Tricyclic-isoxazolidine analogues via intramolecular 1,3-dipolar cycloaddition reactions of nitrones

Article abstract of DOI:10.1016/j.tet.2010.01.062

The tricyclic-isoxazolidine analogues tetrahydrothiochromenoisoxazoles, hexahydroisoxazolequinolines and tetrahydroisoxazolepyranopyridines were prepared by an intramolecular 1,3-dipolar cycloaddition reaction of a nitrone with an alkene. For N-alkylated hexahydroisoxazolequinolines, reduction of the reaction time from two days to 40 min was achieved using microwave heating. The cyclization to form tetrahydroisoxazolepyranopyridines only proceeded when the alkene was substituted with an electron withdrawing group.

Full text of DOI:10.1016/j.tet.2010.01.062

Tetrahedron 66 (2010) 2761–2767
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tricyclic-isoxazolidine analogues via intramolecular 1,3-dipolar cycloaddition
reactions of nitrones
,
a
a
a
a
Simon Saubern a , James M. Macdonald , John H. Ryan , Ruth C.J. Woodgate , Theola S. Louie ,
*
Matthew J. Fuchter a y, Jonathan M. White b, Andrew B. Holmes a
,
,b
a CSIRO Molecular and Health Technologies, Bag 10, Clayton South, VIC 3169, Australia
b School of Chemistry, Bio21 Institute, University of Melbourne, Parkville, VIC 3010, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The tricyclic-isoxazolidine analogues tetrahydrothiochromenoisoxazoles, hexahydroisoxazolequinolines
and tetrahydroisoxazolepyranopyridines were prepared by an intramolecular 1,3-dipolar cycloaddition
reaction of a nitrone with an alkene. For N-alkylated hexahydroisoxazolequinolines, reduction of the
reaction time from two days to 40 min was achieved using microwave heating. The cyclization to form
tetrahydroisoxazolepyranopyridines only proceeded when the alkene was substituted with an electron
withdrawing group.
Received 2 September 2009
Received in revised form 10 December 2009
Accepted 18 January 2010
Available online 28 January 2010
Keywords:
1,3-Dipolar cycloaddition
Nitrones
Ó 2010 Elsevier Ltd. All rights reserved.
Isoxazoles
1. Introduction
Novel ring systems in natural products, such as Martinelline 1
often inspire synthetic chemists to extend the series or prepare
new ring systems.1 The fused pyrrolo-quinoline in alkaloid 1 shares
structural similarity with the chromenoisoxazoles that have found
use in a number of fields. For example, the dihydrochromenoisox-
azoles have shown a range of biological activity, such as selective
serotonin reuptake inhibitors and a2-adrenoceptor antagonists,2
whereas the tetrahydrochromenoisoxazoles 2 have been used
successfully by Masamune as chiral auxiliaries in asymmetric nat-
ural product synthesis.3
We were therefore surprised to find no reports of the preparation
of derivatiseable analogues, such as the tetrahydrothiochro-
menoisoxazoles 3, nor of analogues with heteroaromatic rings
(structure 4). The hexahydroisoxazolequinoline 5 analogue had been
prepared only as its N-methyl derivative by Oppolzer and Keller in
1970,4 and recently bearing an N-chiral auxilary by Broggini et al.5
We herein report our flexible approach to these ring systems using
an intramolecular 1,3-dipolar cycloaddition reaction of a nitrone
with an alkene group (Fig. 1).
Figure 1. Structures of Martinelline 1 and isoxazolidine analogues 2–5.
2. Results and discussion
2.1. Synthesis of tetrahydrothiochromenoisoxazoles
* Corresponding author. Tel.: þ61 3 9545 2222.
E-mail address: simon.saubern@csiro.au (S. Saubern).
Present address: Department of Chemistry, Imperial College London, London
N-Substituted tetrahydrochromenoisoxazoles 2 have been pre-
pared using 1,3-dipolar cycloaddition reactions of the nitrone
formed from condensing a suitable aldehyde with N-substituted
y
SW7 2AZ, UK
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doi:10.1016/j.tet.2010.01.062

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S. Saubern et al. / Tetrahedron 66 (2010) 2761–2767
hydroxylamines.4 We anticipated that the sulfur series 3 would also
be available by this approach (Scheme 1).
Table 1
Tetrahydrothiochromenoisoxazole yields and characterizationa
Compound
R1
R2
Yield (%)
HRMS (m/z)
[Mþ
]
Calc
[Mþ]Obs
10a
10b
10c
10d
11a
11b
11c
11d
12a
12b
12c
12d
13a
13b
13c
13d
H
H
H
H
Me
93
76
90
92
95
84
78
92
85
39
74
90
87
52
59
91
207.0712
235.1025
275.1338
283.1025
284.9804
313.0117
353.0430
361.0128
237.0818
265.1131
305.1417
313.1131
241.0323
269.0636
309.0949
317.0627
207.0710
235.1025
275.1335
283.1026
284.9801
313.0123
353.0436
361.0123
237.0822
265.1129
305.1421
313.1132
241.0325
269.0636
309.0942
317.0627
iPr
cyclohexyl
Bn
8-Br
8-Br
8-Br
8-Br
7-MeO
7-MeO
7-MeO
7-MeO
9-Cl
9-Cl
9-Cl
9-Cl
Me
iPr
cyclohexyl
Bn
Me
iPr
cyclohexyl
Bn
Me
iPr
Scheme 1. Retrosynthesis of tetrahydrothiochromenoisoxazoles.
cyclohexyl
Bn
The utility of this approach would then depend on accessing
a range of 2-alkenylthiobenzaldehydes. These thioethers could be
prepared readily using two approaches. The first approach that we
considered (Route A, Scheme 1) was the alkylation of thiosalicyl-
aldehydes with allylbromide. Production of tetrahydrothio-
chromenoisoxazoles would then be limited to the availability of
substituted thiosalicylaldehydes.
a
Purity of samples determined to be >95% by 1H NMR spectroscopy.
constant J 8 Hz between H3a and H9b in the 1H NMR spectra, similar
in value to the corresponding 7 Hz coupling reported for Martinel-
line 1 itself.1
Preparation of tetrahydrothiochromenoisoxazoles in this man-
ner is limited by the poor range of commercially available hy-
droxylamines. Oppolzer had tried using hydroxylamine to produce
the parent tetrahydrochromenoisoxazole 2 but with poor yield.4
Abiko used 5-hydroxypentanal oxime 14 for the in situ formation
of N-(2-tetrahydropyranyl)hydroxylamine 15. This forms a nitrone
in the presence of catalytic dibutyltin oxide that undergoes the
desired 1,3-dipolar cyclization to provide the isoxazolidine ring
system 2 as its N-tetrahydropyranyl derivative.11
When we applied this method to the tetrahydrothio-
chromenoisoxazole series (Scheme 3), we found that the tetrahy-
dropyranyl derivative 16c could be obtained onprolonged heating of
8 and 5-hydroxypentanal oxime 14. Mild acidic hydrolysis provided
the N-unsubstituted tetrahydrothiochromenoisoxazole 17c in ex-
cellent yields. Similarly, when benzaldehydes 6, 7 and 9 were sub-
jected to the same process, tetrahydrothiochromenoisoxazoles
17a,b and d were obtained. Derivatization of the unprotected ni-
trogen could then provide access to analogues not available from
N-substituted hydroxylamines. For example, 17b was acetylated to
form 18.
Recent work by Wemple described robust conditions for the
Newman–Kwart rearrangement of phenols to thiophenols.6 This
approach had in earlier work allowed us to prepare a number of
novel thiosalicylic acids from substituted salicylic acids,7 and these
acids could in principle be used to prepare the desired thio-
salicylaldehydes. However, during the earlier work we observed
variable yields with several ortho-substituted thiophenols, and
hence looked elsewhere for our current thioether synthesis.
The second approach investigated (route B, Scheme 1) was the
nucleophilic aromatic substitution of variously substituted 2-fluo-
robenzaldehydes with allyl mercaptan.8 This approach gave consis-
tently high yields across a variety of substrates. In this way we were
able to prepare the S-allyl-2-thiobenzaldehydes 6–9 shown in
Scheme 2.
Scheme 2. Reagents: (i) allyl mercaptan, K2CO3, DMF; (ii) R2NHOH, Et3N, PhCH3,
reflux, 2.5 days.
Each of the 2-(allylthio)benzaldehydes 6–9 were reacted with
methylhydroxylamine, isopropylhydroxylamine, cyclohexylhydro-
xylamine and benzylhydroxylamine as their hydrochloride salts in
the presence of triethylamine in refluxing toluene for two days. A
small amount of methanol could be added as a final component to
improve solubility of the hydroxylamine hydrochlorides used in
these reactions.9 All 16 reactions could be conveniently conducted
in parallel using Radleys Carousels.10 The reaction mixtures were
absorbed onto a small cartridge of silica, washed with hexanes to
remove highly non-polar material, then with ethyl acetate to elute
the tetrahydrothiochromenoisoxazoles 10–13 in high yield
(Table 1).
Scheme 3. (a) R1¼H, (b) R1¼8-Br, (c) R1¼7-MeO, (d) R1¼9-Cl. Reagents: (i) Bu2SnO,
The tetrahydrothiochromenoisoxazoles produced in this manner
were racemic and with cis-ring fusion, as indicated by a coupling
PhCH3; (ii) aq HCl, MeOH, 61–82% (two steps); (iii) Ac2O, pyridine, CH2Cl2, 96%.

S. Saubern et al. / Tetrahedron 66 (2010) 2761–2767
2763
2.2. Synthesis of hexahydroisoxazolequinolines
Kappe has developed specialized silicon carbide plugs for this pur-
pose,15 but we found that chips were sufficient for our re-
quirements.16 The Boc protected hexahydroisoxazolequinoline 26
was obtained in 84% yield after workup and purification.
While microwave heating was suitable for the N-alkylated an-
alogues, preparation of the N-tetrahydropyranyl analogue 27 by
similar means resulted in extensive decomposition. Returning to
conventional heating in toluene at 110 ꢀC in the presence of cata-
lytic dibutyltin oxide, followed by hydrolysis of the two protecting
groups, afforded the hexahydroisoxazolequinoline parent ring
system 5 in 74% yield over the two steps.
To form hexahydroisoxazolequinoline 5, we initially in-
vestigated the approach in Scheme 4, similar to that for the thio-
chromenoisoxazoles beginning with 2-fluorobenzaldehyde 19. The
use of diallylamine 20 would provide both an allyl group as
a dipolarophile and a second allyl group as a nitrogen protecting
group. Microwave heating in a sealed vial of the benzaldehyde and
diallylamine in DMF in the presence of potassium carbonate
formed no discernable products for temperatures below 220 ꢀC. At
220 ꢀC some decomposition occurred, but a major component
could be isolated after considerable purification. The 1H NMR
spectrum of this product contained no aldehyde signal and signals
for only one allyl group. Further investigation of the NMR and mass
spectra revealed the product to be the oxo-benzazepine 22 formed
via a cascade keto-ene/cyclization reaction of 21. Jones and Brin-
son12 have reported similar transformations for benzophenones
and acetophenones, but with a much lower temperature for the
formation of the aniline. Under our conditions, we were unable to
observe the formation of aniline 21 without concurrent cyclization
to give 22.
2.3. Synthesis of tetrahydroisoxazolepyranopyridines
Based on some recently reported quinoline work,17 we envis-
aged that the tetrahydroisoxazolepyranopyridine analogues
4
would be available via the route shown in Scheme 6. Beginning
with 2-chloropyridine-3-carbaldehyde 28, the allyl ether 29 was
formed by substitution of the chloride with the sodium allyl alk-
oxide. While the allyl ether 29 could be seen to undergo nitrone
formation of 30 from the distinctive loss of the aldehyde signal in
the 1H NMR spectrum at
d
d
10.5 and appearance of a nitrone signal at
8.5,4 we could not effect the cyclization by either conventional or
microwave heating.
Scheme 4. Reagents and conditions: (i) K2CO3, DMF, 220 ꢀC, MW, 20%.
The hexahydroisoxazolequinoline analogues were prepared in-
stead from 2-aminobenzylalcohol 23 by selectively protecting the
amine as its tert-butylcarbamate (Scheme 5).13 Oxidation of the
alcohol to afford the aminobenzaldehyde 24 has been reported
several times and we found Shapiro’s protocol using MnO2 most
consistent.14 An allyl group was introduced by using allylbromide
and sodium hydride as base to give 25.
Scheme 6. Reagents: (i) allyl alcohol, NaH, (ii) alkylhydroxylamine.
We reasoned that a pyridine group is electron deficient relative
to a phenyl group and that this may cause lowering of the
HOMOnitrone, that in turn would cause a greater energy difference
between the LUMOalkene and the HOMOnitrone relative to the phenyl
series, presuming this is a normal electron-demand reaction.18
Attachment of an electron withdrawing group to the alkene
would result in a lowering of the LUMOalkene energy and a re-
duction of the HOMO/LUMO energy gap. A convenient approach to
a model substrate was a cross-metathesis (CM) reaction between
methyl acrylate and pyridine allyl ether 29, but we were unable to
effect CM reactions on this substrate.19
An alternative route was sought beginning by hydrolyzing the
2-chloropyridine-3-carbaldehyde 28 (Scheme 7) to give pyridinone
31. We found that microwave heating provided gram quantities of
the desired pyridinone 31 in 10 min and near quantitative yield.
Selective O-alkylation to form the ether 32 using ethyl 4-bromoc-
rotonate was achieved by using silver carbonate in toluene.20 Other
bases and solvents surveyed afforded only the N-alkylated material
or a mixture of both N- and O-alkylated pyridinone.
Treatment of pyridine crotonate ether 32 with N-cyclo-
hexylhydroxylamine hydrochloride in toluene at 130 ꢀC with mi-
crowave heating afforded the tetrahydroisoxazolepyranopyridine
33 in 65% yield after chromatography.
Scheme 5. Reagents: (i) (Boc)2O, DCE; (ii) MnO2, CH2Cl2, 66% (two steps); (iii) allyl-
bromide, NaH, DMF, 91%; (iv) N-cyclohexylhydroxylamine hydrochloride, Et3N, PhCH3,
84%; (v) 5-hydroxypentanal oxime, Bu2SnO, PhCH3; (vi) aq HCl, MeOH; (vii) Amberlite
IR-45, MeOH, 74% (three steps).
The N,N-disubstituted aminobenzaldehyde 25 and cyclo-
hexylhydroxylamine hydrochloridewere heated to170 ꢀC in toluene
using microwave heating for 40 min. These higher temperatures for
toluene could be achieved by the addition of silicon carbide chips
into the reaction as a passive absorber of microwave radiation.
The X-ray crystal structure of 33 (Fig. 2) shows an almost
L-shaped ring system formed by cis-ring fusion between the pyr-
anopyridine rings and the isoxazolidine ring.21

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S. Saubern et al. / Tetrahedron 66 (2010) 2761–2767
Mass spectra positive ion EI mass spectra were recorded on
a ThermoQuest MAT95XL mass spectrometer using an ionization
energy of 70 eV. Accurate mass measurements were obtained with
a resolution of 5000–10,000 using PFK as the reference compound.
Positive and negative ion APCI mass spectra were acquired with a VG
Platform mass spectrometer using a cone voltage of 50 V and the
source was maintained at 100 ꢀC. Nitrogen was used as the nebulizer
and sheath gas and the probe temperature was 400 ꢀC. The solvent
system used was methanol with a flow rate of 0.3 ml minꢁ1
.
Infrared spectra were recorded on a Perkin–Elmer 842 spectro-
photometer as neat films between two sodium chloride plates, or as
discs with potassium bromide as the matrix.
Melting points were determined using an Electrothermal 9300
melting point apparatus and are uncorrected.
Microanalyses were determined by the Campbell Microanalyti-
cal Laboratory, Department of Chemistry University of Otago, New
Zealand.
Scheme 7. Reagents: (i) cat. HCl, cat. H2O2, H2O, MW, 98.5%; (ii) Ag2CO3, ethyl
4-bromocrotonate, PhCH3, 82%; (iii) N-cyclohexylhydroxylamine hydrochloride, Et3N,
PhCH3, 65%.
Figure 2. Chem3D produced image of the X-ray structure of 33:21 (a) side view; (b) oblique view.
3. Conclusions
Chromatography was carried out on silica gel [Merck 9385 Kie-
selgel 60 (230–400 ASTM)] or reverse phase C-18 silica gel [Fuji
Silysia Chemicals Chromatorex ODS 100–200 mesh]. Solvent sys-
tems for flash chromatography were chosen to provide Rf¼0.35 as
preferred by Still et al.,22 unless otherwise recorded.
Solvents were dried using a Solvent Dispensing System (Seca
Solvent Systems). Reagents were used as obtained from the sup-
plier. Brine refers to a saturated solution of sodium chloride in
water. DMF refers to N,N-dimethylformamide. DMSO refers to di-
methyl sulfoxide.
We have here demonstrated the utility of the intramolecular
1,3-dipolar cycloaddition reaction in constructing novel iso-
xazolidines as analogues of 1, including the first report of the tet-
rahydroisoxazolepyranopyridine ring system. The use of oxime 14
allows for ready access to the parent isoxazolidine and allows for
easy analoguing around the core ring system.
4. Experimental
4.1. General experimental
4.2. General procedure for allylthio ether formation
Microwave reactions were conducted in a Biotage Initiator-60
(300 W or 400 W) microwave oven in sealed glass vials. Reaction
duration was timed from the point the reaction reached the
recorded temperature.
4.2.1. 2-(Allylthio)benzaldehyde (6)23. 2-Fluorobenzaldehyde (3 g,
24.2 mmol) and allyl mercaptan (3.58 g, 60%, 48.4 mmol) in DMF
(15 ml) were treated with potassium carbonate. The reaction mix-
ture was heated to 55 ꢀC overnight. On cooling to room temperature,
the reaction was poured into water and extracted with ethyl acetate.
The organic extract was washed once with water, then brine, dried
(MgSO4) and concentrated. Flash chromatography using ethyl ace-
tate–petroleum spirits (4:96) as eluant provided 2-(allylth-
io)benzaldehyde (1.91 g, 44%) as an oil. dH (400 MHz) 10.38 (s, 1H),
7.81 (dd, J 7.6,1.5,1H), 7.48 (t, J 7.6,1H), 7.41 (d, J 7.9,1H) 7.29 (dd, J 7.4,
1H), 5.86 (m, 1H), 5.15 (dm, J 17.0, 1H), 5.10 (dm, J 10.0, 1H), 3.56 (d, J
6.8, 2H); m/z (EI) C10H10OSþ requires 178.0447, found 178.0445.
1H NMR and 13C NMR spectra were recorded on Bruker DRX-500
(500 or 125 MHz), AV-400 (400 or 100 MHz), or AV-200 (200 or
50 MHz) instruments using an internal deuterium lock in chloro-
form-d1 at room temperature, unless otherwise recorded. The
chemical shift data for each signal is given in units
d relative to
tetramethylsilane and referenced to the residual solvent. Coupling
constants (J) are quoted in hertz. A doublet of multiplets is desig-
nated by ‘dm’. Many of the signals in the 13C NMR spectra for
compounds 17a,b,d and 5 were absent when the spectra were
recorded at room temperature. Recording spectra for 17a,b and d at
55 ꢀC, and at 5 ꢀC for 5 caused sufficient line narrowing to occur so
that all signals could be observed.
4.2.2. 2-(Allylthio)-5-bromobenzaldehyde (7). Oil. Yield 3.86 g
(77%). dH (400 MHz) 10.34 (s, 1H), 7.94 (d, J 2.3, 1H), 7.60 (dd, J 8.4,

S. Saubern et al. / Tetrahedron 66 (2010) 2761–2767
2765
2.3, 1H), 7.31 (d, J 8.5, 1H), 5.84 (m, 1H), 5.09–5.16 (m, 2H), 3.55 (d, J
6.9, 2H); m/z (EI) C10H9BrOSþ requires 255.9552, found 255.9551.
compound (0.83 g, 78%) as an oil. 1H NMR indicated a purity >95%.
dH (500 MHz, 55 ꢀC) 7.42 (d, J 7.35, 1H), 7.29 (dd, J 7.6, 1.4, 1H), 7.18
(dt, J 7.6, 1.7, 1H), 7.14 (dt, J 7.4, 1.5, 1H), 5.14 (br s, 1H), 4.42 (t, J 7.9,
1H), 4.35 (d, J 8.2, 1H), 3.88 (dd, J 8.4, 6.2, 1H), 3.19 (m, 1H), 2.90 (dd,
J 13.4, 4.7, 1H), 2.64 (dd, J 13.4, 6.5, 1H); dC (125 MHz, 55 ꢀC) 134.79,
132.17 (br), 130.60 (br), 128.80, 128.06, 125.96, 75.57, 62.28 (br),
43.67 (br), 30.54; m/z (EI) C10H11NOSþ requires 193.0556, found
193.0560.
4.2.3. 2-(Allylthio)-4-methoxybenzaldehyde (8). Oil. Yield 4.81 g
(86%). dH (400 MHz) 10.16 (s, 1H), 7.75 (d, J 8.6, 1H), 6.87 (d, J 2.4,
1H), 6.77 (dd, J 8.6, 2.4, 1H), 5.88 (m, 1H), 5.23 (dm, J 17.0, 1H), 5.14
(dm, J 10.1, 1H), 3.85 (s, 3H), 3.57 (d, J 6.7, 2H); m/z (EI) C11H12O2Sþ
requires 208.0553, found 208.0549.
4.2.4. 2-(Allylthio)-6-chlorobenzaldehyde (9). Oil. Yield 2.50 g
(45%). dH (400 MHz) 10.60 (s, 1H), 7.36 (t, J 8.0, 1H), 7.26 (d, J 8.1, 1H),
7.20 (d, J 7.8, 1H), 5.89 (m, 1H), 5.33 (dm, J 17.0, 1H), 5.20 (dm, J 10.1,
1H), 3.59 (d, J 6.6, 2H); m/z (EI) C10H9ClOSþ required 212.0057,
found 212.0054.
4.4.2. 8-Bromo-3,3a,4,9b-tetrahydro-1H-thiochromeno[4,3-c]iso-
xazole (17b). The benzaldehyde 7 (1.66 g, 6.5 mmol), 5-hydrox-
ypentanal oxime 14 (0.91 g, 7.8 mmol) and dibutyltin oxide (30 mg)
in toluene (250 ml) were heated in a Dean–Stark trap overnight.
The reaction was processed as above for 17c, providing the title
compound (1.44 g, 82%) as an oil. 1H NMR indicated a purity >95%.
dH (500 MHz, 55 ꢀC) 7.62 (s, 1H), 7.31 (dd, J 8.3, 2.1, 1H), 7.17 (d, J 8.3,
1H), 5.15 (br s,1H), 4.40 (m,1H), 4.32 (d, J 8.3,1H), 3.88 (dd, J 8.4, 6.1,
1H), 3.23 (m, 1H), 2.93 (dd, J 13.4, 4.7, 1H), 2.63 (dd, J 13.4, 6.9, 1H);
dC (125 MHz, 55 ꢀC) 134.70 (br), 134.11, 131.12 (br), 130.19, 127.13
(br), 119.45, 75.72, 61.89 (br), 43.80 (br), 30.60; m/z (EI)
C10H10BrNOSþ requires 270.9667, found 270.9822.
4.3. General procedure for N-substituted tetrahydrothiochro-
menoisoxazoles: 1-cyclohexyl-7-methoxy-3,3a,4,9b-
tetrahydro-1H-thiochromeno[4,3-c]isoxazole (12c)
The benzaldehyde 8 (220 mg, 1.06 mmol), cyclohexylhydro-
xylamine hydrochloride (288 mg, 1.90 mmol) and triethylamine
(0.5 ml) in toluene (6 ml) were treated with methanol (0.5 ml) and
heated to reflux for 2.5 days. The reaction was concentrated to
a yellow paste, dissolved in ethyl acetate–petroleum spirits (1:4)
and filtered through a small plug of silica using ethyl acetate–
petroleum spirits (1:4) as eluant. The filtrate was concentrated to
afford the title compound (238 mg, 74%) as a solid. Mp 122–
124 ꢀC; nmax/cmꢁ1 3420, 2944, 2850, 1602; dH (400 MHz) 7.40 (d, J
8.6, 1H), 6.80 (d, J 2.6, 1H), 6.72 (dd, J 8.6, 2.7, 1H), 4.21 (d, J 8.5, 1H,
H-9b), 4.13 (t, J 8.2, 1H), 3.87 (dd, J 8.1, 5.4, 1H), 3.77 (s, 3H), 3.38
(tq, J 8.2, 5.3, 1H), 3.09 (dd, J 13.2, 5.1, 1H), 2.63–2.74 (m, 2H), 2.09
(d, J 12.6, 1H), 1.90–1.15 (m, 9H); dC (100 MHz) 158.09 (s), 136.30
(s), 131.45 (d), 127.56 (s), 112.92 (d), 112.54 (d), 69.71 (t), 61.53 (d),
60.88 (d), 55.32 (q), 44.11 (d), 32.02 (t), 30.81 (t), 28.24 (t), 25.98
(t), 25.04 (t), 24.78 (t); m/z (EI) C17H23NO2Sþ requires 305.1417,
found 305.1421.
4.4.3. 9-Chloro-3,3a,4,9b-tetrahydro-1H-thiochromeno[4,3-c]iso-
xazole (17d). The benzaldehyde 9 (1.17 g, 5.5 mmol), 5-hydrox-
ypentanal oxime 14 (0.78 g, 6.0 mmol) and dibutyltin oxide (30 mg)
in toluene (300 ml) were heated in a Dean–Stark trap overnight.
The reaction was processed as above for 17c, providing the title
compound (0.76 g, 61%) as an oil. 1H NMR indicated a purity >95%.
dH (500 MHz, 55 ꢀC) 7.22 (d, J¼8.1,1H), 7.20 (d, J 8.2,1H), 7.10 (t, J 7.9,
1H), 5.29 (br s, 1H), 4.88 (d, J 8.1,1H), 4.41 (t, J 7.8,1H), 3.99 (dd, J 8.3,
6.1, 1H), 3.22 (m, 1H), 2.93 (dd, J 13.5, 4.4, 1H), 2.75 (dd, J 13.3, 4.0,
1H); dC (125 MHz, 55 ꢀC) 137.65, 137.35, 128.73 (br), 128.66, 127.56,
127.44, 74.75, 58.99 (br), 43.26, 30.64 (br); m/z (EI) C10H10ClNOSþ
requires 227.0166, found 227.0166.
4.4.4. 8-Bromo-1-acetyl-3,3a,4,9b-tetrahydro-1H-thiochromeno[4,3-
c]isoxazole (18). A solution of 8-bromo-3,3a,4,9b-tetrahydro-1H-
thiochromeno[4,3-c]isoxazole 17b (27 mg, 0.10 mmol) in dichloro-
methane (5 ml) was treated with acetic anhydride (5 drops) and
pyridine (five drops). The solution was stirred at room temperature
for 1 h, then quenched with water (five drops). After a further
20 min, the reaction mixture was filtered through a plug of silica
using ethyl acetate as eluant to afford the title compound as an oil
(30 mg, 96%). dH (200 MHz) 7.66 (dd, J 2.1, 0.9, 1H), 7.28 (ddd, J 8.3,
2.2, 0.7,1H), 7.13 (d, J 8.3,1H), 5.39 (d, J 8.9,1H), 4.03 (m, 2H), 3.36 (m,
1H), 2.68 (d, J 10.0, 1H), 2.61 (d, J 10.0, 1H), 2.23 (s, 3H); dC (50 MHz)
174.73 (s), 135.67 (s), 133.18 (d), 130.41 (d), 129.73 (d), 128.18 (d),
119.69 (s), 74.74 (t), 55.56 (d), 44.63 (d), 30.15 (t), 20.16 (q); m/z (EI)
C12H12BrNO2Sþ requires 312.9767, found 312.9764.
4.4. General procedure for N-unsubstituted tetrahydrothio-
chromenoisoxazoles: 7-methoxy-3,3a,4,9b-tetrahydro-1H-
thiochromeno[4,3-c]isoxazole (17c)
The benzaldehyde 8 (0.80 g, 4.15 mmol), 5-hydroxypentanal
oxime 14 (535 mg, 4.5 mmol) and dibutyltin oxide (10 mg) in tol-
uene (20 ml) were heated in a Dean–Stark trap for five days. On
cooling, the reaction was filtered through a small pad of silica and
concentrated. The residue was dissolved in ethanol (9 ml) and
treated with aq hydrochloric acid (1 M, 3 ml). The reaction was
stirred at room temperature for two days, then concentrated to
3 ml. The residue was diluted with saturated aq sodium bi-
carbonate, and extracted with ethyl acetate. The combined organic
extracts were dried (MgSO4) and concentrated. Flash chromatog-
raphy using ethyl acetate–petroleum spirits (1:1) afforded the title
compound (626 mg, 68%) as an oil. 1H NMR indicated a purity
>95%. nmax/cmꢁ1 3422, 2940, 2840, 1602; dH (400 MHz) 7.35 (d, J
8.5, 1H), 6.84 (d, J 2.6, 1H), 6.72 (dd, J 8.5, 2.6, 1H), 5.01 (br s, 1H),
4.47 (t, J 8.1, 1H), 4.39 (d, J 8.1, 1H), 3.94 (dd, J 8.4, 6.1, 1H), 3.78 (s,
3H), 3.20 (m, 1H), 2.90 (dd, J 13.5, 4.5, 1H), 2.70 (dd, J 13.5, 6.3, 1H);
dC (50 MHz) 159.26 (s), 135.89 (s), 133.43 (d), 121.73 (br s), 113.61
(d), 112.65 (d), 75.67 (t), 61.80 (d), 55.37 (q), 43.15 (d), 30.46 (t); m/z
(EI) C11H13NO2Sþ requires 223.0662, found 223.0659.
4.4.5. 1-Allyl-2,3,4,5-tetrahydro-1H-2,5-epoxy-1-benzazepine
(22). A solution of 2-fluorobenzaldehyde (124 mg, 1.0 mmol) and
N,N-diallylamine (194 mg, 2.0 mmol) in DMF (2 ml) was treated
with potassium carbonate (140 mg, 1.0 mmol) and sealed in a mi-
crowave vial. The reaction mixture was heated to 220 ꢀC for 50 min,
cooled to room temperature and poured into water (20 ml). The aq
mixture was extracted twice with ethyl acetate, and the combined
organic extracts in turn washed with twice with water and once
with brine. After drying and concentrating, the brown gum
obtained was purified by flash chromatography using ethyl ace-
tate–petroleum spirits (5:95) to afford the title compound as
a yellow oil (40 mg, 20%). dH (200 MHz) 7.11 (dd, J 7.7, 1.7, 1H), 6.91
(dd, J 7.4, 1.7, 1H), 6.70 (dt, J 7.4, 1.1, 1H), 6.66 (d, J 8.2, 1H), 5.94
(dddd, J 17.1, 10.3, 5.5, 4.9, 1H), 5.38–5.12 (m, 3H), 5.03 (m, 1H), 3.91
(tdq, J 16.8, 4.8, 1.7, 2H), 2.28–1.98 (m, 4H); dC (50 MHz) 141.87 (s),
134.79 (d), 128.25 (s), 128.00 (d), 124.25 (d), 117.71 (d), 116.37 (t),
4.4.1. 3,3a,4,9b-Tetrahydro-1H-thiochromeno[4,3-c]isoxazole
(17a). The benzaldehyde 6 (0.98 g, 5.5 mmol), 5-hydroxypentanal
oxime 14 (0.77 g, 6.6 mmol) and dibutyltin oxide (60 mg) in toluene
(300 ml) were heated in a Dean–Stark trap for two days. The re-
action was processed as above for 17c, providing the title

2766
S. Saubern et al. / Tetrahedron 66 (2010) 2761–2767
114.37 (d), 89.79 (d), 77.91 (d), 54.42 (t), 36.81 (t), 33.74 (t); m/z
trap for 18 h. On cooling, the solution was concentrated to an oil,
then dissolved in methanol (5 ml) and treated with concd aq
hydrochloric acid (four drops). The solution was stirred at room
temperature for 2 h, then concentrated to a pale yellow solid; being
the hydrochloride salt of the title compound it was freely soluble in
water. For ease of characterization, the free base was prepared by
stirring a methanolic solution of the salt in the presence of
Amberlite IR-45 weakly basic ion exchange resin. Concentration of
the filtered solution afforded a yellow wax. Flash chromatography
using neat ethyl acetate as eluant afforded the title compound
(50 mg, 74%) as a colourless solid. Mp 119–121 ꢀC; dH (500 MHz,
CD3OD, 5 ꢀC) 7.21 (d, J 7.6, 1H), 7.05 (t, J 7.7, 1H), 6.69 (d, J 8.1, 1H),
6.67 (t, J 7.4, 1H), 4.26 (br s, 1H), 4.09 (m, 1H), 3.69 (m, 1H), 3.20 (dd,
J 11.3, 5.0, 1H), 2.88 (t, J 10.9, 1H), 2.81 (m, 1H); dC (125 MHz, CD3OD,
5 ꢀC) 148.29, 132.39 (2C), 129.75, 118.80, 116.39, 74.91, 59.95, 42.97,
41.65 (br); m/z (EI) C10H12N2Oþ requires 176.0944, found 176.0941.
(APCIþ) 202 (5%), 200 (5, Mþ), 184 (20), 161 (30), 143 (100), 132 (50).
4.4.6. N-tert-Butylcarboxy-2-aminobenzaldehyde (24)14. A solution
of 2-aminobenzylalcohol 23 (1.0 g, 8.1 mmol) in 1,2-dichloroethane
(50 ml) was treated with di-tert-butyl dicarbonate (1.9 g, 8.9 mmol,
1.1 equiv) and heated at reflux for 2 h. On cooling, the reaction was
concentrated to a viscous oil, which was dissolved in dichloro-
methane (50 ml). This solution was treated with manganese(IV)
oxide (6.4 g, 81 mmol, 10 equiv) and heated at reflux for 4 h. The
reaction was cooled to room temperature and filtered through
Celite and concentrated to a viscous oil. This material was suitable
for use in the following step, but for characterization purposes was
further purified by flash chromatography using ethyl acetate–pe-
troleum spirits (1:4) as eluant to provide the title compound as an
oil (1.3 g, 66%). dH (400 MHz) 10.39 (br s, 1H), 9.89 (s, 1H), 8.45 (d, J
8.5, 1H), 7.62 (d, J 7.7, 1H), 7.56 (t, J 7.9, 1H), 7.13 (t, J 7.5, 1H), 1.53 (s,
9H).
4.4.10. Pyridin-2-one-3-carbaldehyde (31)24. 2-Chloropyridine-3-
carbaldehyde 28 (1.50 g, 10.6 mmol) suspended in water (15 ml)
was treated with concd hydrochloric acid (three drops) and aq H2O2
(3 drops, 30%). The mixture was sealed in a microwave vial, and
heated to 170 ꢀC for 15 min. A pressure of 15 bar was reached
during the course of the reaction. On cooling, the dark yellow so-
lution was concentrated to afford the title compound (1.285 g,
98.5%) after drying at 50 ꢀC/0.1 bar overnight. dH (400 MHz, DMSO-
d6) 12.4 (1H, br s, NH), 10.07 (1H, s, CHO), 7.96 (1H, dd, J 7.2, 2.3 Hz),
7.80 (1H, dd, J 6.9, 2.2 Hz), 6.36 (1H, t, J 6.7 Hz).
4.4.7. N-Allyl-N-tert-butylcarboxy-2-aminobenzaldehyde
(25). A
solution of N-tert-butylcarboxy-2-aminobenzaldehyde 24 (1.29 g,
5.83 mmol) and allylbromide (0.76 ml, 8.75 mmol 1.5 equiv) in
DMF (10 ml) cooled to 0 ꢀC was added to a pre-cooled suspension of
sodium hydride (0.26 g, 60% dispersion in oil, 6.41 mmol, 1.2 equiv)
in DMF (4 ml), maintaining an internal temperature below 5 ꢀC. The
deep yellow solution was stirred at 0 ꢀC for 2 h, by which time the
colour had almost dispersed. The reaction was quenched with
saturated aq ammonium chloride (50 ml), and extracted with
a mixture of ethyl acetate–petroleum spirits (1:4) (3ꢂ30 ml). The
combined organic extracts were washed with water (3ꢂ20 ml),
then brine (30 ml). The organic phase was dried (MgSO4) and
concentrated to a pale yellow oil. Flash chromatography on silica
gel using ethyl acetate–petroleum spirits (1:9) as eluant afforded
the title compound as a colourless oil that solidified on standing
(1.39 g, 91%). nmax/cmꢁ1 3356, 3079, 2979, 1706,1598; dH (400 MHz)
10.02 (1H, s, CHO), 7.81 (1H, d, J 7.6 Hz), 7.52 (1H, dd, J 7.6, 7.5 Hz),
7.31 (1H, t, J 7.5, 7.3 Hz), 7.20 (1H, d, J 7.3 Hz), 6.01–5.62 (1H, m,
CH]CH2), 5.18–4.83 (2H, m, CH]CH2), 4.20 (2H, br s, CH2), 1.27
(9H, br s); dC (50 MHz, CDCl3) 189.76 (d, CHO), 154.01 (br s, NCO2),
144.20 (s), 134.42 (d), 132.83 (br d, ]CH), 132.50 (s), 128.25 (br d),
127.85 (br d), 127.09 (d), 118.33 (br t, ]CH2), 80.99 (t), 53.04 (br s),
27.90 (q).
4.4.11. (E)-Ethyl 4-(3-formylpyridin-2-yloxy)but-2-enoate (32)20. Fi-
nely ground, dried pyridin-2-one-3-carbaldehyde 31 (100 mg,
0.81 mmol) and dried silver carbonate (450 mg, 1.62 mmol) in
toluene (4 ml) were treated with (E)-ethyl 4-bromocrotonate
(160 m
l, 75%, 0.87 mmol) and heated to 55 ꢀC in the dark for 18 h.
The reaction was cooled, filtered, and concentrated to a yellow oil.
Flash chromatography on silica gel using petroleum spirits–ethyl
acetate (1:1) afforded the title compound (135 mg, 70%) as a col-
ourless oil, which solidified as an off-white wax on standing.
Subsequently, reactions conducted with 1.5 g of pyridin-2-one-
3-carbaldehyde 31, and purified using reverse phase C-18 silica
with methanol–water (5:1) as eluant provided the product 32 in
82% yield. dH (400 MHz, CD3CN) 10.34 (1H, s, CHO), 8.35 (1H, dd, J
4.8, 1.8, 40-H), 8.09 (1H, dd, J 5.3, 2.2, 60-H), 7.04–7.13 (2H, m, 3-H
and 50-H), 6.15 (1H, dt, J 15.9, 2.1, 2-H), 5.14 (2H, dd, J 4.2, 2.0, 4-H2),
4.15 (2H, q, J 7.2, CH2CH3), 1.24 (3H, t, J 7.2, CH2CH3); dC (100 MHz,
CD3CN) 189.6 (d), 166.6 (s), 163.9 (s), 153.6 (d), 143.4 (d), 139.0 (d),
122.4 (d), 119.8 (s), 118.9 (d), 65.4 (t), 61.2 (t), 14.4 (q).
4.4.8. tert-Butyl
1-cyclohexyl-1,3a,4,9b-tetrahydroisoxazolo[4,3-
c]quinoline-5(3H)-carboxylate (26). N-Allyl-N-tert-butylcarboxy-
2-aminobenzaldehyde 25 (200 mg, 0.765 mmol) and cyclohexyl-
hydroxylamine hydrochloride (128 mg, 0.84 mmol, 1.1 equiv) in
toluene (3 ml) were treated with triethylamine (128
ml, 0.92 mmol,
4.4.12. Ethyl 3(R
*
),3a(S
*
),9b(R )-1-cyclohexyl-1,3a,4,9b-tetrahydro-
*
1.2 equiv). Silicon carbide chips (50 mg) were added to the sus-
pension, which was sealed in a microwave vial and heated to 170 ꢀC
for 40 min. On cooling to room temperature, the solution was fil-
tered through a small plug of silica using ethyl acetate as eluant.
Further chromatography using ethyl acetate–petroleum spirits (1:4)
as eluant afforded the title compound as a colourless foam (230 mg,
84%). dH (200 MHz) 7.43 (d, J 7.8,1H), 7.36 (dd, J 7.4,1.7,1H), 7.21–7.02
(m, 2H), 4.31 (d, J 8.7,1H), 4.08 (t, J 8.4,1H), 3.76 (m, 3H), 3.25 (m,1H),
2.67 (m,1H), 2.07 (m,1H),1.95–1.15 (m, 9H),1.50 (s, 9H); dC (50 MHz)
153.65 (s), 139.57 (s), 130.22 (s), 129.74 (d), 126.62 (d), 124.43(d),
123.96(d), 80.89 (s), 68.44 (t), 61.18 (d), 60.90(d), 45.44 (t), 43.43 (d),
31.97 (t), 28.96 (t), 28.23 (q), 25.84 (t), 24.76 (t), 24.53 (t).
3H-isoxazolo[30,40:4,5]pyrano[2,3-b]pyridine-3-carboxylate (33). A
solution of (E)-ethyl 4-(3-formylpyridin-2-yloxy)but-2-enoate 32
(240 mg, 1.02 mmol) in toluene (4 ml) was treated with cyclo-
hexylhydroxylamine hydrochloride (170 mg, 1.12 mmol) and trie-
thylamine (170 ml, 1.2 mmol). The reaction vial was sealed and
heated to 130 ꢀC in the microwave for 20 min (pressure rises to
1 bar). On cooling, the reaction was concentrated to a yellow syrup.
Filtration through a small pad of reverse phase C-18 silica using
methanol–water (1:1) as eluant afforded a clear yellow oil that
solidified on standing. Recrystallization from ethanol–water affor-
ded colourless needles in a yellow supernatant liquid. The liquid
was decanted, and the crystals were triturated with water until
colourless. The crystals were then dried at the pump, providing the
title compound (220 mg, 65%) as a colourless solid. (Found C, 65.1;
H, 7.3; N, 8.5. C18H24O4N2 requires C, 65.0; H, 7.3; N, 8.4%). Mp 127–
129 ꢀC; dH (400 MHz, CD3CN) 8.07 (1H, dd, J 4.7 and 1.8, H-7), 7.69
(1H, dm, J 7.5, H-9), 6.98 (1H, dd, J 7.5 and 4.8, H-8), 4.78 (1H, d, J 7.2,
H-9b), 4.46 (1H, dd, J 12.2 and 2.3, H-4A), 4.45 (1H, d, J 7.7, H-3), 4.38
4.4.9. 1,3,3a,4,5,9b-Hexahydroisoxazolo[4,3-c]quinoline (5). A mix-
ture of N-allyl-N-tert-butylcarboxy-2-aminobenzaldehyde 25
(100 mg, 0.38 mmol), 5-hydroxypentanal oxime 14 (99 mg,
0.84 mmol, 2.2 equiv) and dibutyltin oxide (19 mg, 0.076 mmol,
0.2 equiv) in toluene (20 ml) was heated to reflux in a Dean–Stark

S. Saubern et al. / Tetrahedron 66 (2010) 2761–2767
2767
6. Lin, S.; Moon, B.; Porter, K. T.; Rossman, C. A.; Zennie, T.; Wemple, J. Org. Prep.
Proced. Int. 2000, 36, 547.
7. Liepa, A. J.; Nguyen, O.; Saubern, S. Aust. J. Chem. 2005, 58, 864.
8. Patel, M. V.; Rohde, J. J.; Gracias, V.; Kolasa, T. Tetrahedron Lett. 2003, 44, 6665.
9. Addition of methanol prior to addition of triethylamine in some cases caused
the formation of dimethylacetal side products.
(1H, dd, J 12.2 and 2.2, H-4B), 4.20 (2H, m, OCH2CH3), 3.39 (1H,
dddd, J 7.6, 7.2, 2.3 and 2.2, H-3a), 2.67 (1H, m), 2.34 (1H, m), 1.71–
1.83 (3H, m), 1.62 (1H, m), 1.38–1.18 (5H, m), 1.27 (3H, t, J 7.1,
OCH2CH3); dC (100 MHz, CD3CN) 172.9 (s, CO2Et), 162.3 (s, C5a),
148.3 (d, C7), 140.8 (d, C9), 119.2 (d, C8), 119.1 (s, C9a), 78.2 (d, C3),
65.2 (t, C4), 63.0 (d), 62.1 (t, OCH2CH3), 59.4 (d, C9b), 44.7 (d, C3a),
32.3 (t), 31.1 (t), 26.7 (t), 25.1 (t), 24.9 (t), 14.4 (q, OCH2CH3); m/z (EI)
332 (100%, M), 289 (50), 218 (60); HRMS (EI) C18H24O4Nþ2 requires
332.1731, found 332.1725.
10. Radleys Discovery Technologies, Essex, UK.
11. Abiko, A. Chem. Lett. 1995, 357.
12. Brinson, R. G.; Jones, P. B. Tetrahedron Lett. 2004, 45, 6155.
13. Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 45, 907.
14. (a) Shapiro, R. WO 91/08207. (b) Chong, P. Y.; Janicki, S. Z.; Petillo, P. A. J. Org.
Chem. 1998, 63, 8515; (c) Nugent, B. M.; Williams, A. L.; Prabhakaran, E. N.;
Johnston, J. N. Tetrahedron 2003, 59, 8877.
15. Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2006, 71, 4651.
16. We thank Prof. Kappe for early access to the information in Ref. 15.
17. Kalita, P. K.; Baruah, B.; Bhuyan, P. J. Tetrahedron Lett. 2006, 47, 7779.
18. Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products, in Chemistry of Heterocyclic
Compounds; Wiley: New York, NY, 2002; Vol. 59.
19. CM reactions proceeded with good yield on the phenyl allyl ethers in model
studies.
20. Hopkins, G. C.; Jonak, J. P.; Minnemeyer, H. J.; Tieckelmann, H. J. Org. Chem. 1967,
32, 4040.
Acknowledgements
We thank Dr. R. Mulder for obtaining the variable temperature
NMR spectra, Dr. A. Riches for useful suggestions and the Australian
Research Council, the Commonwealth Scientific Industrial Research
Organisation and the Victorian Endowment for Science Knowledge
and Innovation for generous financial support. T.S.L. was the
thankful recipient of a CSIRO Summer student scholarship.
21. CCDC 653858 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_
request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax: þ44 1223 336033. Crystal data for 33. C18H24N2O4, M¼332.39, T¼130.
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m(Mo Ka ,
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´
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wR(F2) was 0.0789 (all data).
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´
¨
¨
´
24. Trecourt, F.; Marsais, F.; Gungor, T.; Queguiner, G. J. Chem. Soc., Perkin Trans. 1
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