Azacineole (1,3,3-trimethyl-2-azabicyclo[2.2.2]octane)

Article abstract of DOI:10.1071/CH02189

The synthesis and chemistry of azacineole were investigated. The paper stresses on the synthesis of compound and then seek its presence in various eucalypt trees. In regard with this, the two-step synthesis of azacineole obtained from limonene was present

Full text of DOI:10.1071/CH02189

CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2003, 56, 319–322
Azacineole (1,3,3-Trimethyl-2-azabicyclo[2.2.2]octane)
Raymond M. CarmanA,B and Roger P. C. DerbyshireA
A
Department of Chemistry, The University of Queensland, Brisbane 4072, Australia.
Author to whom correspondence should be addressed (e-mail: carman@chemistry.uq.edu.au).
B
The title compound (5) has been synthesized and its presence sought in various eucalypt leaf oils. Aspects of the
chemistry of the precursor aziridine (14) are discussed.
Manuscript received: 18 September 2002.
Final version: 11 November 2002.
Introduction
water to provide α-terpineol (3), and this is then cyclized
with enzymatic assistance to cineole (1).
We now consider the possibility that cation (2) might also
be trapped by ammonia (or its equivalent) to provide amine
Cineole (1,8-cineole, eucalyptol, 1,3,3-trimethyl-2-oxabi-
cyclo[2.2.2]octane) (1) (see Diagram 1) is the most abundant
and most widespread component of the eucalypt leaf oils.
Its biosynthesis in the tree has been postulated to occur
through cation (2) (or its equivalent), which is trapped by
[
1]
(4), which may then be enzymatically cyclized within the
[2]
tree to provide ‘azacineole’ (5). While eucalypts are widely
reported to be notably sparse in alkaloid content, we never-
theless resolved to synthesize compound (5) and to then seek
its presence in various trees, especially those that abundantly
synthesize cineole (1).
O
+
OH
Results and Discussion
C
(
1)
(2)
(3)
Syntheses for azacineole (5) have been previously reported.
[
3]
Rassat and Rey produced the compound in 1971 in a three-
step synthesis from 1,8-diamino-p-menthane (as a cis/trans
mixture) through azacineole N-oxide in less than 16% overall
10
9
H
H
8
N
N
[
4]
5
4
O
yield. Greene and Gilbert subsequently repeated this work
but achieved significantly lower yields in the first step and
thereby an overall yield of approximately 5%.
3
1
2
6
NH2
7
[
5]
Nelson et al. reported the Wolff–Kishner reduction of
the 3-keto compound (6). This synthesis was based on earlier
(
5)
(6)
N
(
4)
[
6]
work where ketone (6) was made through the double
Michael addition of ammonia to piperitenone (7), which in
turn was synthesized by condensation of mesityl oxide with
methyl vinyl ketone. Nelson et al. reported a low yield for the
Wolff–Kishner step with significant reversion to piperitenone
HO
O
(
7)anditssubsequentreductionunderthealkalineconditions.
NOH
The overall yield of azacineole (5) from methyl vinyl ketone
was 4%.
The brief experimental section of the Nelson paper
employs incorrect numbering for the described compounds,
and the data published is for azacineole (5) and not the
claimed 3-keto derivative (6).The authors report three singlet
(
7)
(8)
N
(9)
[5]
H
1
peaks in the H NMR spectrum for compound (5), at δ 0.98,
O
1.22, and 1.50. On the NMR timescale, we expect rapid inver-
sionaboutthenitrogenatom, leadingtoamoleculecontaining
a symmetry plane through C1, N, C8, and C4. Thus only two
types of methyl singlets, of 2 : 1 integrated area, would be
(
10)
Diagram 1
©
CSIRO 2003
10.1071/CH02189
0004-9425/03/04319

3
20
R. M. Carman and R. P. C. Derbyshire
expected. Clarification of this point provided further reason
to synthesize structure (5) in this current study.
structure of compound (14), a volatile oil, was supported
by NMR evidence especially in light of the one-bond cou-
pling (JC2H2 176 Hz), which is characteristic of a carbon in a
[
7,8]
After this work had commenced, work was published
[13]
claiming considerably higher yields of compound (5).
Hydroxylamine attack on the nitrosochloride of limonene (8)
provided oxime (9), which then required two steps to remove
the oxygen atoms, including a Wolff–Kishner reduction of
ketone (10). The mechanism of cyclization in this synthesis
three-membered ring.
Hydrogenation of aziridine (14) occurred quantitatively at
the less-hindered C2 N bond to afford azacineole (5). This
compound, also a volatile oil, provided NMR data consis-
tent with the proposed structure, showing only two methyl
peaks (ratio 2 : 1) and providing only seven types of carbon
atoms as expected from symmetry arguments.The yield from
limonene (8) ranged between 25% and 33%. A crystalline
derivative, acetamide (15), was prepared for characterization
purposes.
[9]
was modified by Coogan and Knight, who proposed a
reverse Cope-like process. Coogan managed to get through
to compound (9), although his experimental methodology
has not been reported. The experimental section of ref. [7]
seriously misreports the work in some places, for instance
implying that compound (9) is insoluble in ether. Consider-
able modification of this synthesis led us to compound (10)
in 18% yield, but we then had serious trouble with the Wolff–
Kishner reduction to compound (5) (5% yield versus 90%
The chemistry of the interesting aziridine (14) was briefly
explored. The compound was stable towards nucleophilic
attack and in alkaline solution but was reactive when pro-
tonated. In acetic acid compound (14) equilibrated with the
acetate (16), which could be isolated by sodium carbonate
workup (Scheme 2). However, unprotonated compound (16)
slowly reverted back to aziridine (14), again showing the
effectiveparticipationofthenitrogenatominthesolvolysisof
a suitably placed C2 leaving group in structures such as (12)
and (16). When the reaction of aziridine (14) in acetic acid
was quenched with sodium hydroxide the product was the
stable alcohol (17). In strong base acetate hydrolysis occurs
faster than the nitrogen displacement of the leaving group,
while in weaker base the displacement reaction is faster.
The NMR data for these compounds supported the struc-
tures. The H2 signal for compound (16) and (17) appears as
a ddd, which shows the characteristic long-range W-coupling
(J 2.0 Hz) to H6β, and thus defines the stereochemistry at C2.
The availability of synthetic azacineole (5) simplified
the search for the natural presence of this compound in euca-
lypt species by GC and GCMS examination of leaf extracts.
However, a preliminary survey of six locally available
trees (E. citriodora, E. curtisii, E. grandis, E. microcorys,
E. tereticornis, andE. ptychocarpa)providednosignofcom-
pound (5) from neutral leaf extracts, and indeed, no alkaloids
were detected at all from the acid extracts.Wider examination
of the plant kingdom, possibly outside the eucalypts, will be
required.
[8]
claimed yield ). At this stage we had obtained a sample of
the required compound (5), but the overall yield (about 1%)
was so poor that we sought an improved synthetic route.
We now report a direct two-step synthesis of azacineole
(
5) from 8-amino-p-menthene (4), which is available from
limonene (8) (Scheme 1). Addition of mercuric azide, cau-
tiouslygeneratedinsitu, tolimonenefollowedbyborohydride
[10]
reduction of the organomercurial yields azide (11).
The
crude azide, contaminated with unreacted limonene, need not
be purified at this stage as lithium aluminium hydride reduc-
[11]
tion of the mixture affords amine (4),
and separation of
this amine from limonene (8) using acid extraction is then
trivial.
Ring closure of amine (4) with N-bromosuccinimide
might be expected to provide bromide (12). However, the cor-
responding bromide in the oxa-cineole series is unstable due
to the presence of the neighbouring oxygen atom, and in polar
solvents yields breakdown products derived from the oxo-
[12]
nium ion (13). The nitrogen in compound (12) is obviously
more nucleophilic than oxygen and in acetone spontaneously
displaces the bromine to provide isolable aziridine (14). The
1
. Hg(N3)
LiAlH4
2
NBS
Ϫ
2
. BH4
H
H
H
N3
NH2
H +
N
H+
N
(
8)
(11)
(4)
(
14)
H
H
N
N
acetone
N
H2/Pd
1
AcOH
2
Br
12)
(
(14)
(5)
H
H +
H
H
N
N
2OHϪ
N
Na CO3
2
+O
CH3CO
N
OCOCH3
OCOCH3
OH
(
13)
(15)
(16)
(17)
Scheme 1
Scheme 2

Azacineole (1,3,3-Trimethyl-2-azabicyclo[2.2.2]octane)
321
Experimental
carefully added and the mixture stirred (10 h). The organic layer was
decanted and the precipitate washed with diethyl ether with the assis-
tance of ultrasound. The organic layers were combined and extracted
with hydrochloric acid (0.4 M).The combined acid extracts were washed
with diethyl ether and were then basified (2 M sodium hydroxide).
The cloudy alkaline layer was back-extracted into diethyl ether, and
the ether washed with brine and dried over sodium sulfate. Removal
NMR spectra were recorded in CDCl3 solution unless otherwise stated,
using either a BrukerAMX400 orAV400 spectrometer. 13C NMR multi-
plicitieswereassignedbythedistortionlessenhancementbypolarization
transfer (DEPT) pulse sequence. Mass spectra were recorded upon a
Hewlett–Packard MSD5970 spectrometer using a GC inlet and BP5
column. High-resolution mass spectra (HRMS) were recorded on both
Finnigan 2001 FT-MS and Kratos MS25RFA instruments. Infrared
spectra were measured using a Perkin–Elmer 1600 series FT-IR with
NaCl disks. GC analyses were performed upon a BP5 capillary col-
umn with flame ionization detection in a Varian 3300 instrument. Flash
column chromatography was performed using Merck silica, grade 60,
and distilled solvents.
of solvent gave the title amine (4) [(4R)-4-(1-amino-1-methylethyl)-
[16]
1
-methylcyclohexene (766 mg, 5.0 mmol) as a colourless oil (lit.
colourless oil) (>95% pure by GCMS). NMR spectra were consistent
[14]
−1
and provided extra information. νmax (neat)/cm
with the literature
354, 2961, 2922, 1595, 1437, 1381, 1363, 914, 799, 668. δH 5.33 (1 H,
m, Wh/2 13, H2), 2.04–1.86 (3 H, m, H3, H6eq), 1.79 (1 H, dm, width
8 Hz, H5eq), 1.70 (1 H, m, width ca. 40 Hz, H6ax), 1.59 (3 H, br s,
H7), 1.32 (2 H, br s, NH2), 1.30 (1 H, dddd, J 12.3, 11.2, 4.7, 2.3, H4),
.16 (1 H, dddd, J 12.3, 12.3, 11.2, 5.9, H5ax), 1.00 and 0.99 (6 H, 2
s, 2 × Me). δC 133.8 (C1), 120.7 (C2), 51.0 (C8), 45.2 (C4), 31.2
3
2
The numbering of skeletons in compounds (5) and (14)–(17) is based
on cineole numbering; see structure (5).
1
×
(
4R)-8-Azido-p-menth-1-ene (11)
(
C3), 28.3 and 27.6 (C9, C10), 26.7 (C6), 24.0 (C5), 23.2 (C7). Mass
+
•
+•
Caution: Explosions may result if this reaction is sealed, or if a higher
ratio of water to tetrahydrofuran is used.
spectrum (GCMS) m/z 154 (1%, [M + 1] ), 153 (1, M ), 139 (2),
138 (27), 137 (8), 136 (87), 122 (15), 121 (95), 110 (9), 108 (11), 107
(15), 105 (12), 93 (100), 79 (72), 77 (59).
A mixture of tetrahydrofuran (20 mL) and water (25 mL) was chilled
0 C) while separate solutions of sodium azide (3.25 g, 50 mmol) in
◦
(
water (10 mL), and (R)-(+)-limonene (8) (1.36 g, 10 mmol) in tetra-
Aziridine (14)
hydrofuran (5 mL), were prepared.Aqueous tetrafluoroboric acid (50%,
Amine (4) (1.1 g, 7.15 mmol) in acetone (100 mL, previously dried over
anhydrous sodium sulfate) was stirred (16 h) with N-bromosuccinimide
3
.51 g, 20 mmol) and yellow mercuric oxide (2.16 g, 10 mmol) were
mixed in a 300 mL flat-bottomed flask containing a magnetic stirrer
bar. The mixture was sonicated in an ultrasound cleaning bath until all
the solid mercuric oxide had reacted to give a pale yellow solution.
The flask was immediately transferred to an ice–salt bath and stirred
while the previously prepared chilled tetrahydrofuran–water solution
was added.Without delay the sodium azide solution was added dropwise
with rapid stirring, and then the limonene solution in tetrahydrofuran
(
1.27 g, 7.15 mmol). The solvent was carefully reduced to ca. 3 mL
by rotary evaporation (caution: aziridine (14) is highly volatile) and
diethyl ether (30 mL) was added. The mixture was sonicated and
filtered to remove precipitated succinimide, which was afterwards
washed with ether. The combined filtered ether layers were care-
fully taken to dryness to give crude aziridine (14) (1.03 g, 77% pure
by GCMS). Flash chromatography (silica, dichloromethane/methanol,
◦
was added. The reaction was stirred (−5 C, 2 h), allowed to warm to
1
9 : 1) afforded pure aziridine (14) [(2S,5R,7R)-2,8,8-trimethyl-1-
room temperature and then stirred a further 24 h.
2,7
◦
azatricyclo[3.2.1.0 ]octane] (582 mg, 3.85 mmol) as a hygroscopic
colourless oil (Found: C, 77.4; H, 11.9; N, 9.0%; M , 151.1357.
The flask was then cooled to −5 C and a pre-chilled solution of
+
•
sodium borohydride (0.76 g, 20 mmol) in sodium hydroxide solution
+
•
◦
C10H17N + (0.2 H2O) requires C, 77.6; H, 11.3; N, 9.0%; M
,
(
5 M, 5 mL) was added. After 2 h at −5 C the flask was allowed to
−
1
1
1
51.1361). νmax (neat)/cm 3307 (NH and OH), 2930, 1648, 1457,
372, 1301, 1213, 1131, 1072, 1008, 878, 814, 778, 737. δH 2.07
warm to room temperature and was then stirred (24 h) to allow mercury
to collect. The upper layer was decanted into a separatory funnel and
the mercury rinsed with diethyl ether, which was also transferred to the
funnel along with brine (20 mL).The organic layer was collected and the
aqueous layer further extracted with diethyl ether. The combined ether
layers were washed with brine and dried (sodium sulfate).These extracts
contained azide (11) and limonene (8) (ca. 55 : 45 by GC analysis; over
many attempts under identical conditions the amount of azide (11) var-
ied between 55% and 70%). This mixture of azide (11) and limonene
(
1 H, br d, H2), 2.02 (1 H, dddd, J3α,3β −12.6, J3β,4 7.0, J2,3β 4.4,
J3β,5β 2.6, H3β), 1.78 (1 H, ddd, J6α,6β −15.3, J5α,6α 11.6, J5β,6α
4
1
.6, H6α), 1.72 (1 H, dddd, J5β,6β 9.7, J5α,6β 5.9, J2,6β 1.1, H6β),
.67 (1 H, br d, H3α), 1.61 (1 H, dddd, J5α,5β −13.0, J4,5β 3.0,
H5β), 1.44 (1 H, ddd, J4,5α 3.0, H4), 1.30 (1 H, dddd, H5α), 1.20
and 1.00 (6 H, 2 × s, H9,10), 0.97 (3 H, s, H7). δC 60.9 (C8), 45.6
(
2
C2,JC2H2 177 Hz), 38.3 (C1), 36.9 (C4), 31.1 (C3), 28.8, 25.5,
1
2.9 (3 × Me), 23.0 (C5), 20.7 (C6); with remaining JCH couplings
(
8), obtained by removal of solvent from the dried ether extracts, was
between 140 and 160 Hz. Mass spectrum (GCMS) m/z 152 (3%,
used for further reaction. A pure sample of the title azide (11) [(4R)-
4
bp 212 C/690 mmHg) was obtained by flash chromatography (silica,
hexane). NMR spectra were consistent with the literature
vided extra information. νmax (neat)/cm 2966, 2924, 2099 (s, azide
stretch), 1388, 1369, 1260, 1220, 1159, 1133, 799. δH ([D6]benzene)
+
•
[
14]
[M + 1] ), 151 (32), 137 (5), 136 (35), 122 (9), 111 (9), 110 (100),
108 (22), 96 (14), 95 (99), 94 (47), 93 (20), 91 (17), 83 (78), 82 (26),
79 (59), 77 (32).
-(1-azido-1-methylethyl)-1-methylcyclohexene] as a clear oil (lit.
◦
[
14,15]
and pro-
−
1
Azacineole (5)
5
.28 (1 H, m, Wh/2 10, H2), 1.88–1.71 (3 H, m, H3, H6), 1.70–1.60 (2 H,
m, H5eq, H6), 1.56 (3 H, br s, H7), 1.34 (1 H, dddd, J 11.9, 11.4, 4.9,
.5, H4), 1.09 (1 H, dddd, J 12.4, 12.3, 11.4, 5.9, H5ax), 0.94 and 0.92
Aziridine(14)(140 mg, 0.926 mmol)inethylacetate(10 mL)washydro-
genated (atmospheric pressure, 20 h) over palladium (10% on carbon,
2
1
4 mg). The solution was filtered (celite) and the solvent removed to
(
(
6 H, 2 × s, 2 × Me). δC ([D6]benzene] 133.6 (C1), 120.7 (C2), 63.8
give pure azacineole (5) [1,3,3-trimethyl-2-azabicyclo[2.2.2]octane] as
C8), 43.6 (C4), 31.0 (C3), 27.0 (C6), 24.3 (C5), 23.4 (C7), 22.8 and
[3,5−8]
◦
a colourless oil (121 mg, 0.787 mmol) (lit.
colourless oil, bp 90 C
+
•
23.6 (C9, C10). Mass spectrum (GCMS) m/z 150 (1%, [M − 29] ),
138 (1), 137 (12), 136 (23), 123 (3), 122 (6), 121 (33), 119 (4), 110 (22),
109 (5), 108 (38), 107 (6), 105 (5), 94 (84), 79 (100).
+•
+•
at 3–4Torr) (Found: M , 153.1519; [M − CH3] , 138.1291. C10H19N
+•
+•
−1
requires M , 153.1517; [M − CH3] , 138.1283). νmax (neat)/cm
3
1
384, 2937, 2803, 2725, 2501, 1712, 1660, 1622, 1590, 1469, 1395,
381, 1287, 1230, 1174, 1091, 1061, 916, 732. δH 8.80 (1 H, s, NH), 2.18
(
4R)-8-Amino-p-menth-1-ene (4)
The mixture (1.6 g) of dry azide (11) (5.5 mmol) and limonene (8)
4.5 mmol) was stirred in dry tetrahydrofuran (80 mL, distilled from
(
2 H, m), 2.04 (2 H, m), 1.60 (6 H, 2 × s, H9,10), 1.57 (3 H, s, H7), 1.64–
1.48 (5 H, m). The spectrum was overlapped and second order, therefore
no reliable coupling constants were available. δC 58.1 and 55.0 (C1, C8),
33.4 (C4), 28.4 (C2,6), 27.8 (C9, C10), 24.4 (C7), 21.5 (C3, C5). Mass
(
sodium) while lithium aluminium hydride (0.5 g, 14 mmol) was added
in small portions.A reflux condenser was connected and, after the initial
vigorous bubbling had ceased, the mixture was refluxed (4 h). Undried
diethyl ether (40 mL) and then sodium sulfate decahydrate (7 g) were
+
•
+•
spectrum (GCMS) m/z 154 (3%, [M + 1] ), 153 (27, M ), 139 (11),
+
•
138 (100, [M − CH3] ), 125 (9), 124 (49), 111 (8), 110 (87), 108 (15),
98 (26), 96 (26), 94 (11), 93 (9), 82 (23), 81 (13), 70 (81).

3
22
R. M. Carman and R. P. C. Derbyshire
N-Acetyl-azacineole (15)
3141 br, 1338, 1233, 1199, 1145, 1131, 1100, 1079, 1069, 1036, 989,
9
2
1
1
7
1
73, 925, 908, 802, 722. δH 3.57 (1 H, ddd, J2β,3β 9.6, J2β,3α 3.7, J2β,6β
.0, H2β), 2.44 (1 H, dddd, J3α,3β −14.1, J3β,4 = J3β,5β 3.3, H3β),
.91 (1 H, ddddd, J5α,5β −14.0, J5β,6β 12.0, J4,5β 4.0, J5β,6α 3.0, H5β),
.83 (1 H, ddd, J6α,6β −14.0, J5α,6α 11.5, H6α), 1.48 (1 H, dddd, J5α,6β
.0, J4,5α 2.5, H5α), 1.39 (1 H, dddd (app. pentuplet), J3α,4 3.0, H4),
.30 (1 H, dddd, H6β), 1.25 (1 H, ddd, H3α), 1.18 and 1.09 (6 H, 2 × s,
Azacineole (5) (50 mg, 0.326 mmol) was stored (16 h) with acetic
anhydride (5 mL) and triethylamine (1 mL). Normal workup, includ-
ing ether extraction and washing with sodium carbonate solution and
with dilute aqueous acid, gave a residue which comprised >98%
purity (by GCMS) the N-acetyl derivative (15). Flash chromatography
(
silica, diethyl ether/pentane, 50 : 50, RF 0.3) gave analytically pure title
H9,10), 0.94 (3 H, s, H7); all couplings were supported by 2D spectra.
δC 73.0 (C2), 52.2 and 51.3 (C1, C8), 35.1 (C4), 35.0 (C3), 30.9 and
compound (15) [2-acetyl-1,3,3-trimethyl-2-azabicyclo[2.2.2]octane]
◦
(
38 mg, 0.195 mmol) as small colourless prisms, mp 74–75 C (Found:
3
0.8 (C9, C10), 25.7 (C6), 24.7 (C7), 22.5 (C5). Mass spectrum (GCMS)
C, 73.7; H, 11.0; N, 7.0%. C12H21NO requires C, 73.8; H, 10.8; N,
+
•
−
1
m/z 169 (20%, M ), 155 (5), 154 (35), 152 (3), 138 (4), 136 (5), 125
7
7
2
.2%). νmax (nujol)/cm 1654, 1632, 1324, 1278, 1163, 1098, 1030,
23. δH 2.10 (3 H, s, H12), 2.01 (2 H, m), 1.89 (2 H, m), 1.52 (6 H,
× s, H9,10), 1.39 (3 H, s, H7), 1.50–1.38 (5 H, m). The spectrum was
(
(
25), 124 (19), 111 (9), 110 (100), 108 (16), 107 (6), 98 (7), 97 (9), 96
17), 95 (15), 94 (10), 93 (10), 91 (5), 83 (12), 82 (22), 81 (6), 80 (5),
7
9 (10), 77 (7), 70 (20).
overlapped and second order, therefore no reliable coupling constants
were available. δC 171.6 (C11), 59.1 and 54.5 (C1, C8), 40.1 (C4), 34.0
Eucalyptus Leaf Extraction
(
C2, C6), 29.2 and 28.5 (C7, C12), 27.7 (C9, C10), 22.3 (C3, C5). Mass
+
•
+•
spectrum (GCMS) m/z 196 (5%, [M + 1] ), 195 (37, M ), 181 (6),
Fresh eucalypt leaves (10 g) were finely cut with scissors into a round-
bottomed flask. A mixture of acetone (40 mL) and hexane (40 mL)
was added and the flask was sonicated (10 min). The mixture was then
refluxed (4 h) and the solvent was decanted. The remaining leaf matter
was subjected to a further round of sonication and reflux with a fresh
portion of solvent. The combined extracts were taken to dryness and
the green residue was weighed and taken into diethyl ether (140 mL),
which was separated into two equal portions. The solvent was removed
from one of the portions and the residue was taken up into ethyl acetate
(2 mL) and centrifuged. The supernatant was filtered and analyzed by
GCMS (total extract).The other portion was extracted with hydrochloric
acid (0.4 M, 5 × 20 mL). The acid extracts were basified (dilute sodium
hydroxide) and re-extracted back into ether. These ether extracts were
dried, the solvent was removed, and the residue was taken up into ethyl
acetate (2 mL) and centrifuged. The supernatant was filtered and ana-
+
•
+•
1
(
(
80 (51, [M − CH3] ), 166 (7), 153 (6), 152 (18, [M − CH3] ), 139
10), 138 (100), 124 (21), 110 (26), 99 (8), 98 (8), 96 (8), 93 (8), 82
13), 81 (9).
Acid Treatment of Aziridine (14)
Aziridine (14) (100 mg) was refluxed in glacial acetic acid (20 mL).
After 1 h an aliquot was worked up by adding excess sodium carbonate
solution followed by extraction into diethyl ether.Analysis of this aliquot
showed starting aziridine (14) and acetate (16) (40 : 60 by GCMS). Fur-
ther aliquots taken after additional periods of reflux showed increasing
amounts of acetate (16). When these worked up aliquots were examined
(
(
GCMS) several days later the mixtures had reverted to aziridine (14)
100%).
Workup (sodium carbonate) of the acetic acid mixture followed by
rapid extraction into cold dichloromethane gave an oil which was rapidly
flash-chromatographed over silica using dichloromethane/methanol
[1]
lyzed by GCMS (acid extract). Standard terpenoid compounds were
observed, but no peaks corresponding to compound (5) were observed
in either the total or acid extracts.
(
87 : 13) as eluent. Aziridine (14) eluted first, followed by (1S,2S,4R)-
1
,8-azacineole-2-acetate(16)[(1S,4R,6S)-1,3,3-trimethyl-2-azabicyclo
[
2.2.2]octan-6-yl acetate] (30 mg), which was an unstable, colourless
References
+
•
+•
and viscous oil (Found: M , 211.1569. C12H21NO2 requires M
,
−
1
2
1
2
2
5
1
11.1572). νmax (neat)/cm 3314, 2965, 1736, 1654, 1560, 1458, 1371,
244, 1169, 1066, 1027. δH 4.67 (1 H, ddd, J2β,3β 9.6, J2β,3α 3.6, J2β,6β
.0, H2β), 2.54 (1 H, dddd, J3α,3β −15.0, J3β,4 3.6, J3β,5β 3.5, H3β),
.02 (3 H, s, OAc), 1.93 (1 H, ddddd, J5α,5β −14.0, J5β,6β ca. 12, J5β,6α
.3, J4,5β 4.0, H5β), 1.83 (1 H, ddd, J6α,6β −13.4, J5α,6α 13.3, H6α),
.52 (1 H, dddd, J5α,6β 7.0, J4,5α 3.0, H5α), 1.44 (1 H, dddd, H4), 1.25
[1] D. J. Boland, J. J. Brophy A. P. N. House (Eds), Eucalyptus
Leaf Oils, Use, Chemistry, Distillation and Marketing 1991
(Inkata: Melbourne).
[2] R. Croteau, W. R. Alonso, A. E. Koepp, M. A. Johnson, Arch.
Biochem. Biophys. 1994, 309, 184.
[3] A. Rassat, P. Rey, J. Chem. Soc., Chem. Commun. 1971, 1409.
[4] F. D. Greene, K. E. Gilbert, J. Org. Chem. 1975, 40, 1409.
[5] S. F. Nelson, R. J. Qualy, P. M. Gannett, J. Org. Chem. 1982,
47, 4879.
(
1 H, dddd, H6β), 1.22 (1 H, ddd, H3α), 1.26 and 1.21 (6 H, 2 × s, H9,
H10), 1.01 (3 H, s, H 7). δC 170.5 (C11), 73.5 (C2), 52.8 and 52.0 (C1,
C8), 34.6 (C4), 32.6 (C3), 29.8 and 29.7 (C9, C10), 25.5 (C6), 21.9
(
2
1
C5), 23.6 and 21.2 (C7, C12). Mass spectrum (GCMS) m/z 213 (1%),
[6] A. Rassat, P. Rey, Tetrahedron 1972, 28, 741.
[7] S. A. Bakunov, A. Y. Denisov, A. V. Tkachev, Tetrahedron 1995,
51, 8565.
+
•
+•
+•
12 (7, [M + 1] ), 211 (55, M ), 197 (10), 196 (83, [M − CH3] ),
69 (29), 168 (78), 154 (6), 153 (8), 152 (73), 151 (10), 138 (8), 136
(
(
(
33), 125 (32), 124 (62), 123 (10), 111 (10), 110 (100), 109 (13), 108
44), 107 (19), 98 (16), 96 (23), 95 (26), 94 (17), 93 (22), 83 (27), 82
33), 81 (13), 79 (19), 77 (15).
[8] S. Bakunov, A. Tkachev, Liebigs Ann./Recl. 1997, 1587.
[9] M. P. Coogan, D. W. Knight, Tetrahedron Lett. 1996, 37, 6417.
[10] M. C. S. de Mattos, W. B. Kover, F. Aznar, J. Barluenga,
Tetrahedron Lett. 1992, 33, 4863.
Afurtheraliquotfromtheaceticacidreactionwasworkedupbyaddi-
tion to sodium hydroxide solution (5 M) and extraction into diethyl ether.
Analysis showed aziridine (14) and alcohol (17) (15 : 85 by GCMS).
After 2 h, a similar acetic acid reaction was added dropwise to a stirred
sodium hydroxide solution (5 M, 100 mL). After 30 min, the solution
was extracted with diethyl ether, the ether extract was washed with brine
and dried over sodium sulfate. Analysis (GCMS) showed alcohol (17)
[11] K. Shishido, K. Hiroya, K. Fukumoto, T. Kametani, J. Chem.
Res., Synop. 1989, 100.
[12] R. M. Carman, M. T. Fletcher, Aust. J. Chem. 1986, 39, 1723.
[13] F. W. Wehrli, T. Wirthlin, Interpretation of Carbon-13 NMR
Spectra 1978, pp. 50–53 (Heyden & Son: London).
[14] B. Ravindranath, P. Srinivas, Indian J. Chem., Sect. B 1985,
24, 1178.
[15] A. Pancrazi, I. Kabore, Q. Khuong-Huu, Bull. Soc. Chim. Fr.
1977, 162.
[16] T. Darbre, C. Nussbaumer, H.-J. Borschberg, Helv. Chim. Acta
1984, 67, 1041.
(
96%).Thesolventwasremovedtogiveacrystallinesolid(93 mg)which
◦
was sublimed (50 C/0.05 mmHg) to give (1S,2S,4R)-2-hydroxy-1,8-
azacineole (17) [(1S,4R,6S)-1,3,3-trimethyl-2-azabicyclo[2.2.2]octan-
6
8
◦
-ol] as colourless chunks, mp 108–110 C (Found: C, 70.8; H, 11.6; N,
−
1
.0%. C10H19NO requires C, 71.0; H, 11.3; N, 8.3%). νmax (nujol)/cm