Synthesis of functionalised azecine and azonine derivatives via an enolate assisted aza Claisen rearrangement

Article abstract of DOI:10.1016/j.tet.2005.01.061

This paper describes the synthesis of functionalised azecine and azonine derivatives incorporating the adrenaline motif. In a key step, an enolate assisted aza Claisen rearrangement was employed to interconvert from 6- and 5-membered heterocycles to their corresponding 10- and 9-membered lactams.

Full text of DOI:10.1016/j.tet.2005.01.061

Tetrahedron 61 (2005) 2659–2665
Synthesis of functionalised azecine and azonine derivatives
via an enolate assisted aza Claisen rearrangement
*
John B. Bremner and David F. Perkins
Department of Chemistry, Institute for Biomolecular Science, University of Wollongong, Wollongong, NSW 2522, Australia
Received 24 February 2004; revised 22 December 2004; accepted 14 January 2005
Abstract—This paper describes the synthesis of functionalised azecine and azonine derivatives incorporating the adrenaline motif. In a key
step, an enolate assisted aza Claisen rearrangement was employed to interconvert from 6- and 5-membered heterocycles to their
corresponding 10- and 9-membered lactams.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
9-membered aza-heterocycles 1 and 2, respectively, were
predicted to selectively bind to the abovementioned mutant
receptor over the wild type. This paper now reports concise
syntheses of these systems.
Medium ring heterocycles have, in the past, proven difficult
to synthesise via mechanisms involving ring closure making
them an under-exploited resource in terms of their chemical
and pharmacological application. There is a sound basis for
their appeal in pharmacological research; they are of
moderate size giving rise to their potential as ligands for
receptors, and they offer semi-restricted conformational
flexibility allowing considerable scope for selective binding
with a range of functional groups. In this connection, we
were interested in substituted medium-sized aza ring
systems incorporating an imprint of the adrenaline motif
as potentially selective signalling agents at adrenergic
receptors, in particular the a1B receptor. Such agents
could be effective therapeutics, for example, as
hypotensives.
A constitutively active Cys128Phe mutant of the a1B-adreno
ceptor has previously been reported to act, in the absence of
ligand, as a signalling specific ceptor, activating a single
biochemical-signalling pathway.1 This observation
suggested that a ligand with a greater affinity for this
mutant receptor over the wild-type a1B-adrenoceptor might
increase the equilibrium concentration of this activated
conformation of the wild-type receptor.
2. Synthesis
The approach to both ring systems involved a ring
interconversion strategy from 6- and 5-membered ring
precursors (14 and 15) via an enolate assisted aza Claisen
rearrangement2 to give the racemic 10- and 9- membered
ring compounds (16 and 17). This is an adaptation of the
approach first described by Suh et al. for the 10-membered
ring system.3,4
From modelling studies based on a restricted range of
phenethylamine and imidazoline ligands, the 10- and
The first step in the synthesis in the overall approach to the
target molecules was the straightforward N-benzylation of
the appropriate lactam 3 or 4 with benzyl bromide in the
presence of sodium hydride (step a, Scheme 1).
Keywords: Aza Claisen; Azecine; Azonine; 9-Membered rings;
10-Membered rings; Adrenaline.
* Corresponding author. Tel.: C61 2 4221 4255; fax: C61 2 4221 5431;
e-mail: john_bremner@uow.edu.au
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.061

2660
J. B. Bremner, D. F. Perkins / Tetrahedron 61 (2005) 2659–2665
Scheme 1. Reagents: (a) i—NaH, ii—benzyl bromide, THF; (b) i—LiAlH4 1/2 equiv, ii—Vinyl MgBr, THF; (c) TrocCl, Na2CO3, acetonitrile, (reflux);
(d) Zn/CH3COOH; (e) TBDMSOTf, 2,6-lutidine/acetonitrile, (K78 8C); (f) Na2CO3, water/MeOH; (g) 13, EDCI/DMAP/acetonitrile.
The resulting N-benzyl derivatives 5 and 6 were then treated
with one half equivalent of LiAlH4 as well as the Grignard
reagent, vinyl magnesium bromide, to afford the 2-vinyl
substituted compounds 7 and 8 (step b, Scheme 1). We also
investigated an alternative route to 7 and 8 employing a
palladium catalysed intramolecular cyclisation of allyl-
benzotriazole derivatives.5 However, this route required an
extra step and was not amenable to increased reaction scales.
Na2CO3. This step eliminated the necessity of hydrogen-
ation to remove the benzyl group, which would compromise
the vinylic double bond, and also gave rise to carbamates 9
and 10, which could be readily deprotected under relatively
mild conditions (Zn8/CH3COOH/room temperature). The
resulting unstable secondary bases 2-vinylpiperidine6 or
2-vinylpyrrolidine7 were not isolated or characterised but
were used directly in the subsequent step.
The benzyl groups in 7 and 8 were then substituted with
2,2,2-trichloroethylformate (Troc) groups using 2,2,2-tri-
chloroethyl chloroformate in acetonitrile in the presence of
The next step involved the coupling of the resulting crude
free bases with a-tert-butyldimethylsilyloxy-a-phenyletha-
noic acid (13), which was synthesised in turn from the bis
Scheme 2. Reagents: (h) i—LHMDS, ii—water, toluene; (i) Red-Al, THF; (j) TBAF, THF and (k) 16, LiAlH4, THF.

J. B. Bremner, D. F. Perkins / Tetrahedron 61 (2005) 2659–2665
2661
O-protection of mandelic acid (11, step e), to form 12,
followed by the subsequent hydrolysis of the silyl ester
group to give 13. Coupling of 13 with 9 or 10 in the presence
of EDCI and 4-N,N-dimethylaminopyridine (DMAP)
afforded the a-silyloxyamides 14 and 15 (step g, Scheme 1).
The base-induced (lithium hexamethyldisilazide, LHMDS)
aza Claisen rearrangement (Scheme 2) of 14 and 15 then
proceeded smoothly in refluxing toluene to give the
medium-sized lactams 16 and 17, respectively, in good
yield. Computer-based molecular modelling using the
computer program Spartan ’028 (AM1)9 suggested that the
newly formed annular double bond would be more stable in
Figure 1. PM3-generated local minima of the lithium enolate salts of 14
(left) and 15.
equidistant between the two oxygen atoms, causes the
enolate double bond to adopt a Z configuration (Fig. 1),
which is approximately 10 kcal molK1 more favourable
than the E configuration of the enolate double bond in the
presence of the lithium ion.
the E configuration than its Z counterpart by 4.2 kcal molK1
,
and the observed coupling constants between the olefinic
protons of 16 and 17 (15.5 Hz in both cases) in the 1H NMR
verify that the double bond formed in the rearrangement is
in fact generated with an E configuration.
The transition state (Fig. 2) for the rearrangement of 14,
adopts a chair–chair conformation similar to that implied for
the systems investigated by Suh et al.4
The presence of the double bond in both 16 and 17 rendered
the reduction of the lactams problematic; reductants such as
diborane, for example, have the capability of adding across
the double bond.10 With this in mind, LiAlH4 was used in an
attempt to reduce 16 to its corresponding silyl protected
phenethylamine 18. However, while the reduction of the
amide carbonyl in 16 in the presence of LiAlH4 was
successful, intramolecular cyclisation occurred to give only
20 in good yield (76%) and none of the desired reduced
product (18) with the double bond intact was isolated
(Scheme 2).
The above problem was overcome through the use of
sodium bis(2-methoxyethoxy) aluminium hydride (Red-
Alw). In the absence of lithium ions, the reduction of the
amide carbonyls in 16 and 17 proceeded in good yield (76
and 72%) without destroying the double bond.
Figure 2. Transition state for the aza Claisen rearrangement of 14.
4. Future work
We are currently investigating the extension of the current
project to incorporate catechol derivatives in the aryl moiety
to more closely mimic adrenaline. The pharmacological
activities of these compounds and those discussed here will
be reported separately.
¨
While TBDMS groups may be removed with Bronsted
acids, molecular models of 18 and 19 suggested that
protonation of the double bond may lead to an intraannular
ring closure similar to that observed in the presence of
LiAlH4. Furthermore, the tertiary alcohol formed in the
reaction would be extremely susceptible to acid-catalysed
dehydration. For this reason, tetrabutylammonium fluoride
in tetrahydrofuran was used to deprotect the TBDMS groups
to afford the target compounds 1 and 2. This system has
proved to have several advantages; it was high yielding,
involved an easy work-up, and both the double bond and the
tertiary hydroxyl group remained intact.
5. Experimental
5.1. General
All starting materials were used without further purification
with the exception of zinc powder which was activated as
described below, and EDCI which was dehydrated under
high vacuum for twelve hours prior to use. Tetrahydrofuran
and diethyl ether were distilled from sodium in the presence
of benzophenone. Acetonitrile and toluene were freshly
distilled over calcium hydride prior to use. Reaction flasks
were air dried in an oven at 70 8C and purged with argon or
nitrogen where appropriate. The term petroleum spirit refers
to petroleum spirit within the boiling range of 40–60 8C.
Column chromatography was performed with the indicated
For comparative purposes, the amides, 21 and 22, and the
base 23, were also prepared for pharmacological testing
(Scheme 2).
3. Molecular modelling
Molecular modelling (Spartan ’028, PM312) of the lithium
salt of the enolate ion generated in the aza Claisen
rearrangement of 14 and 15 suggested that both molecules
are able to adopt a conformation in which the bulky TBDMS
groups do not sterically impede the rearrangement. The
presence of the lithium ion, which is positioned almost
solvents freshly distilled over molecular sieves (4 A).
Column chromatography was performed using silica gel
60 (230–400 mesh, Merck) or neutral alumina (activated
˚
˚
Brockmann 1, standard grade w150 mesh, 58 A, Aldrich).
Reactions were followed with thin layer chromatography
(0.25 mm aluminium backed silica gel plates) using

2662
J. B. Bremner, D. F. Perkins / Tetrahedron 61 (2005) 2659–2665
analytical grade solvents. Chromatographic solvent mix-
tures are quoted as volume ratios. Organic solvents were
dried over anhydrous sodium sulfate (except where
indicated in the text) and the solvent was removed under
reduced pressure with a Bu¨chi rotary evaporator. All
compounds were judged to be greater than 95% purity by
1H NMR and TLC analysis. High-resolution electrospray
mass spectra were recorded on a Q-TOF2 high-resolution
electrospray mass spectrometer and the low resolution CI
mass spectrum on a Shimadzu QP-5000 mass spectrometer.
1H and 13C NMR spectra were recorded on a Varian
Mercury 300 NMR spectrometer running at 299.5 MHz for
1H spectra and 74.99 MHz for 13C spectra. All spectra were
4.53 g, 26.5 mmol) was then injected slowly over 10 min
through a rubber septum. The reaction mixture was allowed
to warm to room temperature and was stirred for a further
3 h. The solvent was evaporated in vacuo and the residue
partitioned between dichloromethane (100 mL) and water
(100 mL). The organic phase was washed several times with
water, dried and evaporated. The residue was purified by
column chromatography (silica gel, petroleum spirit–ethyl
acetate, 1:1), to afford 511 as a colourless oil (3.39 g,
1
17.9 mmol, 71%). H NMR (CDCl3) d 1.58 (m, 4H), 2.20
(t, JZ8 Hz, 2H), 3.21 (t, JZ8 Hz, 2H), 4.45 (s, 2H), 7.10–
7.20, (m, 5H); 13C NMR (CDCl3) d 23.1, 26.9, 32.6, 42.8,
49.6, 128.0, 128.6, 127.1, 136.5, 169.3.
1
run in CDCl3 with 1% tetramethylsilane (TMS) and all H
NMR spectra are referenced to TMS. 1H NMR spectral data
are reported in the order of chemical shift, multiplicity,
(s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet
of doublet of doublets; t, triplet; tt, triplet of triplets; m,
multiplet), coupling constant(s) in hertz (Hz) and number of
protons. 13C spectra are referenced to the central deuterated
solvent peak. The melting point (mp) determination was
recorded on a Reichert melting point apparatus and is
reported uncorrected.
5.4.2. N-Benzylpyrrolidin-2-one (6).13 In a similar manner
to that described above for the synthesis of 5, pyrrolidin-2-
one (2.5 g, 29.4 mmol), NaH (60% suspension in paraffin,
1.24 g, 32.4 mmol) and benzyl bromide (5.03 g, 29.4 mmol)
yielded 613 as a colourless oil (3.91 g, 22.4 mmol, 76%); 1H
NMR (CDCl3) d 2.03 (quintet, JZ7 Hz, 2H), 2.25 (t, JZ
7 Hz, 2H), 3.40 (t, JZ7 Hz, 2H), 4.48 (s, 2H), 7.08–7.18,
(m, 5H); 13C NMR (CDCl3) d 18.9, 32.9, 46.0, 49.4, 128.1,
128.6, 127.2, 136.7, 173.3.
For identification purposes, the numbering of protons for 1H
NMR chemical shift assignments is set out below.
5.4.3. N-Benzyl-2-vinylpiperidine (7).5 To a stirred
solution of 5 (1.50 g, 7.94 mmol) in anhydrous THF
(50 mL) over an ice bath, was added LiAlH4 (0.166 g,
4.36 mmol). The mixture was allowed to stir at 0 8C for 1 h
and vinyl magnesium bromide (1 M solution in THF,
24 mL, 24 mmol) was injected through a rubber septum.
The mixture was maintained at 0 8C for 10 h and then
allowed to warm to room temperature. The reaction mixture
was stirred for a further 12 h at room temperature. Methanol
(20 mL) was then added slowly to quench unreacted
Grignard reagent. The solvent was removed under reduced
pressure and the residue partitioned between dichloro-
methane (100 mL) and water (50 mL). Both fractions were
filtered over a celite pad and the solid washed several times
with warm dichloromethane. The combined organic frac-
tions were dried and the solvent removed under reduced
pressure. The resulting brown oily residue was purified by
column chromatography (silica gel, ethyl acetate–petroleum
spirit, 1:50) to yield 75 as a colourless oil (0.973 g,
5.2. Computational studies
Computational studies were carried out on a Silicon
Graphics Fuel processor running at 600 MHz with
1523 Mb of random access memory (RAM). Minimisations
involving lithium were carried out using the PM312 force
field while others were performed using AM19 running on
the computer program Spartan’02.8
1
4.84 mmol, 61%). H NMR (CDCl3) d 1.25–1.98 (m, 7H),
2.64–2.71 (m, 1H), 2.78–2.84 (m, 1H, H4), 3.05 (d, JZ
13.5 Hz, 1H, benzyl), 4.08 (d, JZ13.5 Hz, 1H, benzyl), 5.10
(dd, JZ1.7, 10 Hz, 1H, H1), 5.19 (d, JZ17 Hz, 1H, H2),
5.90 (ddd, JZ1.7, 10, 17 Hz, 1H, H3), 7.20–7.31 (m, 5H,
HAr); 13C NMR (CDCl3) d 23.9, 26.4, 32.0, 52.1, 58.3, 67.8,
115.6, 127.3, 128.5, 128.9, 135.5, 137.6.
5.3. Activation of zinc powder
Zinc powder (5.01 g, 78.2 mmol) was suspended in 0.1 M
HCl, (20 mL) and the mixture stirred at room temperature
for 1 min. The mixture was then filtered and the solid
washed with distilled water, then ethanol and finally diethyl
ether. The air-dried zinc powder was then stored in a
vacuum desiccator over silica gel desiccant until used.
5.4.4. N-Benzyl-2-vinylpyrrolidine (8).14 In a similar
manner to that described above for the synthesis of 7,
N-benzyl-pyrrolidin-2-one (2.6 g, 14.9 mmol), LiAlH4
(0.310 g, 0.817 mmol) and 1 M vinyl magnesium bromide
in THF (45 mL, 45 mmol) yielded 814 as a colourless oil
5.4. Synthetic procedures
1
(1.72 g, 9.21 mmol, 62%). H NMR (CDCl3) d 1.62–1.72
5.4.1. N-Benzyl-2-piperidone (5).11 To a stirred solution of
2-piperidone (2.5 g, 25.3 mmol) in anhydrous THF (50 mL)
over an ice bath, was added a suspension of sodium hydride
in paraffin oil (60%, 1.1 g, 28.7 mmol). The mixture was
stirred for 30 min at 0 8C and benzyl bromide (3.2 mL,
(m, 3H), 1.82–2.02 (m, 1H), 2.11 (q, JZ9 Hz, 1H), 2.78 (q,
JZ8 Hz, 1H), 2.91 (t, JZ7 Hz, 1H, H4), 3.06 (d, JZ
12.5 Hz, 1H, benzyl), 4.03 (d, JZ12.5 Hz, 1H, benzyl), 5.13
(dd, JZ1.4, 10 Hz, 1H, H1), 5.17 (d, JZ17 Hz, 1H, H2),
5.79 (ddd, JZ17, 10, 1.5 Hz, 1H, H3), 7.20–7.30 (m, 5H,

J. B. Bremner, D. F. Perkins / Tetrahedron 61 (2005) 2659–2665
2663
HAr); (CDCl3) d 22.0, 31.5, 53.1, 58.1, 68.4, 116.5, 126.7,
128.1, 129.1, 139.8, 141.0.
a white solid, which was recrystallised from dichloro-
methane/diethyl ether to yield 13 as a white crystalline solid
(0.330 g, 1.24 mmol, 94%); mp 98–100 8C; 1H NMR
(CDCl3) d 0.08 (s, 6H, SiCH3), 1.05 (s, 9H, But), 5.38 (s,
1H, CHOSi), 7.12–7.26, (m, 5H, ArH); 13C NMR (CDCl3) d
K5.8, 18.2, 25.8, 83.5, 127.7, 128.7, 129.5, 135.8, 178.7;
HRMS (ES, Kve) calcd for C14H22O3Si–H: 265.1265;
found: 265.1269.
5.4.5. 2,2,2-Trichloroethyl 2-vinylpiperidine-1-carboxyl-
ate (9). To a stirred solution of 7 (1.30 g, 6.47 mmol) and a
suspension of anhydrous K2CO3 (1.30 g, 9.41 mmol) in
anhydrous acetonitrile (50 mL) at room temperature, under
a nitrogen atmosphere was added dropwise, 2,2,2-trichloro-
ethyl chloroformate (1.4 g, 6.61 mmol). The mixture was
heated to reflux and stirred for 2 h. The solvent was
evaporated in vacuo and the residue partitioned between
dichloromethane (100 mL) and water (100 mL). The
organic phase was washed several times with water, dried
and evaporated in vacuo. The residue was purified by
column chromatography (silica gel, ethyl acetate–petroleum
spirit, 1:50), yielding 9 as a colourless oil (1.58 g,
5.4.9. 2-(tert-Butyldimethylsilyloxy)-2-phenyl-1-(2-vinyl-
piperidin-1-yl)ethan-1-one (14). To a stirred solution of 9
(1.81 g, 6.32 mmol) in glacial acetic acid (5 mL) was added
freshly activated Zn (0.5 g, 7.94 mmol). The vigorously
bubbling reaction was stirred at room temperature for 3 h
under argon. Water (30 mL) was added and the pH of the
solution was made basic (pH 9) with aqueous sodium
carbonate (1 M). The mixture was extracted with dichloro-
methane (50 mL) and the organic phase dried with
anhydrous sodium carbonate. The dichloromethane was
removed under a slight vacuum, and the residue dissolved in
anhydrous acetonitrile. To this was added EDCI (1.25 g,
6.52 mmol), DMAP (0.8 g, 6.55 mmol) and 13 (1.60 g,
6.01 mmol). The reaction mixture was stirred for 24 h at
room temperature under argon. The solvent was then
removed in vacuo and the residue partitioned between
dichloromethane (50 mL) and water (50 mL). The organic
phase was dried and evaporated and the residue purified on a
chromatographic column (neutral alumina, petroleum
spirit–ethyl acetate 50:1) yielding 14 as a colourless oil
(1.02 g, 2.84 mmol, 45%). 1H NMR (CDCl3) d 0.08 (s, 6H,
SiCH3), 1.03 (s, 9H, But), 1.41–2.13 (m, 7H), 3.05 (m, 1H),
3.95 (m, 1H, H4), 5.13 (ddd, JZ17.2, 2.2, 1.2 Hz, 1H, H2),
5.22 (ddd, JZ10.5, 2.2, 1.2 Hz, 1H, H1), 5.45, (s, 1H,
CHOSi), 5.83 (ddd, JZ17.2, 10.5, 4.5 Hz, 1H, H3), 7.19–
7.31 (m, 5H, ArH); 13C NMR (CDCl3) d K6.1, 17.6, 23.6,
25.8, 25.8, 31.4, 43.1, 52.9, 80.4, 115.9, 127.6, 129.0, 129.6,
136.7, 138.0, 172.7; HRMS (ES Cve) calcd for C21H33-
NO2SiCH: 360.2353; found: 360.2349.
1
5.55 mmol, 84%). H NMR (CDCl3) d 1.41–2.13 (m, 7H),
2.95 (m, 1H), 4.02 (m, 1H, H4), 4.82 (bs, 2H, CH2CCl3),
5.11 (ddd, JZ17.2, 2.2, 1.2 Hz, 1H, H2), 5.19 (ddd, JZ
10.5, 2.2, 1.2 Hz, 1H, H1), 5.78 (ddd, JZ17.2, 10.5, 4.5 Hz,
1H, H3); 13C NMR (CDCl3) d 23.6, 25.8, 31.4, 44.2, 53.8,
74.8, 77.2, 115.7, 139.0, 154.8; HRMS (ES Cve) calcd for
C10H Cl3NO2CH: 286.0163; found: 286.0169.
35
14
5.4.6. 2,2,2-Trichloroethyl 2-vinylpyrrolidine-1-carbox-
ylate (10). In a similar manner to that described above for
the synthesis of 9, N-benzyl-2-vinylpyrrolidine (1.25 g,
6.68 mmol), 2,2,2-trichloroethyl chloroformate (1.52 g,
7.20 mmol) and K2CO3 (1.30 g, 9.41 mmol) yielded 10 as
a colourless oil (1.41 g, 5.21 mmol, 71%) 1H NMR (CDCl3)
d 1.45–1.82 (m, 5H), 2.85 (m, 1H), 3.98 (m, 1H, H4), 4.85
(bs, 2H,CH2CCl3), 5.13 (ddd, JZ17.5, 2.2, 1.2 Hz, 1H, H2),
5.21 (ddd, JZ10.5, 2.2, 1.2 Hz, 1H, H1), 5.82 (ddd, JZ
17.5, 10.5, 4.5 Hz, 1H, H3); 13C NMR (CDCl3) d 23.2, 33.5,
48.3, 57.9, 75.5, 77.9, 115.8, 137.8, 155.1; HRMS (ES Cve)
calcd for C9H Cl3NO2CH: 272.0006; found: 271.9998.
35
12
5.4.7. tert-Butyldimethylsilyl 2-tert-butyldimethylsilyl-
oxy 2-phenylethanoate (12). To a stirred solution of 11,
(1.00 g, 6.67 mmol) in acetonitrile at K78 8C was added
2,6-lutidine (1.43 g, 13.3 mmol) and tert-butyldimethylsilyl
triflate (3.52 g, 13.3 mmol). The mixture was stirred for 3 h
at K78 8C. The solvent was then removed under reduced
pressure and the residue partitioned between dichloro-
methane (50 mL) and water (50 mL). The organic fraction
was dried and the solvent removed unde reduced pressure.
The residue was purified by column chromatography (silica
gel, ethyl acetate–petroleum spirit, 1:50), yielding 12 as a
colourless oil (1.98 g, 5.20 mmol, 78%). 1H NMR (CDCl3)
d 0.06 (s, 6H, OSiCH3), 0.08 (s, 6H, COOSiCH3), 1.08 (s,
18H, But), 5.34 (s, 1H, CHOSi), 7.12–7.26, (m, 5H, ArH);
13C NMR (CDCl3) d K6.9, K5.7, 17.2, 18.1, 25.8, 25.9,
84.3, 127.6, 128.8, 129.6, 135.0, 179.0; HRMS (ES Cve)
calcd for C20H36O3Si2C H: 381.2276; found: 381.2281.
5.4.10. 2-(tert-Butyldimethylsilyloxy)-2-phenyl-1-(2-
vinylpyrrolidin-1-yl)ethan-1-one (15). In a similar manner
to that described above for the synthesis of 14, 10 (1.32 g,
4.63 mmol), Zn (powder, 0.5 g, 7.94 mmol), EDCI (0.90 g,
4.71 mmol), DMAP (0.58 g, 4.75 mmol) and 13 (1.20 g,
4.51 mmol) yielded 15 as a colourless oil (0.737 g,
2.13 mmol, 46%). 1H NMR (CDCl3) d 0.08 (s, 6H,
SiCH3), 1.01 (s, 9H, But), 1.61–2.13 (m, 5H), 3.15 (m,
1H), 4.03 (m, 1H, H4), 5.14 (ddd, JZ17.2, 2.2, 1.2 Hz, 1H,
H2), 5.22 (ddd, JZ10.5, 2.2, 1.2 Hz, 1H, H1), 5.45, (s, 1H,
CHOSi), 5.80 (ddd, JZ17.2, 10.5, 4.5 Hz, 1H, H3), 7.19–
7.31 (m, 5H, ArH); 13C NMR (CDCl3) d K5.8, 17.6, 23.3,
25.9, 33.3, 47.1, 55.8, 81.5, 115.8, 127.6, 129.3, 129.8,
136.5, 137.7, 172.3; HRMS (ES Cve) for C20H31NO2SiC
H: 346.2197; found: 346.2191.
5.4.8. 2-tert-Butyldimethylsilyloxy-2-phenylethanoic
acid (13). A solution of 12 (0.50 g, 1.32 mmol) in a 1 M
solution of K2CO3 in methanol–water (1:1, 100 mL) was
stirred at reflux for 1 h. The volume was then reduced to
approximately 30 mL under vacuum at 40 8C. The pH was
then slowly lowered to pH 5 with aqueous HCl (0.5 M) and
the mixture extracted with dichloromethane (3!30 mL).
The solvent was evaporated under reduced pressure to yield
5.4.11. (E)-3-(tert-Butyldimethylsilyloxy)-3,4,7,8,9,10-
hexahydro-3-phenylazecin-2(1H)-one (16). To a stirred
solution of 14 (0.301 g, 0.833 mmol) in refluxing anhydrous
toluene under argon, was added a 1 M solution of lithium
hexamethyldisilazide (LHMDS) in toluene, (1.4 mL,
1.4 mmol) through a rubber septum. The reaction was
stirred at reflux for 3 h. Water (1 mL) was then added and
the solvent removed under reduced pressure. The residue

2664
J. B. Bremner, D. F. Perkins / Tetrahedron 61 (2005) 2659–2665
was purified using column chromatography (neutral
alumina, dichloromethane–ethylacetate–petroleum spirit,
0.5:1:1) yielding 16 as a thick pale yellow oil (0.223 g,
0.617 mmol, 74%) 1H NMR (CDCl3) d 0.08 (s, 6H, SiCH3),
0.99 (s, 9H, But), 1.33 (tt, JZ10, 3.5 Hz, 1H), 1.41–2.18 (m,
8H), 2.52 (dd, JZ10, 3.5 Hz, 1H, H3), 2.77, (dd, JZ10,
3.5 Hz, 1H, H30), 5.18 (ddd, JZ15.5, 10.5, 4 Hz, 1H, H1),
5.35 (ddd, JZ15.5, 10.5, 4 Hz, 1H, H2), 7.20–7.30 (m, 5H,
ArH); 13C NMR (CDCl3) d K5.8, 18.4, 25.8, 27.4, 28.1,
36.3, 43.1, 43.8, 84.5, 127.8, 129.0, 129.3, 130.1, 134.0,
139.0, 175.3; HRMS (ES Cve) calcd for C21H33NO2SiCH:
360.2353; found: 360.2349.
(d, JZ12 Hz, 1H), 5.13 (ddd, JZ17, 10.5, 4 Hz, 1H), 5.28
(ddd, JZ17, 10.5, 4 Hz, 1H), 7.20–7.30 (m, 5H); 13C NMR
(CDCl3) d K5.1, 18.7, 25.8, 32.6, 34.3, 44.9, 45.1, 63.9,
74.3, 125.8, 126.2, 128.0, 128.2, 129.1, 149.9; HRMS (ES)
for C20H33NOSiCH: 332.2404; found: 332.2391.
5.4.15. (E)-1,2,3,4,7,8,9,10-Octahydro-3-phenylazecin-3-
ol (1). To a stirred solution of 18 (0.080 g, 0.22 mmol) in
anhydrous THF (5 mL) was added a 1 M solution of
tetrabutyl ammonium fluoride (TBAF) (0.3 mL, 0.3 mmol).
The reaction was heated to reflux and stirred under nitrogen
for 3 h. The solvent was then removed under reduced
pressure and the residue placed under high vacuum for
several hours at 40 8C. The residue was then partitioned
between dichloromethane (10 mL) and water (30 mL). The
organic phase was washed several times with water (30 mL)
until the 1H NMR spectrum of a representative sample of the
dried organic phase indicated the absence of any tetrabutyl
ammonium salts. The organic phase was collected and dried
and the solvent removed under reduced pressure yielding
pure 1 as a colourless waxy glass (0.0493 g, 0.213 mmol,
5.4.12. (E)-3-(tert-Butyldimethylsilyloxy)-1,3,6,7,8,9-hex-
ahydro-3-phenyl-2H-azonin-2-one (17). In a similar
manner to that described above for the synthesis of 16, 15
(0.281 g, 0.812 mmol) and (LHMDS), (1.4 mL, 1.4 mmol)
yielded 17 as a thick colourless oil, (0.213 g, 6.17 mmol,
76%) 1H NMR (CDCl3) d 0.08 (s, 6H, SiCH3), 0.99 (s, 9H,
But), 1.41–2.18 (m, 6H), 2.52 (dd, JZ10, 3.5 Hz, 1H, H3),
2.77 (dd, JZ10, 3.5 Hz, 1H, H30), 5.18 (ddd, JZ15.5, 10.5,
4 Hz, 1H, H1), 5.35 (ddd, JZ15.5, 10.5, 4 Hz, 1H, H2),
7.20–7.30 (m, 5H, ArH); 13C NMR (CDCl3) d K5.7, 17.7,
27.6, 28.2, 36.5, 43.1, 43.5, 84.8, 128.0, 129.1, 129.7, 130.3,
134.2, 139.2, 175.2; HRMS (ES Cve) calcd for
C20H31NO2Si C H: 346.2197; found: 346.2198.
1
94%). H NMR (CDCl3) d 1.31 (tt, JZ10, 3.5 Hz, 1H),
1.38–2.13 (m, 8H), 2.51 (dd, JZ10, 3.5 Hz, 1H), 2.65 (d,
JZ12 Hz, 1H) 2.78, (dd, JZ10, 3.5 Hz, 1H) 3.13 (d, JZ
12 Hz, 1H), 5.10 (ddd, JZ17, 10.5, 4 Hz, 1H), 5.28 (ddd,
JZ17, 10.5, 4 Hz, 1H), 5.40 (bs, 1H), 7.20–7.30 (m, 5H);
13C NMR (CDCl3) d 27.7, 28.4, 36.4, 43.8, 44.2, 63.0, 80.2,
126.1, 126.3, 128.2, 130.4, 133.1, 149.9; HRMS (ES Cve)
calcd for C15H21NOC H: 232.1696; found: 232.1688.
5.4.13. (E)-3-(tert-Butyldimethylsilyloxy)-1,2,3,4,7,8,9,
10-octahydro-3-phenylazecine (18). To a stirred solution
of 16 (0.120 g, 0.333 mmol) in anhydrous THF (15 mL) at
0 8C, was added drop wise a 70% solution of sodium bis(2-
methoxyethoxy) aluminium hydride in toluene (Red-Alw)
(0.124 g, 0.733 mmol) through a rubber septum. The
reaction mixture was heated to reflux and stirred for 3 h
under an atmosphere of nitrogen gas. The reaction was
quenched with iced water (10 mL) followed by cold
aqueous 1 M NaOH (30 mL) the mixture was then filtered
over a bed of celite and the solid residue washed several
times with hot chloroform. The two-phased supernatant was
partitioned in a separating funnel and the organic phase was
collected, dried and the solvent removed in vacuo. The
resulting dark yellow residue was purified by column
chromatography (neutral alumina, methanol–dichloro-
methane–concd NH4OH, 1:10:0.01) yielding 18 as a
colourless oil (0.0874 g, 0.253 mmol, 76%); 1H NMR
(CDCl3) d 0.07 (s, 6H), 1.02 (s, 9H), 1.32 (tt, JZ10,
3.5 Hz, 1H), 1.38–2.03 (m, 8H), 2.54 (dd, JZ10, 3.5 Hz,
1H), 2.68 (d, JZ12 Hz, 1H) 2.81, (dd, JZ10, 3.5 Hz, 1H)
3.11 (d, JZ12 Hz, 1H), 5.13 (ddd, JZ17, 10.5, 4 Hz, 1H),
5.28 (ddd, JZ17, 10.5, 4 Hz, 1H), 7.20–7.30 (m, 5H); 13C
NMR (CDCl3) d K5.1, 18.8, 25.8, 27.2, 28.5, 36.3, 43.9,
45.2, 64.0, 74.5, 126.0, 126.2, 128.5, 130.3, 133.1, 150.0;
HRMS (ES) for C21H35NOSiCH: 346.2561; found:
346.2568.
5.4.16. (E)-2,3,6,7,8,9-Hexahydro-3-phenyl-1H-azonin-
3-ol (2). In a similar manner to that described above for
the synthesis of 1, 19 (0.061 g, 0.184 mmol) and TBAF
(1 M THF solution, 0.3 mL, 0.3 mmol) yielded 2 as a
1
colourless waxy glass; (0.0360 g, 0.165 mmol, 90%). H
NMR (CDCl3) d 1.42–2.23 (m, 7H), 2.53 (dd, JZ10,
3.5 Hz, 1H), 2.65 (d, JZ12 Hz, 1H) 2.82, (dd, JZ10,
3.5 Hz, 1H) 3.18 (d, JZ12 Hz, 1H), 5.10 (ddd, JZ17, 10.5,
4 Hz, 1H), 5.28 (ddd, JZ17, 10.5, 4 Hz, 1H), 5.67 (bs, 1H),
7.20–7.30 (m, 5H); 13C NMR (CDCl3) d 32.2, 34.4, 44.1,
44.9, 63.3, 78.0, 126.0, 126.2, 128.4, 128.8, 129.9, 149.9.
HRMS (ES) for C14H19NOCH: 218.1539; found:
218.1531.
5.4.17. (E)-3,4,7,8,9,10-Hexahydro-3-hydroxy-3-phenyl-
azecin-2(1H)-one (21). In a similar manner to that
described above for the synthesis of 1, 16 (0.082 g,
0.228 mmol) and TBAF (1 M THF solution, 0.3 mL,
0.3 mmol) yielded 21 as a cream coloured waxy glass
1
(0.051 g, 0.207 mmol, 91%). H NMR (CDCl3) d 1.33 (tt,
JZ10, 3.5 Hz, 1H), 1.38–2.13 (m, 7H), 2.53 (dd, JZ10,
3.5 Hz, 1H), 2.81, (dd, JZ10, 3.5 Hz, 1H), 5.10 (ddd, JZ
15, 10, 4 Hz, 1H), 5.28 (ddd, JZ15, 10, 4 Hz, 1H), 5.62 (bs,
1H), 7.10–7.25 (m, 5H), 7.50 (bs, 1H); 13C NMR (CDCl3) d
27.3, 28.0, 36.3, 42.4, 43.9, 88.2, 127.7, 129.3, 129.7, 130.1,
133.8, 139.0, 175.7; HRMS (ES Cve) calcd for
C15H19NO2CH: 246.1489; found: 246.1481.
5.4.14. (E)-3-(tert-Butyldimethylsilyloxy)-2,3,6,7,8,9-
hexahydro-3-phenyl-1H-azonine (19). In a similar manner
to that described above for the synthesis of 18, 16 (0.11 g,
0.318 mmol) and Red-Al (70% solution in toluene, (0.120 g,
0.709 mmol) yielded 19 as a colourless oil (0.076 g,
5.4.18. (E)-1,3,6,7,8,9-Hexahydro-3-hydroxy-3-phenyl-
2H-azonin-2-one (22). In a similar manner to that described
above for the synthesis of 1, 17 (0.075 g, 0.217 mmol) and
tetrabutyl ammonium fluoride (1 M THF solution, 0.3 mL,
0.3 mmol) yielded 22 as a cream coloured waxy glass
1
0.23 mmol, 72%); H NMR (CDCl3) d 0.07 (s, 6H), 1.02
(s, 9H), 1.32–2.03 (m, 6H), 2.54 (dd, JZ10, 3.5 Hz, 1H),
2.68 (d, JZ12 Hz, 1H) 2.81, (dd, JZ10, 3.5 Hz, 1H) 3.11

J. B. Bremner, D. F. Perkins / Tetrahedron 61 (2005) 2659–2665
2665
(0.045 g, 0.194 mmol, 89%). 1H NMR (CDCl3) d 1.55–2.23
(m, 6H), 2.53 (dd, JZ10, 3.5 Hz, 1H), 2.81, (dd, JZ10,
3.5 Hz, 1H), 5.15 (ddd, JZ15, 10, 3.5 Hz, 1H), 5.38 (ddd,
JZ15, 10, 3.5 Hz, 1H), 5.62 (bs, 1H), 7.10–7.25 (m, 5H)
7.43 (bs, 1H); 13C NMR (CDCl3) d 31.76, 34.21, 42.38,
46.34, 87.91, 127.32, 127.72, 128.65, 129.31, 129.78,
139.13, 175.38; HRMS (ES) for C14H17NO2CH:
232.1332; found: 232.1340.
128.6, 140.6; HRMS (ES Cve) calcd for C15H21NOCH:
232.1696; found: 232.1692.
Acknowledgements
The authors gratefully acknowledge the NHMRC for
financial support for this project.
5.4.19. 1,3,4,6,7,8,9,9a-Octahydro-3-(tert-butyldimethyl-
silyloxy)-3-phenyl-2H-quinolizine (20). To a stirred solu-
tion of 16 (0.120 g, 0.333 mmol) in anhydrous THF (15 mL)
at 0 8C, was added lithium aluminium hydride (0.032 g,
0.830 mmol). The reaction mixture was heated to reflux and
stirred for 3 h under an atmosphere of nitrogen gas. The
reaction was quenched with iced water (10 mL) followed by
cold aqueous 1 M NaOH (30 mL) the mixture was then
filtered over a bed of celite and the solid residue washed
several times with hot chloroform. The two-phased
supernatant was partitioned in a separating funnel and the
organic phase was collected, dried and evaporated. The
resulting dark yellow residue was purified by column
chromatography (neutral alumina, methanol–dichloro-
methane–concd NH4OH, 1:10:0.01) yielding 20 as a
colourless oil (0.0874 g, 0.253 mg, 76%); 1H NMR
(CDCl3) d 0.08 (s, 6H), 1.06 (s, 9H), 1.25–2.45 (m, 13H),
2.56 (d, JZ12 Hz, 1H), 2.83, (d, JZ12 Hz, 1H), 7.17–7.35
(m, 5H); 13C NMR (CDCl3) d K5.0, 22.5, 23.8, 25.8, 26.3,
31.5, 37.5, 52.6, 63.1, 64.0, 68.1, 126.1, 128.3, 128.6, 140.6;
MS (CI Cve) m/z 346 (MCH).
References and notes
1. Perez, D. M.; Hwa, J.; Gaivin, R.; Methur, M.; Brown, F.;
Graham, R. M. Mol. Pharmacol. 1996, 49, 112–122.
2. Lindstrom, U. M.; Somfai, P. Chemistry 2001, 7, 94–98.
3. Suh, Y.-G.; Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.; Min, K.-H.;
Koo, B.-A.; Kim, H.-S. Angew. Chem., Int. Ed. 1999, 38,
3545–3547.
4. Suh, Y.-G.; Lee, J.-Y.; Kim, S.-A.; Jung, J.-K. Synth. Commun.
1996, 26, 1675–1680.
5. Katritzky, A. R.; Yao, J.; Yang, B. J. Org. Chem. 1999, 64,
6066–6070.
6. Cohen, H. L.; Minsk, L. M. J. Am. Chem. Soc. 1957, 79,
1759–1762.
7. Arrendo, V. M.; McDonald, F. E.; Marks, T. J. J. Am. Chem.
Soc. 1998, 120, 4871–4872.
8. Spartan ’02; Wavefunction Inc., 2002.
9. Dewar, M. J. S.; Zoebisch, E. G.; Healey, E. F.; Stewart, J. J. P.
J. Am. Chem. Soc. 1985, 107, 3902–3909.
5.4.20. 1,2,3,6,7,8,9,9a-Octahydro-3-phenyl-2H-quinoli-
zin-3-ol (23). In a similar manner to that described above
for the synthesis of 1, 20 (0.058 g, 0.161 mmol) and
tetrabutyl ammonium fluoride (1 M THF solution, 0.2 mL,
0.2 mmol) yielded 23 as a cream coloured waxy glass
(0.035 g, 0.151 mmol, 94%). 1H NMR (CDCl3) d 1.25–2.45
(m, 13H), 2.53 (d, JZ12 Hz, 1H), 2.81, (d, JZ12 Hz, 1H),
4.62 (bs, 1H), 7.17–7.35 (m, 5H); 13C NMR (CDCl3) d 22.7,
23.6, 26.2, 31.5, 37.5, 52.7, 63.1, 63.6, 71.8, 126.1, 128.3,
10. Bottoni, A.; Lombardo, M.; Neri, A.; Trombini, C. J. Org.
Chem. 2003, 68, 3397–3405.
11. Dyer, J.; King, A.; Keeling, S.; Moloney, M. G. Perkin Trans.
1 2000, 2793–2804.
12. Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209–213.
13. Hayat, S.; Atta-ur-Rahman; Choudhary, M. I.; Khan, K. M.;
Schumann, W.; Bayer, E. Tetrahedron 2001, 57, 9951–9957.
14. Zhou, J. Q.; Alper, H. J. Org. Chem. 1992, 57, 3328–3331.