non-3-en-6-yl)benzamide (12, C24H28N2O)
25
A yellow solid (1.03 g, 42 %); m.p.: 59 °C; ½aꢁD
=
?147.6° (c = 1, CH2Cl2); Rf = 0.54 (neutral alumina,
ꢀ
10 % EtOAc/light petroleum); IR (film): m = 3,300, 2,969,
1
2,933, 1,641,1,570, 1,525 cm-1; H NMR: d = 7.86 (dd,
2-Chloro-N-((1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-
2-yl)acetamide (11, C12H20ClNO)
A white solid with red flecks (0.468 g, 2.04 mmol, 19 %);
J = 1.5, 7.5 Hz, 2H, 2HAr), 7.77 (dd, J = 1.5, 7.5 Hz, 2H,
2HAr), 7.48 (td, J = 1.5, 7.5, 7.5 Hz, 1H, HAr), 7.45 (td,
J = 1.5, 7.5, 7.5 Hz, 1H, 2HAr), 7.34–7.40 (m, 4H, 4HAr),
6.13 (s, 1H, HN), 4.40 (s, 1H, H-5), 2.03 (ddd, J = 2.5, 2.5,
13.0 Hz, 1H, H-9), 1.95–1.88 (m, 3H, H-9, 2H-8),
1.76–1.72 (m, 1H, H-1), 1.55–1.52 (m, 2H, 2H-7), 1.41
(s, 3H, CH3-40), 1.27 (s, 3H, CH3-20), 1.10 (s, 3H, CH3-20)
ppm; 13C NMR: d = 167.2 (CO), 165.7 (C-4), 142.2 (C),
135.7 (C), 131.4 (2CH), 129.1 (2CH), 128.7 (2CH), 128.4
(2CH), 127.1 (CH), 126.7 (CH), 58.8 (C-2), 56.6 (C-8),
34.9 (CH-5), 34.3 (CH-1), 33.8 (CH2-7), 31.6 (COCH3),
27.4 (CH3-20), 26.6 (CH3-20), 24.9 (CH2-9), 24.3 (CH2)
ppm; GC–MS (EI): Rt = 27.20 min, m/z (%) = 360 (60,
M?), 345 (25), 239 (70), 196 (85); HR-ESI–MS:
[M ? H]? found 361.22760, C24H29N2O requires
361.22744.
m.p.: 70 °C; Rf = 0.51 (1.5:8.5 EtOAc/petroleum spirits);
25
ꢀ
½aꢁD = ? 1.4° (c = 1.78, CHCl3); IR (neat): m = 3,324,
2,952, 2,877, 1,654, 1,542, 1,458, 1,393, 1,371, 1,242,
1,032, 931, 793, 680 cm-1; 1H NMR: d = 6.63 (1H, NH),
4.04 (d, J = 4.0 Hz, 2H, COCH2Cl), 3.89 (td, J = 5.5,
9.0 Hz, 1H, H-2), 1.88 (dd, J = 9.0, 13.0 Hz, 1H, H-3a),
1.78 (t, J = 5.0 Hz, 1H, H-4), 1.73 (dddd, J = 5.0, 4.0 Hz,
1H, H-5a), 1.64–1.62 (m, 1H, H-3b), 1.59 (dd, J = 5.0,
12.0 Hz, 1H, H-6a), 1.30 (ddd, J = 4.0, 4.5, 12.0 Hz, 1H,
H-6b), 1.18 (ddd, J = 2.5, 4.0, 12.0 Hz, 1H, H-5b), 0.95 (s,
3H, CH3-70), 0.84 (s, 6H, CH3-70, CH3-10) ppm; 13C NMR:
d = 164.9 (C=O), 57.0 (CH, C-2), 54.3 (C-7), 51.8 (C-1),
44.9 (CH, C-4), 42.9 (CH2Cl, C-40), 38.9 (CH2, C-3), 35.8
(CH2, C-6), 27.0 (CH2, C-5), 20.2 (CH3, C-70), 20.1 (CH3,
C-70), 11.7 (CH3, C-10) ppm; GC–MS (EI): Rt =
15.65 min, m/z (%) = 229 (2, M?), 194 (4), 136 (20),
121 (49), 95 (100); HR-ESI–MS: [M ? H]? found
230.12343, C12H21ClNO requires 230.12334.
(4S,8S)-4,4,8-Trimethyl-2-phenyl-3-azabicyclo-
[3.3.1]nona-2,7-diene (13, C17H21N)
25
A waxy solid (0.39 g, 24 %); ½aꢁD = ?33.4° (c = 1,
CH2Cl2); Rf = 0.83 (neutral alumina, 10 % EtOAc/light
ꢀ
petroleum); IR (film): m = 2,965, 2,937, 2,888, 2,834,
1,631, 1,550 cm-1 1H NMR: d = 7.76 (dd, J = 1.5,
;
Bridged Ritter reaction of (-)-b-pinene with PhCN
7.5 Hz, 2H, 2HAr), 7.61 (td, J = 1.5, 7.5, 7.5 Hz, 1H,
HAr), 7.48 (td, J = 1.5, 7.5, 7.5 Hz, 2H, 2HAr), 5.32 (dd,
1H, J = 1.5, 1.5 Hz, H-7), 3.35 (br s, 1H, H-5), 2.27–2.23
(m, 2H, 2H-8), 2.40–1.96 (m, 2H, Ha-9, H-1), 1.78 (ddd,
J = 2.0, 2.0, 12.1 Hz, 1H, H-9), 1.42 (qd, J = 1.5, 3.5 Hz,
3H, CH3-60), 1.32 (s, 3H, CH3-2), 1.29 (s, 3H, CH3-2) ppm;
13C NMR: d = 166.6 (C-4), 140.9 (C-6), 135.1 (C), 132.1
(CH), 129.1 (2CH), 128.2 (2CH), 121.3 (CH-7), 59.5 (C-2),
36.5 (CH-5), 33.8 (CH-1), 31.9 (CH3-60), 29.0 (CH2), 27.7
(CH3-20), 25.8 (CH2), 23.5 (CH3-20) ppm; GC–MS (EI):
Rt = 17.65 min, m/z (%) = 239 (35), 198 (20); HR-ESI–
MS: [M ? H]? found 240.17740, C17H22N requires
240.17522.
A mixture of 10 cm3 PhCN (97 mmol) and 2 cm3 18 M
H2SO4 (37 mmol) in round-bottom flask fitted with a
condenser and a drying tube was stirred at 0 °C. To the
reaction mixture was added drop-wise a solution of 0.94 g
(-)-b-pinene (1.1 cm3, 6.9 mmol) in 8 cm3 benzene via
the condenser. The reaction mixture was stirred at 0 °C for
30 min and then left to stand, without stirring, at room
temperature for 24 h. Water (2 cm3) was added to the
reaction flask, followed by 100 cm3 diethyl ether. The
mixture was then set to stir for 10 min. The ether layer was
removed and the aqueous layer basified with 4 M NaOH
until pH 12. The aqueous layer was then extracted with
chloroform (30 cm3 9 3). The combined extracts were
washed with 30 cm3 saturated NaCl solution, dried over
anhydrous Na2CO3, and filtered. The solvent was removed
under reduced pressure, and the crude product was purified
by a neutral aluminium oxide column chromatography
(EtOAc/light petroleum, 1:9) to give 0.337 g (?)-12
(14 %) and 1.193 g (?)-13 (73 % yield).
Kinetic study
A mixture of 10 cm3 PhCN (97 mmol) and 2 cm3 18 M
H2SO4 (37 mmol) was stirred in a round-bottom flask fitted
with a condenser and a drying tube at 0 °C. To the reaction
mixture was added drop-wise a solution of 0.94 g (-)-b-
123

Formation of 3-azabicyclo[3.3.1]non-3-enes
991
of the crude product was prepared as part of the GC/MS
analysis for the kinetic study.
Table 2 Numerical details of the solution and refinement of com-
pound 7
Crystal data
X-ray crystallographic data
Chemical formula
Mr
C12H21NO
195.30
Suitable single crystals of compound 7 were selected under the
polarizing microscope (Leica M165Z) and were picked up on a
MicroMount (MiTeGen, USA) consistingof a thin polymer tip
with a wicking aperture. The X-ray diffraction measurements
were carried out on a Bruker kappa-II CCD diffractometer at
150 K by using graphite-monochromated Mo-Ka radiation
Crystal system, space group
Temperature/K
Monoclinic, C2/c
150
˚
a, b, c/A
11.0156(11), 9.7589(11),
21.982(3)
b/°
102.826(12)
3
˚
V/A
2,304.1(5)
˚
(k = 0.710723 A). The single crystals, mounted on the goni-
Z
8
ometer using cryo loops for intensity measurements, were
coated with paraffin oil and then quickly transferred to the cold
stream using an Oxford Cryo stream attachment. Symmetry-
related absorption corrections using the program SADABS
[37] were applied, and the data were corrected for Lorentz and
polarisation effects using Bruker APEX2 software [38]. All
structures were solved by direct methods, and the full-matrix
least-square refinements were carried out using SHELXL [39].
The non-hydrogen atoms were refined anisotropically. The
molecular graphic was generated using Mercury [40]. Key
crystallographic data and refinement details are presented in
Tables 1 and 2. Crystallographic data (excluding structure
factors) for the structures in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC 960059. The data can be
obtained free of charge via http://www.ccdc.cam.ac.uk, by
e-mailing data_request@ccdc.cam.ac.uk or by contacting The
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: (?44) 1223/336-033, Tel.:
(?44) 1223/336-408.
Radiation type
l/mm-1
Crystal size/mm3
Data collection
Diffractometer
Mo Ka
0.07
0.12 9 0.09 9 0.03
Bruker kappa APEXII
CCD Diffractometer
Absorption correction
Multi-scan SADABS
(Bruker, 2001)
Tmin, Tmax
0.992, 0.998
No. of measured, independent, and
16,124, 2,035, 1,541
observed [I [ 2r(I)] reflections
Rint
-1
0.081
0.595
˚
(sin h/k)max/A
Refinement
R[F2 [ 2r(F2)], wR(F2), S
No. of reflections
No. of parameters
No. of restraints
0.061, 0.183, 1.09
2,035
131
0
H-atom treatment
H-atom parameters
constrained
-3
˚
Dimax, Dimin /e A
0.36, -0.19
Acknowledgments We are grateful to the Faculty of Science, UTS,
for providing financial support for this project. We thank Dr. Ronald
Shimmon and Dr. Linda Xiao for providing NMR and GC/MS
trainings to Steven Williams and Alexander Angeloski.
pinene (1.1 cm3, 6.9 mmol) in 8 cm3 benzene via the
condenser. The reaction mixture was stirred at 0 °C for
30 min; an aliquot (0.5 cm3) of the reaction mixture was
taken and transferred into a sample vial that contained
1 cm3 water. While stirring, the mixture in the sample vial
was basified with 4 M NaOH until pH [ 10. The aqueous
mixture was extracted with CHCl3 (by adding 1–2 cm3 of
CHCl3 while stirring). After the two layers were separated,
a small volume of the CHCl3 was removed and set aside
and kept at 0 °C for the GC/MS analysis. The process was
repeated at the 30-min mark at 0 °C. After the reaction had
been allowed to stir at room temperature, the process was
repeated at an hour interval for another five aliquots (see
the time intervals below).
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123