Stereocontrolled approaches to 2-(2-aminoalkyl)-1-hydroxycyclopropanes

Article abstract of DOI:10.1016/S0040-4020(01)00996-6

(1S,2S)-2[(S)-Amino(4-methoxyphenyl)methyl]cyclopropan-1-ol together with a range of racemic 2-(2-aminoalkyl)-1-hydroxycyclopropanes were prepared by a stepwise procedure involving a 1,3-dipolar cycloaddition of a nitrile oxide to a cyclopropene followed

Full text of DOI:10.1016/S0040-4020(01)00996-6

TETRAHEDRON
Pergamon
Tetrahedron 57 &2001) 9849±9858
Stereocontrolled approaches to
2-ꢀ2-aminoalkyl)-1-hydroxycyclopropanes
Mark S. Baird,a,p Florian A. M. Hubera and William Cleggb
aDepartment of Chemistry, University of Wales, Bangor, Gwynedd, LL57 2UW Wales, UK
bDepartment of Chemistry, University of Newcastle upon Tyne, NE1 7RU Newcastle upon Tyne, UK
Received 20 July 2001;accepted 18 October 2001
AbstractÐ&1S,2S)-2[&S)-Amino&4-methoxyphenyl)methyl]cyclopropan-1-ol together with a range of racemic 2-&2-aminoalkyl)-1-hydroxy-
cyclopropanes were prepared by a stepwise procedure involving a 1,3-dipolar cycloaddition of a nitrile oxide to a cyclopropene followed by
reduction of the derived bicycle. q 2001 Elsevier Science Ltd. All rights reserved.
Isoxazolines are readily obtained by cycloaddition of nitrile
oxides to alkenes. The reduction of the ring is known to
provide access to g-aminoalcohols, in some cases with a
high degree of stereo-control,1±3 in a reaction effectively
amounting to selective 1-hydroxy-2-aminoalkylation of an
alkene &Scheme 1).
nitrile oxides were prepared by standard methods.7 The
adduct &1), formed from 2,4,6-trimethoxybenzonitrile
oxide and 3-methyl-3-phenyl-cyclopropene did not react
with lithium aluminium hydride &Scheme 2).
However, the corresponding adduct of 4-methoxybenzo-
nitrile oxide, compound &2) was reduced to a single
aminoalcohol &8) in reasonable yield &51%), as a pair of
enantiomers. The structure of this product was con®rmed
by a single crystal X-ray determination, and is shown in
Fig. 1. This can be explained in terms of a selective addition
of hydride to the convex face of the azabicycle, ®xing the
stereochemistry at C-4, followed by N±O cleavage
&Scheme 3).
With alkyl or other non-coordinating groups at C-4 or C-5 of
the isoxazoline, hydrogen addition takes place predomi-
nantly anti &trans) to the substituents to give the syn-1,3-
disubstituted aminoalcohol. Hydroxyl or hydroxymethyl-
substituents, however, direct the reducing agent to the syn
face of the CvN bond, leading predominantly to the anti-
aminoalcohol.4,5 Although there has been considerable
interest in the formation of isoxazolines by the cyclo-
addition of nitrile oxides to cyclopropenes, little is known
about their subsequent ring-opening to 2-aminoalkyl-1-
Presumably in the case of &1), the two o-OMe groups cause
the aryl group to be twisted out of the plane of the CvN
Scheme 1.
hydroxycyclopropanes. In view of the considerable range
of biological activity shown by amino-substituted cyclo-
propanes,6 we now report the results of such an
examination.
Cycloadducts between a number of cyclopropenes and
Keywords: isoxazolines;allyl alcohol;cyclopropenes;cyclopropanes.
Corresponding author. Tel.: 144-1248-382-374;fax: 144-1248-370-
528;e-mail: chs028@bangor.ac.uk
p
Scheme 2.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020&01)00996-6

9850
M. S. Baird et al. / Tetrahedron 57 *2001) 9849±9858
Figure 1. The single crystal X-ray structure of &8, Arˆ4-methoxy-C6H4), showing both independent molecules in the asymmetric unit.
Scheme 3.
bond and to hinder the approach of the hydride to either face
of the latter.
The corresponding adduct of 4-methoxybenzonitrile oxide
with 3,3-dimethylcyclopropene, compound &3) was also
reduced by lithium aluminium hydride to give &9) &68%);
the stereochemistry was assigned by analogy to that for &8).
However, the inclusion of an extra methyl group as in &4) led
to a bicycle that did not react with lithium aluminium
hydride. Again, this may re¯ect increased steric hindrance
to the attack of hydride ion, in this case blocking the
normally favoured convex face. In this case, reduction did
occur with NaBH4, NiCl2´6H2O in MeOH over 40 min but
the product was a 68:32 mixture of diastereoisomeric
aminoalcohols &11, RˆMe) in which the cyclopropane
ring had been removed. Reduction of &3) with this reagent
combination was also successful, leading to &10, RˆH),
albeit only in low yield, while the bicycle &2) was reduced
to a crystalline material provisionally characterised as &13).
Surprisingly, the butyl system &5) was, however, ef®ciently
reduced to &12) on reaction with 2 mol equiv. of lithium
aluminium hydride. Apparently the lack of reactivity of
&4) re¯ects the presence of substituents at both C-1 and
C-6. Reduction of the ester &6, RˆPh) with lithium
aluminium hydride led only to the corresponding alcohol
&14, RˆPh). However, the analogue &7, RˆMe) also

M. S. Baird et al. / Tetrahedron 57 *2001) 9849±9858
9851
underwent cleavage of the isoxazoline to produce &16),
albeit in low yield.
In order to test the ef®ciency of the method, it was ®rst
carried out on the chloride &20) prepared directly from
allyl chloride.
Although this does represent a useful approach to racemic
2-aminoalkyl-1-hydroxycyclopropanes, it would have
greater potential if there were a ready route to single
enantiomers of 2-oxa-3-azabicyclo[3.1.0]hex-3-enes. Such
compounds are in principle available by asymmetric induc-
tion in the cycloaddition of nitrile oxides to cyclopropenes;
this might be achieved either by using a single enantiomer
of cyclopropene or by using a chiral nitrile oxide. The ®rst
of these methods is made more practical by the availability
of such cyclopropenes by catalytic asymmetric cyclo-
propenation of alkynes.8 We have had limited success in
the second, e.g. obtaining only very moderate diastereomer
ratios in reactions of &17) with 3,3-dimethyl-cyclopropene
or 1-butylcyclopropene.9 However, a third approach is
available based on Ukaji's catalytic asymmetric addition
of nitrile oxides to allyl alcohol to give &18).10
The racemic aminoalcohol &22) was obtained as a single
diastereoisomer in 88% yield. In the optically active series,
allyl alcohol was converted into &18) &64, 99% ee) as
described by Ukaji.10 The alcohol &18) could be converted
into the corresponding chloride &23) &ee 94%) by re¯uxing
with thionyl chloride in pyridine;11 however, the yield was
poor &44%). Instead, the alcohol was converted into its
mesylate &24) &85%) which could be transformed without
puri®cation into &25) on reaction with KOBut-DMSO for 1 h
at room temperature &73% from &17), ee 99%). Reduction
of this with lithium aluminium hydride led to a single
enantiomer of the cyclopropane &26) in 98% yield.
Unfortunately, the original Ukaji papers only report the
application of the asymmetric isoxazolination to allyl
alcohol itself, leading to &18) with no additional substituents
at either saturated ring carbon. Indeed, we have examined
the reaction with a number of substituted allylic alcohols,
and found only very poor enantiomeric excesses. This
clearly limits the application of such methodology;however,
a recent paper by Ukaji does report the successful application
of the chiral reaction to E- and Z-2-buten-1-ol and to ethyl
&E)-4-hydroxy-2-butenoate.13 Moreover, stereoselective
alkylation of C-4 of the isoxazoline &18) has been reported,13
offering the potential for the introduction of a second sub-
stituent at C-2 of the 2-aminoalkylcyclopropane. To date, no
routes appear to be available to introduce substituents at C-5
of &18) with control of absolute stereochemistry.
It is also known that, in the racemic series, such alcohols &as
19) may be converted into the corresponding chlorides
&20),10 and that these may be dehydrochlorinated by base
to give the bicycle &21).12
Hydrogenation of the product was also reported, but led to
complex mixtures.12

9852
M. S. Baird et al. / Tetrahedron 57 *2001) 9849±9858
1. Experimental
&CH, aromatic), 100.6, 126.3, 127.9, 128.6, 144.0, 153.6,
160.0, 162.6 &C-4); nmax 3008 s, 2929 s, 2839 s, 1604 s,
1500 s, 1459 s, 1413 s, 1344 s, 1226 s, 1205 s, 1156 s,
1134 s, 1068 s, 1034 s, 1015 s, 1002 s, 992 s, 846 s, 755
s, 700 s, 627 s, cm21; m/z, % 340, 3;339, 3 &M 1);311, 23;
310, 24;309, 11;308, 10;281, 9;280, 9;265, 5;192, 88;
193, 100;165, 11;146, 27;117, 12.
1.1. General
Commercial reagents were used without further puri®cation
unless stated. Solvents were puri®ed when necessary using
standard methods;14 dichloromethane was distilled over
calcium hydride, diethyl ether, 1,4-dioxane and tetrahydro-
furan over sodium wire. Chloroform was washed with water
and dried with phosphorus pentoxide. Petroleum ether was
of boiling point 40±608C unless stated. Reactions requiring
anhydrous conditions were performed using oven dried
glassware &1608C) cooled under a stream of dry nitrogen
or argon;the experiments were conducted under a positive
atmosphere of one of these gases. Unless stated, organic
solutions were dried over anhydrous magnesium sulfate,
and evaporated at 14 mmHg;yields quoted are for puri®ed
compounds and any ratios given are calculated by com-
paring integrals in the 1H NMR spectrum. New compounds
were homogenous by TLC or GLC. GLC was conducted
using a Carlo Erba HRGC 5300 &FID, on a capillary
column). TLC was performed using Aldrich silica plates
coated with silica gel 60 &F254). Compounds were
visualised using an ultraviolet source, by exposure to iodine
vapour or by contact with phosphomolybdic acid hydrate
&2% in ethanol) followed by heating to 1808C. Column
chromatography was conducted with Fisher Scienti®c Silica
Gel 60 under medium pressure. HPLC was performed on a
Milton Roy system &solvent delivering system: consta
Metric 3000;variable wavelength detector: spectro Monitor
3100);the chiral column used was a Chiracel OD from
Daicel Chemical Industries, 0.46£25 cm2;solvent mixtures:
2-propanol/hexane 2, 5 and 10%, respectively;pressure:
30 psi;¯owrate: 0.80 ml/min, UV-detection: 254 nm;
concentration of sample 5±10 mg/1 l solvent.
1.1.2. 4-ꢀ4-Methoxyphenyl)-6-methyl-6-phenyl-2-oxa-3-
azabicyclo[3.1.0]hex-3-ene ꢀ2). Triethylamine &1.46 ml,
10.5 mmol) was added dropwise to a stirred solution of
N-hydroxy-4-methoxy-benzimidoyl
chloride
&1.94 g,
10.5 mmol) and 3-methyl-3-phenylcyclopropene &1.50 g,
11.5 mmol) in ether &20 ml) at 08C;triethylammonium
chloride precipitated. The mixture was stirred at room
temperature for 6 h and then treated with hydrochloric
acid &2%, 15 ml) to dissolve the precipitate. The aqueous
layer was extracted with ether &3£15 ml) and the combined
organic layers were dried and evaporated to give crude 4-
*4-methoxyphenyl)-6-methyl-6-phenyl-2-oxa-3-azabicyclo-
[3.1.0]hex-3-ene as a 85:15 mixture of endo and exo
isomers. Chromatography &petrol/ether, 3:1 to 1:5) gave
the major isomer, endo-Me &2) &2.13 g, 73%), a white
solid, mp 958C &Found: C 77.3, H 6.0, N 5.3. C18H17NO2
requires: C 77.40, H 6.13, N 5.01) showed dH 1.24 &3H, s,
CH3), 3.25 &1H, d, Jˆ5.8 Hz, H-5), 3.87 &3H, s, OCH3), 5.07
&1H, d, Jˆ5.8 Hz, H-1), 6.95±7.00 &2H, m, aromatic), 7.27±
7.42 &5H, m, aromatic), 7.73±7.77 &2H, m, aromatic); dC
12.6 &CH3), 21.1 &C-6), 40.9 &C-5), 55.4 &OCH3), 74.5
&C-1), 114.2, 122.1, 126.7, 126.8, 128.8, 128.9, 143.0,
158.3, 161.4 &C-4); nmax 1608 s, 1515 s, 1498 s, 1420 s,
1370 s, 1251 s, 1177 s, 1023 s, 1004 s, 994 s, 868 s, 847
s, 808 s, 759 s, 748 s, 696 s cm21; m/z, % 279, 3 &M1);264,
2;250, 11;146, 42;145, 100;133, 27;131, 25;117, 11;103,
10;91;10;77, 10;and the minor isomer, exo-Me &480 mg,
16%), a white solid, mp 1228C &Found: C 77.3, H 6.1, N 5.1.
C18H17NO2 requires: C 77.40, H 6.13, N 5.01) which
showed dH 1.44 &3H, s, CH3), 3.14 &1H, d, Jˆ5.5 Hz,
H-5), 3.85 &3H, s, OCH3), 5.02 &1H, d, Jˆ5.5 Hz, H-1),
6.89±6.95 &2H, m, aromatic), 7.16±7.27 &5H, m, aromatic),
7.64±7.70 &2H, m, aromatic); dC 24.4 &C-6), 24.7 &CH3),
40.7 &C-5), 55.3 &OCH3), 73.7 &C-1), 114.1, 122.3, 127.1,
128.4, 128.7, 129.5, 137.0, 158.1, 161.0 &C-4); nmax 1608 s,
1514 s, 1458 s, 1444 s, 1377 s, 1303 s, 1252 s, 1176 s, 1021
s, 858 s, 839 s, 704 s cm21; m/z, % 279, 22 &M1);264, 4;
250, 43;146, 54;145, 100;133, 23;131, 24;117, 13;115,
12;103, 7.
Melting points are uncorrected. Infrared spectra were
obtained as KBr discs or as liquid ®lms on a Perkin±
Elmer 1600 FTIR spectrometer. Low resolution mass
spectra were obtained on a Finnigan 8430 spectrometer.
Accurate mass measurements refer to 79Br and 35Cl isotopes
unless stated and were obtained from the Swansea Mass
Spectrometry Service. Microanalyses were performed on a
Carlo Erba Model 1106 CHN analyser. NMR spectra were
recorded in CDCl3, unless stated, on a Bruker AC250 at
250 MHz for protons, at 62.9 MHz for carbons and in the
latter case were either broad-band or gated decoupled.
1.1.3. 4-ꢀ4-Methoxyphenyl)-6,6-dimethyl-2-oxa-3-aza-
bicyclo[3.1.0]hex-3-ene ꢀ3). Methyllithium &29.6 ml,
1.5 M) was added dropwise to a stirred solution of 1,1-
dibromo-3-chloro-2,2-dimethylcyclopropane &5.3 g, 20
mmol) in dry ether &15 ml) at 2788C.16 The mixture was
allowed to reach room temperature, cooled again to 2408C,
then quenched with water &5 ml), extracted with ether
&3£10 ml) and the combined organic layers were dried.
N-Hydroxy-4-methoxybenzimidoyl chloride &3 g, 0.016 mol)
was dissolved in the above solution &containing 3,3-di-
methylcyclopropene) and the mixture was cooled to
2158C. Triethylamine &2.25 ml, 0.016 mol) was added
dropwise;triethylammonium chloride precipitated. The
mixture was stirred at room temperature for 12 h and then
treated with hydrochloric acid &2%, 30 ml) to dissolve the
1.1.1. 6-Methyl-6-phenyl-4-ꢀ2,4,6-trimethoxyphenyl)-2-
oxa-3-azabicyclo[3.1.0]hex-3-ene ꢀ1). 2,4,6-Trimethoxy-
benzonitrile oxide15 &438 mg, 2.1 mmol) in dichloro-
methane &10 ml) was added to 3-methyl-3-phenyl-
cyclopropene &300 mg, 2.3 mmol) in dichloromethane
&5 ml) and stirred for 12 h. Evaporation gave a colourless
oil. Storage in a freezer for 18 h gave 6-methyl-6-phenyl-4-
*2,4,6-trimethoxy-phenyl)-2-oxa-3-azabicyclo[3.1.0]hex-3-
ene &1) &670 mg, 94%) as a white solid, mp 1068C &Found: C
70.8, H 6.2, N 4.2. C20H21NO4 requires: C 70.78, H 6.24, N
4.13) which showed dH 1.33 &3H, s, CH3), 3.18 &1H, d,
Jˆ5.6 Hz, H-5), 3.88 &6H, s, 2OCH3), 3.89 &3H, s, OCH3),
5.01 &1H, d, Jˆ5.6 Hz, H-1), 6.22 &2H, s, CH, aromatic),
7.22±7.41 &5H, m, aromatic); dC 13.3 &CH3), 20.8 &C-6),
45.0 &C-5), 55.4 &OCH3), 55.9 &OCH3), 73.4 &C-1), 90.8

M. S. Baird et al. / Tetrahedron 57 *2001) 9849±9858
9853
precipitate. The aqueous layer was extracted with ether
&3£20 ml) and the combined organic layers were dried
and evaporated. The residue was puri®ed by chromato-
graphy &petrol/ether, 2.5:1) to give 4-*4-methoxyphenyl)-
6,6-dimethyl-2-oxa-3-azabicyclo[3.1.0]hex-3-ene &3) &2.42 g,
69%) as a white solid, mp 648C &Found: C 71.5, H 6.9, N
6.6. C13H15NO2 requires: C 71.87, H 6.96, N 6.45) which
showed dH 0.91 &3H, s, CH3), 1.18 &3H, s, CH3), 2.27 &1H, d,
Jˆ5.6 Hz, H-5), 3.84 &3H, s, OCH3), 4.64 &1H, d, Jˆ5.6 Hz,
H-1), 6.91±6.96 &2H, m, aromatic), 7.64±7.68 &2H, m,
aromatic); dC 12.7 &CH3), 13.4 &C-6), 22.5 &CH3), 39.5
&C-5), 55.3 &OCH3), 74.4 &C-1), 114.1, 122.4, 128.8,
158.0, 161.1 &C-4); nmax 1607 s, 1515 s, 1462 s, 1421 s,
1303 s, 1253 s, 1175 s, 1030 s, 999 s, 869 s, 851 s, 834 s
cm21; m/z, % 217, 16 &M1);188, 46;134, 35;133, 100;103,
13;81, 13. Bis*4-methoxyphenyl)furoxan7,18 &260 mg, 10%)
was isolated as a by-product.
&5 ml), extracted with ether &3£10 ml) and the combined
organic layers were dried. N-Hydroxy-4-methoxybenzi-
midoyl chloride &970 mg, 6.0 mmol) was dissolved in the
ethereal solution &containing 1-butylcyclopropene) and the
mixture was cooled to 2158C. Triethylamine &0.83 ml,
6.0 mmol) was added dropwise;triethylammonium chloride
precipitated. The mixture was stirred at room temperature
for 12 h. Work up and chromatography &petrol/ether, 2.5:1)
as given earlier gave 1-butyl-4-*4-methoxyphenyl)-2-oxa-3-
azabicyclo[3.1.0]hex-3-ene &5) &585 mg, 46%) as a white
solid, mp 53±548C &Found: C 73.0, H, 7.8, N 5.8.
C15H19NO2 requires: C 73.44, H 7.81, N 5.71) which
showed dH 0.51 &1H, dd, Jˆ3.9, 5.2 Hz, Hendo-6), 0.93
&3H, t, Jˆ7.2 Hz, CH3), 1.10 &1H, dd, Jˆ5.2, 9.3 Hz,
Hexo-6), 1.33±1.60 &4H, m, CH2CH2CH2CH3), 1.85±2.12
&2H, m, CH2CH2CH2CH3), 2.59 &1H, dd, Jˆ3.9, 9.3 Hz,
H-5), 3.85 &3H, s, OCH3), 6.91±6.96 &2H, m, aromatic),
7.68±7.73 &2H, m, aromatic); dC 12.2 &C-6), 14.0 &CH3),
22.5 &CH2), 28.4 &CH2), 29.1 &C-5), 31.3 &CH2), 55.3
&OCH3), 75.3 &C-1), 114.0, 122.7, 128.5;161.4 and 162.1
&C-4 and aromatic C); nmax 2957 s, 2935 s, 1608 s, 1517 s,
1426 s, 1254s, 1029 s, 883 s, 828 s cm21; m/z, % 245, 5
&M1);161, 11;160, 100;133, 6;106, 4;77, 10;57, 18.
Bis*4-methoxyphenyl)furoxan &95 mg, 12%) was isolated
as a by-product.
1.1.4. 4-ꢀ4-Methoxyphenyl)-1,6,6-trimethyl-2-oxa-3-aza-
bicyclo[3.1.0]hex-3-ene ꢀ4). Methyllithium &7.54 ml,
1.5 M) was added dropwise to a stirred solution of 1,2,2-
tribromo-1,3,3-trimethylcyclopropane &1.73 g, 5.4 mmol) in
ether &15 ml) at 2788C.16 The mixture was allowed to reach
room temperature, cooled again to 2408C, then quenched
with water &5 ml) and extracted with ether &3£10 ml). The
combined organic layers were dried; N-Hydroxy-4-
methoxybenzimidoyl chloride &1 g, 5.4 mmol) was added
to the stirred solution &containing 1,3,3-trimethylcyclo-
propene) and cooled to 2158C. A solution of triethylamine
&0.75 ml, 5.4 mmol) in dry ether &10 ml) was added drop-
wise;triethylammonium chloride precipitated. After 24 h at
room temperature, it was washed with hydrochloric acid
&2%, 20 ml) and water &2H 30 ml), dried and evaporated;
chromatography &petrol/ether, 3:1) gave 4-*4-methoxy-
phenyl)-1,6,6-trimethyl-2-oxa-3-azabicyclo[3.1.0]hex-3-ene
&4) &820 mg, 66%) as a white solid, mp 798C &Found: C
73.0, H 7.5, N 6.3. C14H17NO2 requires: C 72.70, H 7.41,
N 6.06) which showed dH 0.85 &3H, s, CH3), 1.25 &3H, s,
CH3), 1.64 &3H, s, CH3), 2.27 &1H, s, H-5), 3.81 &3H, s,
OCH3), 6.86±6.92 &2H, m, aromatic), 7.58±7.63 &2H, m,
aromatic); dC 13.6 &CH3), 14.0 &CH3), 17.0 &C-6), 21.7
&CH3), 41.8 &C-5), 55.3 &OCH3), 79.9 &C-1), 114.0, 122.9,
128.5, 158.4, 161.0 &C-4); nmax 1609 s, 1584 m, 1515 s,
1459 s, 1427 s, 1420 s, 1255 s, 1176 s, 1030 s, 903 s, 876
s, 842 s, 821 s cm21; m/z, % 231, 10 &M1);216, 40;188,
1.1.6. Ethyl 6-methyl-6-phenyl-2-oxa-3-azabicyclo-
[3.1.0]hex-3-ene-4-carboxylate ꢀ6, RˆPh). Triethylamine
&0.29 ml, 2.1 mmol) in ether &5 ml) was added dropwise to a
stirred solution of ethyl 2-chloro-2-&hydroximino)acetate
&317 mg, 2.1 mmol) and 3-methyl-3-phenylcyclopropene
&300 mg, 2.3 mmol) in ether &15 ml) at 08C;triethyl-
ammonium chloride precipitated. After stirring at room
temperature for 24 h, work up as given earlier gave crude
ethyl 6-methyl-6-phenyl-2-oxa-3-azabicyclo-[3.1.0]hex-3-
ene-4-carboxylate as a mixture of endo and exo isomers
&75:25) which was separated by chromatography &petrol/
ether, 3:1). The major isomer, endo-Me &6, RˆPh)
&150 mg, 29%), a colourless oil &Found [M1NH4]1:
263.1402. C14H15NO31NH4 requires: 263.1396) showed
dH 1.18 &3H, s, CH3), 1.41 &3H, t, Jˆ7.1 Hz, CO2CH2CH3),
3.31 &1H, d, Jˆ5.6 Hz, H-5), 4.40 &2H, q, Jˆ7.1 Hz,
CO2CH2CH3), 5.17 &1H, d, Jˆ5.6 Hz, H-1), 7.23±7.41
&5H, m, aromatic); dC 13.2 &CH3), 14.1 &CO2CH2CH3),
19.8 &C-6), 39.4 &C-5), 62.3 &CO2CH2CH3), 77.0 &C-1),
127.1, 128.9, 141.6, 153.4 &CvO), 160.2 &C-4); nmax 1741
s, 1721 s, 1601 w, 1258 s, 1221 s, 1127 s, 993 s, 779 s, 756 s,
700 s cm21; m/z &CI, NH41), % 263, 25 [M1NH4]1;246, 10
[MH]1;218, 100;201, 18;146, 51;145, 70. The minor
isomer, exo-Me &11, RˆPh) &50 mg, 10%), a colourless
oil showed dH 1.31 &3H, t, Jˆ7.1 Hz, CO2CH2CH3), 1.38
&3H, s, CH3), 3.20 &1H, d, Jˆ5.4 Hz, H-5), 4.30 &2H, q,
Jˆ7.1 Hz, CO2CH2CH3), 5.11 &1H, d, Jˆ5.4 Hz, H-1),
7.18±7.36 &5H, m); dC 14.0 &CO2CH2CH3), 22.8 &C-6),
24.2 &CH3), 39.6 &C-5), 62.0 &CO2CH2CH3), 75.8 &C-1),
127.4, 128.7, 129.6, 136.4, 153.6 &CvO), 160.5 &C-4);
100;173, 23;133, 64;83, 73;43, 37. A by-product
3-*4-
methoxyphenyl)-5-methyl-5-prop-1-ynyl-4,5-dihydroisoxa-
zole [dH 1.67 &3H, s, CH3), 1.83 &3H, s, CH3), 3.23 &1H, d,
Jˆ16.3 Hz, ®rst of H-4), 3.52 &1H, d, Jˆ16.3 Hz, second of
H-4), 3.87 &3H, s, OCH3), 6.85±6.9 &2H, m, aromatic),
7.53±7.58 &2H, m, aromatic); dC 3.8 &C/C±CH3), 27.8
&CH3), 48.7 &C-4), 55.3 &OCH3), 79.9 &C-5), 80.3 &C/C),
81.4 &C/C), 114.1, 122.2, 128.1, 156.9, 161.1 &C-3); m/z,
% 229, 100 &M1)] together with a small amount of bis*4-
methoxyphenyl)furoxan,7,18 a beige solid &total 136 mg,
compounds not separated) was also isolated.
nmax 1742 s, 1721 s, 1261 s, 1181 s, 1118 s, 702 s cm21
m/z, % 216, 16 &M12CH3CH2);146, 33;145, 100;131, 25;
117, 15;115, 19;103, 12;91, 8;77, 12.
;
1.1.5. 1-Butyl-4-ꢀ4-methoxyphenyl)-2-oxa-3-azabicyclo-
[3.1.0]hex-3-ene ꢀ5). Methyllithium &8.8 ml, 1.5 M) was
added dropwise to a stirred solution of 1,1,2-tribromo-2-
butylcyclo-propane &2.0 g, 6.0 mmol) in dry ether &15 ml)
at 2788C.16 The mixture was allowed to reach room
temperature, cooled again to 2408C, quenched with water
1.1.7. Ethyl 6,6-dimethyl-2-oxa-3-azabicyclo[3.1.0]hex-
3-ene-4-carboxylate ꢀ7, RˆMe). Triethylamine &2.76 ml,
0.020 mol) was added dropwise to a stirred solution of ethyl

9854
M. S. Baird et al. / Tetrahedron 57 *2001) 9849±9858
2-chloro-2-&hydroximino)acetate &3 g, 0.020 mol) and 3,3-
dimethylcyclopropene &prepared from 1,1-dibromo-3-
chloro-2,2-dimethylcyclopropane &6.5 g, 0.025 mol) and
methyllithium &36.3 ml, 1.5 M) as given earlier) in ether at
2158C;triethylammonium chloride precipitated. After
stirring at room temperature for 12 h, work up as given
earlier and chromatography &petrol/ether, 2.5:1) gave a
colourless oil, ethyl 6,6-dimethyl-2-oxa-3-azabicyclo-
[3.1.0]-hex-3-ene-4-carboxylate &7, RˆMe)17 &1.62 g,
45%) which showed dH 0.84 &3H, s, CH3), 1.11 &3H, s,
CH3), 1.36 &3H, t, Jˆ7.1 Hz, CO2CH2CH3), 2.73 &1H, d,
Jˆ5.5 Hz, H-5), 4.33 &2H, q, Jˆ7.1 Hz, CO2CH2CH3),
4.74 &1H, d, Jˆ5.5 Hz, H-1); dC 11.8 &C-6), 12.7 &CH3),
14.0 &CO2CH2CH3), 21.9 &CH3), 38.5 &C-5), 62.0
&CO2CH2CH3), 77.1 &C-1), 153.0 &CvO), 160.4 &C-4);
nmax 1723 s, 1262 s, 1204 s, 1121 s, 1000 s, 896 s, 779 s
cm21; m/z, % 183, 1 &M1);168, 2;156, 4;154, 3;138, 6;
126, 15;110, 15;96, 7;84, 39;83, 79;82, 100;55, 48;41,
37.
7.7, N 5.1. C18H21NO2 requires: C 76.30, H 7.47, N 4.94)
which showed dH 1.45 &1H, dd, Jˆ7.1, 10.1 Hz, H-3), 1.63
&3H, s, CH3), 1.98 &3H, br s, NH2 and OH), 3.64 &1H, d,
Jˆ7.1 Hz, H-1), 3.82 &3H, s, OCH3), 4.16 &1H, d,
Jˆ10.1 Hz, CH±NH2), 6.87±6.92 &2H, m, aromatic),
7.16±7.35 &5H, m, aromatic), 7.41±7.45 &2H, m, aromatic);
dC 13.8 &CH3), 28.3 &C-2), 36.6 &C-3), 50.4 &CH±NH2), 55.3
&OCH3), 58.0 &C-1), 114.0, 125.9, 127.2, 127.7, 128.4,
137.6, 147.0, 158.7; nmax 3418 br s, 3145 br s, 1512 s,
1247 s, 1034 s, 701 s cm21; m/z, % 266, 1 &M12OH);
237, 28;149, 41;136, 100;134, 22;57, 20;43, 18.
1.2. Crystal structure determination for 8
Crystal data: C18H21NO2, Mˆ283.36, triclinic, space
Ê
Å
group P1, aˆ10.3811&7), bˆ11.7378&7), cˆ13.2022&8) A,
aˆ77.928&2),
bˆ89.118&2),
gˆ80.323&2)8,
Vˆ
1550.42&17) A , Zˆ4, Dcˆ1.214 g cm23, mˆ0.08 mm21
Ê 3
Ê
&Mo Ka, lˆ0.71073 A), Tˆ160 K. Of 12,506 re¯ections
measured on a Bruker AXS SMART CCD diffractometer,
7049 were unique &u,29.08, Rintˆ0.0169). The structure
was solved by standard direct methods and re®ned on F2
values;H atoms bonded to O and N were freely re®ned,
others were constrained with a riding model. Rˆ0.0518 &F
values, F2.2s), R2ˆ0.1364 &F2 values, all data), goodness-
of-®tˆ1.016, ®nal difference map extremes 10.82 and
1.1.8. Attempted reduction of 6-methyl-6-phenyl-4-
ꢀ2,4,6-trimethoxyphenyl)-2-oxa-3-azabicyclo[3.1.0]hex-
3-ene ꢀ1) with LiAlH4. A solution of 6-endo-methyl-6-
phenyl-4-&2,4,6-trimethoxyphenyl)-2-oxa-3-azabicyclo-
[3.1.0]-hex-3-ene &1) &270 mg, 0.8 mmol) in dry THF
&10 ml) was added to a suspension of LiAlH4 &49 mg,
1.3 mmol) in dry ether &8 ml). The mixture was re¯uxed
for 24 h. Drops of sat. aq. Na2SO4 were then added until
no further reaction with the excess of LiAlH4 was observed.
To the white-grey suspension dichloromethane &15 ml) &or
alternatively ethyl acetate) and a small amount of anhydrous
MgSO4 were added. The suspension was ®ltered through a
layer of anhydrous MgSO4. The solvent was removed from
the ®ltrate under vacuum to give the crude product. Only
starting material &243 mg, 90%) was recovered.
Ê 23
20.46 e A . Software: Bruker SMART, SAINT, and
²
SHELXTL.
1.2.1. 3-[Aminoꢀ4-methoxyphenyl)methyl]-2,2-dimethyl-
cyclopropanol ꢀ9). 4-&4-Methoxyphenyl)-6,6-dimethyl-2-
oxa-3-azabicyclo[3.1.0]hex-3-ene &3) &550 mg, 2.5 mmol)
in dry ether &10 ml) was added to a suspension of LiAlH4
&192 mg, 5.1 mmol) in ether &10 ml). The mixture was
re¯uxed for 20 h. Work-up as given earlier and recrystal-
lisation from ether/petrol gave 3-[amino*4-methoxyphenyl)-
methyl]-2,2-dimethylcyclopropanol &9) &380 mg, 68%) as a
white solid, mp 102±1038C &Found: C 70.5, H 8.8, N 6.5.
C13H19NO2 requires: C 70.56, H 8.65, N 6.33), dH 0.77 &1H,
dd, Jˆ6.8, 10.1 Hz, H-3), 1.03 &3H, s, CH3), 1.25 &3H, s,
CH3), 1.78 &3H, br s, NH2 and OH), 3.08 &1H, d, Jˆ6.8 Hz,
H-1), 3.77 &3H, s, OCH3), 3.89 &1H, d, Jˆ10.1 Hz, CH±
NH2), 6.82±6.86 &2H, m, aromatic), 7.31±7.34 &2H, m,
aromatic); dC 13.3 &CH3), 19.1 &C-2), 26.4 &CH3), 35.7
&C-3), 50.6 &CH±NH2), 55.3 &OCH3), 57.9 &C-1), 113.9,
127.5, 138.2, 158.5; nmax 3126 br s, 2950 s, 1610 s, 1581
s, 1512 s, 1303 s, 1272 s, 1248 s, 1178 s, 1148 s, 1038 s, 951
s, 831 s cm21; m/z, % 204, 12 &M12OH);175, 58;149, 46;
136, 100;134, 34;121, 10;109, 12;58, 5.
1.1.9. Attempted reduction of 4-ꢀ4-methoxyphenyl)-
1,6,6-trimethyl-2-oxa-3-azabicyclo[3.1.0]hex-3-ene ꢀ4)
with LiAlH4. A solution of 4-&4-methoxyphenyl)-1,6,6-
trimethyl-2-oxa-3-azabicyclo[3.1.0]hex-3-ene
&300 mg,
1.3 mmol) in dry ether &10 ml) was added to a suspension
of LiAlH4 &59 mg, 1.6 mmol) in dry ether &8 ml). The
mixture was re¯uxed for 72 h. TLC did not show any
conversion;more LiAlH &133 mg) was added and the
4
mixture was re¯uxed for further 24 h. Work-up as given
earlier gave only starting material &4).
1.1.10. 3-[Aminoꢀ4-methoxyphenyl)methyl]-2-methyl-2-
phenylcyclopropanol ꢀ8). A solution of 4-&4-methoxy-
phenyl)-6-methyl-6-phenyl-2-oxa-3-azabicyclo[3.1.0]hex-
3-ene &2) &390 mg, 1.4 mmol) in dry ether &10 ml) was
added to a suspension of LiAlH4 &90 mg, 2.8 mmol) in dry
ether &10 ml). The mixture was re¯uxed for 20 h. Drops of
sat. aq. Na2SO4 were then added until no further reaction
with the excess of LiAlH4 was observed. To the white-grey
suspension dichloromethane &15 ml) &or alternatively ethyl
acetate) and a small amount of anhydrous MgSO4 were
added. The suspension was ®ltered through a layer of
anhydrous MgSO4. The solvent was removed under vacuum
to give the crude product. The residue was recrystallised
from ethyl acetate to give 3-[amino*4-methoxyphenyl)-
methyl]-2-methyl-2-phenyl-cyclopropanol &8) &200 mg,
51%) as a white solid, mp 116±1208C &Found: C 76.3, H
1.2.2. 4-Amino-4-ꢀ4-methoxyphenyl)-2,2-dimethylbutan-
1-ol ꢀ10). Sodium borohydride &348 mg, 9.2 mmol) was
added in portions to a stirred solution of 4-&4-methoxy-
phenyl)-6,6-dimethyl-2-oxa-3-azabicyclo[3.1.0]hex-3-ene
&3) &400 mg, 1.8 mmol) and NiCl2´6H20 &875 mg,
3.7 mmol) in methanol &50 ml) at 2158C. After 5 min the
mixture was allowed to reach room temperature and stirred
for 20 min. Methanol was removed under reduced pressure,
²
Crystallographic data have been deposited at the CCDC, 12, Union Road,
Cambridge CB2 1EZ, UK and copies can be obtained on request, free of
charge, by quoting the publication citation and the deposition reference
number 169658.

M. S. Baird et al. / Tetrahedron 57 *2001) 9849±9858
9855
aq. ammonia &d 0.88, 40 ml) and dichloromethane &40 ml)
were added carefully, and the black mixture was stirred
under air until the organic layer became almost clear
&about 20 min). The aqueous layer was extracted with
dichloro-methane &3£40 ml), the combined organic layers
were dried and evaporated to give a yellow oil &337 mg).
Chromatography &petrol/ether, 2.5:1, then ether) gave a pale
yellow oil, 4-amino-4-*4-methoxy-phenyl)-2,2-dimethyl-
butan-1-ol &10, RˆH) &90 mg, 22%) &M1 &223) not
observed) which showed dH 1.16 &3H, s, CH3), 1.18 &3H,
s, CH3), 1.54 &1H, dd, Jˆ9.8, 12.5 Hz, ®rst of H-3), 1.96
&1H, dd, Jˆ7.1, 12.5 Hz, second of H-3), 2.10 &1H, br s,
OH), 2.80 &1H, d, Jˆ10.2 Hz, ®rst of H-1), 2.93 &1H, d,
Jˆ10.2 Hz, second of H-1), 3.82 &3H, s, OCH3), 4.26 &1H,
dd, Jˆ7.1, 9.8 Hz, H-4), 6.86±6.90 &2H, m, aromatic),
7.29±7.33 &2H, m, aromatic); dC 27.9 &CH3), 28.7 &CH3),
39.5 &C-2), 50.0 &C-3), 55.2 &OCH3), 61.1 &C-1), 62.0 &C-4),
113.7, 127.5, 137.0, 158.4; nmax 3342 br m, 2952 s, 1513 s,
1245 s cm21; m/z, % 203, 3;202, 28;201, 42;200, 33;186,
5;171, 8;158, 14;146, 45;145, 100;133, 19;131, 9;118,
10;116, 10;96, 7;89, 8;75, 6.
&M1 not observed) which showed dH 0.68 &1H, dd, Jˆ5.7,
9.5 Hz, Hcis-3), 0.78 &1H, dd, Jˆ5.7, 6.2 Hz, Htrans-3), 0.84
&3H, t, Jˆ7.1 Hz, CH3), 0.93 &1H, ddd, Jˆ5.8, 6.2, 9.5 Hz,
H-2), 1.24±1.53 &6H, m, CH2CH2CH2CH3), 2.68 &3H, br s,
NH2 and OH), 3.77 &3H, s, OCH3), 4.06 &1H, d, Jˆ5.8 Hz,
CH±NH2), 6.83±6.87 &2H, m, aromatic), 7.29±7.32 &2H, m,
aromatic); dC 14.1 &CH3), 15.4 &C-3), 22.6 &CH2), 27.8
&CH2), 28.9 &C-2), 38.5 &CH2), 53.2 &CH±NH2), 55.3
&OCH3), 58.7 &C-1), 114.0, 127.2, 138.6, 158.6; nmax 3340
br s, 2956 s, 2931 s, 1513 s, 1246 s cm21; m/z, % 233, 10;
232, 33 &M12OH);189, 35;176, 19;162, 8;147, 100;136,
83;121, 20;102, 37;91, 21;85, 15;77, 18;57, 33.
1.2.5. Reduction of 4-ꢀ4-methoxyphenyl)-6-methyl-6-
phenyl-2-oxa-3-azabicyclo[3.1.0]hex-3-ene with sodium
borohydride. Sodium borohydride &271 mg, 7.2 mmol)
was added in portions to a stirred solution of 4-&4-methoxy-
phenyl)-6-endo-methyl-6-phenyl-2-oxa-3-azabicyclo[3.1.0]-
hex-3-ene &2) &400 mg, 1.4 mmol) and NiCl2´6H20 &681 mg,
2.9 mmol) in methanol &50 ml) at 2358C. After 5 min the
mixture was allowed to reach room temperature and stirred
for 10 min. Work-up as for &10) gave a yellow oil &295 mg).
A white precipitate &65 mg) formed when this was treated
with ether, mp 1628C &Found: C 78.1, H 6.8, N 4.9.
C18H19NO2 requires: C 76.84, H 6.81, N 4.98) which was
provisionally characterised as &13) and showed dH 1.32 &3H,
s, CH3), 3.21 &1H, d, Jˆ17 Hz), 3.30 &1H, d, Jˆ17 Hz), 3.84
&3H, s, OCH3), 5.8 &1H, s), 6.92±6.96 &2H, m, aromatic),
7.18±7.36 &5H, m, aromatic), 7.84±7.88 &2H, m, aromatic);
dC 20.3 &CH3), 48.1 &CH2), 51.2, 55.3 &OCH3), 99.9 &CH),
114.0, 126.2, 126.3, 127.3, 128.4, 129.5, 147.4, 162.1 &q),
170.8 &q); nmax 3078 br s, 1516 s, 1333 s, 1256 s, 1177 s,
1122 s, 1058 s, 1034 s, 832 s, 697 s cm21; m/z, % 281, 42;
266, 27;263, 25;248, 18;236, 23;221, 15;204, 9;176, 28;
164, 68;162, 68;134, 100;121, 39;115, 25;103, 23;91, 28;
77, 40.
1.2.3. 5-Amino-5-ꢀ4-methoxyphenyl)-3,3-dimethylpentan-
2-ol ꢀ11). Sodium borohydride &131 mg, 3.4 mmol) was
added in portions with stirring to 4-&4-methoxyphenyl)-
1,6,6-trimethyl-2-oxa-3-azabicyclo[3.1.0]hex-3-ene
&4)
&160 mg, 0.7 mmol) and NiCl2´6H20 &329 mg, 1.4 mmol)
in methanol &30 ml) at 2208C under nitrogen. After
5 min, the mixture was allowed to reach room temperature
and stirred for 40 min. After work-up as given earlier, the
residue was passed over a short column of silica, eluting
with ether, to give a pale yellow oil, 5-amino-5-*4-methoxy-
phenyl)-3,3-dimethylpentan-2-ol &11, RˆMe) &115 mg,
70%) as a 62:38 mixture of diastereomers &no M1 was
observed). The major isomer showed: dH 0.98 &3H, s,
CH3), 1.08 &3H, s, CH3), 1.09 &3H, d, 6.4 Hz, CH3), 1.69
&1H, dd, Jˆ10.0, 12.5 Hz, ®rst of H-4), 1.98 &1H, br s, OH),
2.07 &1H, dd, Jˆ7.2, 12.5 Hz, second of H-4), 3.14 &1H, q,
Jˆ6.4 Hz, H-2), 3.84 &3H, s, OCH3), 4.34 &1H, dd, Jˆ7.2,
10.0 Hz, H-5), 6.88±6.92 &2H, m, aromatic), 7.30±7.34 &2H,
m, aromatic); dC 14.9 &CH3), 20.5 &C-1), 25.7 &CH3), 42.0
&C-3), 51.7 &C-4), 55.3 &OCH3), 58.5 &C-5), 63.2 &C-2),
113.8, 127.2, 139.4, 158.2 &all aromatic C). The minor
isomer showed: dH 1.00 &3H, s, CH3), 1.12 &3H, s, CH3),
1.13 &3H, d, 6.4 Hz, CH3), 1.62 &1H, dd, Jˆ8.4, 12.9 Hz,
®rst of H-4), 1.98 &1H, br s, OH), 2.06 &1H, dd, Jˆ8.4,
12.9 Hz, second of H-4), 2.96 &1H, q, Jˆ6.4 Hz, H-2),
3.84 &3H, s, OCH3), 4.18 &1H, t, Jˆ8.4 Hz, H-5), 6.88±
6.92 &2H, m, aromatic), 7.30±7.34 &2H, m, aromatic); dC
15.6 &CH3), 24.5 &C-1), 27.8 &CH3), 40.3 &C-3), 50.0
&C-4), 55.3 &OCH3), 59.6 &C-5), 63.8 &C-2), 113.7, 127.7,
1.2.6. [6-ꢀ4-Methoxyphenyl)-6-methyl-2-oxa-3-azabicy-
clo[3.1.0]hex-3-en-4-yl]methanol ꢀ14). A solution of
methyl endo-6-methyl-6-phenyl-2-oxa-3-azabicyclo[3.1.0]-
hex-3-ene-4-carboxylate &6, RˆPh) &60 mg, 0.24 mmol) in
dry ether &5 ml) was added to a suspension of LiAlH4
&30 mg, 0.79 mmol) in dry ether &5 ml). The mixture was
re¯uxed for 2 h. Work-up as for &8) gave pure [6-*4-meth-
oxyphenyl)-6-methyl-2-oxa-3-aza-bicyclo[3.1.0]hex-3-en-
4-yl]methanol &14, RˆPh) &40 mg, 80%). The compound
was not fully characterised but showed dH 1.21 &3H, s,
CH3), 2.99 &1H, br s, OH), 3.02 &1H, d, Jˆ5.5 Hz, H-5),
4.51 &2H, s, CH2OH), 4.98 &1H, d, Jˆ5.5 Hz, H-1), 7.20±
7.40 &5H, m, aromatic); dC 12.8 &CH3), 20.5 &C-6), 40.8
&C-5), 58.1 &CH2OH), 74.7 &C-1), 126.3, 128.7, 142.4,
160.4 &C-4).
136.9, 156.1; nmax &mixture) 2955 s, 1511 s, 1244 s cm21
m/z, % 220, 12 &M12OH);219, 28;218, 17;176, 19;163,
100;162, 75;161, 73;148, 16;134, 16;121, 15;91, 8;77, 8.
;
1.2.7. 3-ꢀ1-Amino-2-hydroxyethyl)-2,2-dimethylcyclo-
propanol ꢀ16). Lithium aluminium hydride &414 mg,
10.9 mmol) was added in small portions to a solution of
methyl 6,6-dimethyl-2-oxa-3-azabicyclo[3.1.0]hex-3-ene-
4-carboxylate &7, RˆMe) &1 g, 5.4 mmol) in dry ether
&50 ml). The mixture was stirred for 2 h at room tempera-
ture. Drops of sat. aq. Na2SO4 were added as given earlier.
The resulting suspension was ®ltered through a layer of
anhydrous MgSO4 and a clear solution &I) was obtained.
Washing the ®lter residue with ethyl acetate &2£15 ml)
1.2.4. 2-[Aminoꢀ4-methoxyphenyl)methyl]-1-butylcyclo-
propanol ꢀ12). 1-Butyl-4-&4-methoxyphenyl)-2-oxa-3-
azabicyclo[3.1.0]hex-3-ene &400 mg, 1.6 mmol) in dry
ether &10 ml) was added to a suspension of LiAlH4
&124 mg, 3.3 mmol) in dry ether &10 ml). The mixture was
re¯uxed for 27 h. Work-up as for &8) gave a yellow oil, 2-
[amino*4-methoxyphenyl)methyl]-1-butylcyclopropanol
&12) &330 mg, 81%);further puri®cation was not required

9856
M. S. Baird et al. / Tetrahedron 57 *2001) 9849±9858
gave solution &II). Solution &I) was concentrated to give a
crude mixture of 3-*1-amino-2-hydroxyethyl)-2,2-dimethyl-
cyclopropanol &16, RˆMe) and [6,6-dimethyl-2-oxa-3-
azabicyclo[3.1.0]hex-3-en-4-yl]methanol &15, RˆMe)
&ratio, 71:29;total 400 mg). Solution &II) was left to stand
overnight and colourless crystals formed, identi®ed as &16,
RˆMe) &110 mg, 14%), mp 109±1118C &Found: C 58.1, H
10.4, N 9.8. C7H15NO2 requires: C 57.90, H 10.41, N 9.65)
which showed dH &CD3OD) 0.40 &1H, dd, Jˆ7.0, 10.2 Hz,
H-3), 1.04 &3H, s, CH3), 1.21 &3H, s, CH3), 2.88 &1H, ddd,
Jˆ4.5, 7.2, 10.2 Hz, CH±NH2), 3.10 &1H, d, Jˆ7.0 Hz,
H-1), 3.43 &1H, dd, Jˆ7.2, 10.3 Hz, ®rst H of CH2OH),
3.67 &1H, dd, Jˆ4.5, 10.3 Hz, second H of CH2OH), 4.90
&4H, br s, 2H, OH and NH2); dC &CDOD) 14.3 &CH3), 19.9
&C-2), 27.3 &CH3), 32.4 &C-3), 50.5 &CH±NH2), 58.8 &C-1),
68.3 &CH2OH); nmax 3376 br s, 3319 s, 3263 s, 3086 br s,
2973 br s, 2688 br s, 1601 s, 1459 s, 1418 s, 1332 s, 1196 s,
&separately) and the residue recrystallised from ethyl
acetate. Solution &I) yielded 14% &80% ee), solution &II)
yielded 64% &99% ee) &total yield 78%). The reaction was
also repeated using modi®ed conditions: stirring for 24 h at
room temperature gave a yield of 76% &93% ee);stirring for
24 h at 2708C gave 95% &79% ee).
1.2.9. [ꢀ5RS)-3-ꢀ4-Methoxyphenyl)-4,5-dihydroisoxazol-
5-yl]methanol ꢀArˆ4-MeOC6H4) ꢀ19). Triethylamine
&2.7±2.8 mmol) was added dropwise to a stirred solution
of N-hydroxy-4-methoxybenz-imidoyl chloride &500 mg,
13.5 mmol) &2.7 mmol) and allyl alcohol &1.1 ml,
16.2 mmol) in ether &20 ml) at 08C;triethylammonium
chloride precipitated. The mixture was stirred at room
temperature for 12 h and then treated with hydrochloric
acid &2%, 10 ml), extracted with ethyl acetate &3£10 ml)
and the combined organic layers dried. The solvent was
removed and the residue was recrystallised from ethyl
acetate/petrol to give [*5RS)-3-*4-methoxyphenyl)-4,5-di-
hydroisoxazol-5-yl]methanol &19) &1.6 g, 57%) as a white
crystalline solid;mp 135 8C. NMR, IR and MS data were
identical to those given for &5R)-&18)) &described earlier).
1146 s, 1043 s, 978 s, 893 s, 863 s, 709 s, 667 s, 520 s cm21
;
m/z, % 146, 3 &M111);116, 9;114, 18;99, 10;97, 10;81,
26;60, 100;58, 30;43, 58.5. Compound &
15, RˆMe)
showed: dH 0.85 &3H, s, CH3), 1.06 &3H, s, CH3), 2.41
&1H, d, Jˆ5.5 Hz, H-5), 4.32 &2H, s, CH2OH), 4.52 &1H,
d, Jˆ5.5 Hz, H-1).
1.2.10. ꢀ5RS)-5-Chloromethyl-3-ꢀ4-methoxyphenyl)-4,5-
dihydroisoxazole ꢀ20). The procedure given in Section
1.2.9 was used to react allyl chloride &0.33 ml, 4.05 mmol)
with N-hydroxy-4-methoxybenzimidoyl chloride &250 mg,
1.35 mmol), yielding *5RS)-5-chloromethyl-3-*4-methoxy-
phenyl)-4,5-dihydroisoxazole &20) &185 mg, 61%) as a
white solid;mp 70 8C. NMR, IR and MS data were identical
to those given for the enantiomerically pure compound &see
Section 1.2.11).
1.2.8. [ꢀ5R)-3-ꢀ4-Methoxyphenyl)-4,5-dihydroisoxazol-5-
yl]methanol ꢀ18) ꢀArˆ4-MeOC6H4). Diethylzinc
&1.2 mol equiv., 1.1 M in toluene or 1.0 M in hexane) was
added at 08C to a CHCl3 &6 ml) solution of allyl alcohol
&2.7 mmol) under argon and the mixture was stirred for
10 min. A CHCl3 &6 ml) solution of &R,R)-DIPT &0.2 mol
equiv.) was added and the mixture was stirred for 1 h. A
CHCl3 &6 ml) solution of with N-hydroxy-4-methoxybenzi-
midoyl chloride &500 mg, 2.7 mmol, 1.0 mol equiv.) and
1,4-dioxane &1.5 mol equiv.) was added;the resulting solu-
tion was stirred for 24 h at 08C. Sat. aq. NH4Cl was added,
followed by hydrochloric acid &2%). The aqueous layer was
extracted with CHCl3 and the combined organic layers were
dried and evaporated. Chromatography &petrol/ethyl
acetate, 1:1) gave [*5R)-3-*4-methoxyphenyl)-4,5-dihydro-
isoxazol-5-yl]methanol &18) &379 mg, 68%) with 97% ee,
1.2.11. ꢀ5R)-5-Chloromethyl-3-ꢀ4-methoxyphenyl)-4,5-
dihydroisoxazole ꢀ23). A solution of [&5R)-3-&4-methoxy-
phenyl)-4,5-dihydroisoxazol-5-yl]methanol &18) &200 mg,
0.96 mmol) and thionyl chloride &0.7 ml, 9.6 mmol) in
pyridine &10 ml) was stirred for 6 h at 1008C. Excess thionyl
chloride was removed by ¯ash distillation, dichloromethane
&20 ml) and hydrochloric acid &2%, 20 ml) were added. The
aqueous layer was extracted with dichloromethane
&2£20 ml). The combined organic layers were washed
with hydrochloric acid &2%, 2£40 ml) and water &40 ml),
dried and evaporated. Chromatography of the residue
&petrol then petrol/ether, 1:1) gave *5R)-5-chloromethyl-3-
*4-methoxyphenyl)-4,5-dihydro-isoxazole &23) &96 mg,
30
25
[a]D ˆ11408 &c 0.4, MeOH) &lit.13,19: [a]D ˆ11208 &c
0.4, MeOH)), a white crystalline solid, mp 1578C &Found:
C 64.3, H 6.6, N 6.81. C11H13NO3 requires: C 63.76, H 6.32,
N 6.76) which showed dH 1.89 &1H, br s, OH), 3.23 &1H, dd,
Jˆ7.9, 16.5 Hz, ®rst of H-4), 3.36 &1H, dd, Jˆ10.5, 16.5 Hz,
second of H-4), 3.64 &1H, dd, Jˆ4.7, 12.1 Hz, ®rst H of
CH2OH), 3.81 &3H, s, OCH3), 3.83 &1H, dd, Jˆ3.2,
12.1 Hz, second H of CH2OH), 4.82 &1H, dddd, Jˆ3.2,
4.7, 7.9, 10.6 Hz, H-5), 6.86±6.90 &2H, m, aromatic),
7.55±7.59 &2H, m, aromatic); dC &CD3OD) 37.9 &C-4),
56.1 &OCH3), 64.4 &CH2OH), 83.0 &C-5), 115.5, 123.7,
129.6, 158.4, 163.0 &C-3); nmax 3361 br s, 1611 s, 1520 s,
1364 s, 1263 s, 1183 s, 1106 m, 1053 s, 929 s, 904 s, 833 s,
813 s cm21; m/z, % 207, 100 &M1);176, 68;148, 27;121,
56;92, 13;77, 23.
26
44%), [a]D ˆ250.48 &c 0.4, CHCl3), a white solid mp
858C &Found: C 58.6, H 5.2, N 6.4. C11H12ClNO2 requires:
C 58.54, H 5.36, N 6.21) which showed dH 3.29 &1H, dd,
Jˆ6.4, 16.9 Hz, ®rst of H-4), 3.37 &1H, dd, Jˆ10.3, 16.9 Hz,
second of H-4), 3.54 &1H, dd, Jˆ7.6, 11.2 Hz, ®rst H of
CH2Cl), 3.69 &1H, dd, Jˆ4.4, 11.2 Hz, second H of
CH2Cl), 3.82 &3H, s, OCH3), 4.94 &1H, dddd, Jˆ4.4, 6.4,
7.6, 10.3 Hz, H-5), 6.89±6.93 &2H, m, aromatic), 7.58±7.62
&2H, m, aromatic); dC 38.8 &C-4), 44.8 &CH2Cl), 55.3
&OCH3), 79.5 &C-5), 114.1, 121.5, 128.3, 155.7, 161.2 &C-3);
When the reaction was repeated on a larger scale &27 mmol)
the work-up procedure was altered, due to the poor solu-
bility of &18): after stirring for 24 h, the mixture was
quenched with a few drops of a sat. aq. NH4Cl and ®ltered
through anhydrous MgSO4 when a clear solution &I) was
obtained. Washing the ®lter residue with hot ethyl acetate
gave solution &II). The solutions were concentrated
nmax 1609 s, 1598 s, 1517 s, 1460 s, 1420 s, 1360 s, 1311 s,
1255 s, 1180 s, 1040 s, 1021 s, 911 s, 887 s, 836 s, 816 s, 677 s,
608 s, 538 s cm21; m/z, % 227, 26;225, 70 &M 1);176, 62;148,
33;133, 13;132, 121, 100;107, 13;92, 28;77, 50;63, 18.
1.2.12. [ꢀ5R)-3-ꢀ4-Methoxyphenyl)-4,5-dihydroisoxazol-
5-yl]methyl mesylate ꢀ24). Methanesulfonyl chloride

M. S. Baird et al. / Tetrahedron 57 *2001) 9849±9858
9857
&0.03 ml, 0.43 mmol, 0.6 mol equiv.) was added to [&5R)-3-
&4-methoxyphenyl)-4,5-dihydroisoxazol-5-yl]methanol
&18) &150 mg, 0.72 mmol) and triethylamine &0.06 ml,
0.43 mmol, 0.6 mol equiv.) in dichloromethane &5 ml) and
stirred for 20 min at room temperature. More triethylamine
&0.06 ml, 0.43 mmol, 0.6 mol equiv.) and methanesulfonyl
chloride &0.03 ml, 0.43 mmol, 0.6 mol equiv.) were added
&a total of 1.2 mol equiv. of MsCl and base were used). After
an additional 20 min, water &10 ml) was added and the
aqueous layer was extracted with dichloromethane
&3£15 ml). The combined organic layers were washed
with water &30 ml), dried and evaporated. The residue was
recrystallised from ethyl acetate/petrol to give [*5R)-3-*4-
methoxyphenyl)-4,5-dihydro-isoxazol-5-yl]methyl mesylate
recrystallised from ether/petrol to give *1RS,5RS)-4-*4-
methoxyphenyl)-2-oxa-3-azabicyclo[3.1.0]hex-3-ene &21)
&1.09 g, 52%), as a white solid, mp 838C. Analytical data
were identical to those of the enantiomerically pure
compound &see Section 1.2.13).
1.2.15. ꢀ1S,2S)-2-[ꢀS)-Aminoꢀ4-methoxyphenyl)methyl]-
cyclopropan-1-ol ꢀ26). A solution of azabicycle &25)
&200 mg, 1.06 mmol) in dry ether &15 ml) was added to a
suspension of LiAlH4 &80 mg, 2.12 mmol) in ether &10 ml)
and the mixture was re¯uxed for 16 h. Work-up as for &8)
gave *1S,2S)-2-[*S)-amino*4-methoxyphenyl)-methyl]-cyclo-
propan-1-ol &26) &118 mg, 58%) as a white solid, mp 80±
26
838C, [a]D ˆ165.58 &c 0.4, MeOH) &Found: C 68.2, H 8.1,
26
N 7.2. C11H15NO2 requires: C 68.37, H 7.82, N 7.25) which
showed dH 0.56 &1H, dt, Jˆ3.3, 6.7 Hz, Hcis-3 &relative to
H-1)), 0.76 &1H, td, Jˆ6.7, 9.2 Hz Htrans-3 &relative to
H-1)), 0.94 &1H, tdd, Jˆ6.7, 7.0, 9.2 Hz, H-2), 2.60 &3H, br
s, NH2 and OH), 3.45 &1H, dt, Jˆ3.3, 6.7 Hz, H-1), 3.74 &3H,
s, OCH3), 3.91 &1H, d, Jˆ7.0 Hz, CH±NH2), 6.81±6.85 &2H,
m, aromatic), 7.28±7.32 &2H, m, aromatic); dC 10.6 &C-3),
24.0 &C-2), 49.8 &CH±NH2), 52.9 &C-1), 55.2 &OCH3), 113.8,
127.3, 138.4, 158.5; nmax 3340 br s, 2999 s, 2934 s, 2836 s,
1614 s, 1514 s, 1462 s, 1252 s, 1177 s, 1035 s, 834 s cm21;
m/z, % 177, 10;176, 67 &M 12OH);173, 25;158, 13;149, 37;
147, 100;136, 53;134, 99;121, 23;109, 18;91, 21;77, 18.
&24) &175 mg, 85%), [a]D ˆ2137.68 &c 1.0, CHCl3) as
colourless crystals, mp 1618C &Found: C 50.4, H 5.1, N
5.0. C12H15NO5S requires: C 50.52, H 5.30, N 4.91) which
showed dH 3.07 &3H, s, SO2CH3), 3.25 &1H, dd, Jˆ7.0,
16.8 Hz, ®rst of H-4), 3.46 &1H, dd, Jˆ10.8, 16.8 Hz,
second of H-4), 3.83 &3H, s, OCH3), 4.32 &1H, dd, Jˆ4.9,
11.4 Hz, ®rst H of CH2O), 4.37 &1H, dd, Jˆ4.1, 11.4 Hz,
second H of CH2O), 4.97 &1H, dddd, Jˆ4.1, 4.9, 7.0,
10.8 Hz, CH±O), 6.89±6.93 &2H, m, aromatic), 7.56±7.69
&2H, m, aromatic); dC 37.2 &C-4), 37.8 &SO2CH3), 55.4
&OCH3), 69.5 &CH2O), 77.5 &C-5), 114.2, 121.2, 128.3,
156.0, 161.4 &C-3); nmax 1607 s, 1594 s, 1517 s, 1458 s,
1422 s, 1320 s, 1254 s, 1004 s, 972 s, 907 s, 875 s, 834 s,
817 s cm21; m/z, % 285, 42 &M1);176, 100;160, 9;148, 18;
147, 20;134, 10;132, 11;107, 7;92, 11;77, 17.
1.2.16.
ꢀ1RS,2RS)-2-[ꢀRS)-Aminoꢀ4-methoxyphenyl)-
methyl]cyclopropan-1-ol ꢀ22). A solution of azabicycle
&21) &100 mg, 0.53 mmol) in dry ether &10 ml) was added
to a suspension of LiAlH4 &40 mg, 1.06 mmol) in ether
&10 ml) and the mixture re¯uxed for 24 h. Work-up as
for &8) gave *1RS,2RS)-2-[*RS)-amino*4-methoxyphenyl)-
methyl]-cyclopropan-1-ol &22) &90 mg, 88%) as a yellow
oil. Spectroscopic data were identical to those of the
enantiomerically pure compound &see Section 1.2.15).
1.2.13. ꢀ1S,5S)-4-ꢀ4-Methoxyphenyl)-2-oxa-3-azabicyclo-
[3.1.0]hex-3-ene ꢀ25). Potassium t-butoxide &1.62 g,
14.5 mmol) was added in small portions to &5R)-3-&4-meth-
oxyphenyl)-4,5-dihydroisoxazol-5-ylmethyl mesylate &1.38 g,
4.8 mmol) &crude 24, prepared from chiral alcohol 18 &1.0 g,
4.8 mmol) as described earlier) in anhydrous dimethyl
sulfoxide &15 ml) at room temperature. After stirring for
1 h, water &30 ml) was added and the aqueous layer was
extracted with ethyl acetate &3£30 ml). The combined
organic layers were washed with water &2£80 ml), dried
and evaporated;chromatography of the residue &petrol/
ethyl acetate, 3:1) gave *1S,5S)-4-*4-methoxyphenyl)-2-
oxa-3-azabicyclo[3.1.0]hex-3-ene &25) &670 mg, 73% over
Acknowledgements
We thank Eastman Peboc for partial support for F. A. M. H.
26
two steps), [a]D ˆ2154.68 &c 1.0, CHCl3) as a white solid,
mp 1098C &Found: C 69.6, H 5.9, N 7.6. C11H11NO2
requires: C 69.83, H 5.86, N 7.40) which showed dH 0.43
&1H, ddd, Jˆ2.2, 3.8, 5.5 Hz, Hendo-6), 1.04 &1H, dt, Jˆ5.5,
9.2 Hz, Hexo-6), 2.84 &1H, ddd, Jˆ3.8, 5.5, 9.2 Hz, H-5),
3.83 &3H, s, OCH3), 4.99 &1H, dt, Jˆ2.2, 5.5 Hz, H-1),
6.91±6.95 &2H, m, aromatic), 7.70±7.74 &2H, m, aromatic);
dC 8.0 &C-6), 25.9 &C-5), 55.3 &OCH3), 63.9 &C-1), 114.1,
121.6, 128.7, 161.2 and 161.3 &aromatic C and C-4); nmax
1608 s, 1584 s, 1517 s, 1425 s, 1377 s, 1308 s, 1249 s, 1189
s, 1178 s, 1113 s, 1081 s, 1028 s, 975 s, 936 s, 871 s, 848 s,
823 s, 790 s, 665 m, 603 s, 532 s cm21; m/z, % 189, 25 &M1);
160, 100;134, 10;115, 5;107, 7;103, 6;92, 13;77, 17;64,
10.
References
È
1. Jager, V.;Buss, V.;Schwab, W. Tetrahedron Lett. 1978, 3133.
È
2. Jager, V.;Buss, V. Liebigs Ann. Chem. 1980, 101.
È
3. Jager, V.;Buss, V.;Schwab, W. Liebigs Ann. Chem. 1980,
122.
4. Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Tetrahedron OrganicChemistry Series , Vol. 8;Pergamon:
Oxford, 1990.
È
È
5. Jager, V.;Mu ller, I. Tetrahedron Lett. 1985, 26, 2997.
6. Salaun, J.;Baird, M. S. Curr. Med. Chem. 1995, 2, 511.
7. See for e.g. Bolesov, I. G.;Ignatchenko, A. V.;Bovin, N. A.;
Prudchenko, I. A.;Surmina, L. S.;Plemenkov, V. V.;Petrovs-
kii, P. V.;Romanov, I. V.;Mel'nik, I. I. J. Org. Chem. USSR
1990, 87.
1.2.14. ꢀ1RS,5RS)-4-ꢀ4-Methoxyphenyl)-2-oxa-3-azabi-
cyclo[3.1.0]hex-3-ene ꢀ21). &5RS)-5-Chloromethyl-3-&4-
methoxyphenyl)-4,5-dihydroisoxazole &19) &2.5 g, 0.011
mol) was treated with potassium t-butoxide &3.73 g,
0.033 mol) as given earlier. The crude product was
8. Doyle, M. P.;Protopopova, M. N.;Muller, P.;Ene, D. J. Am.
Chem. Soc. 1994, 116, 8492.
9. Huber, F. A. M. PhD Thesis, University of Wales, 1999.
10. Shimizu, M.;Ukaji, Y.;Inomata, K. Chem. Lett. 1996, 455.

9858
M. S. Baird et al. / Tetrahedron 57 *2001) 9849±9858
11. Ashraf, M. C.;Burrows, T. G.;Jackson, W. R. Aust. J. Chem
1976, 29, 2643.
Perkin Trans. 1 1986, 1845. Al Dulayymi, J. R.;Baird, M. S.;
Simpson, M.;Nyman, S.;Port, G. R. Tetrahedron 1996, 52,
12509.
12. Burrows, T. G.;Jackson, W. R.;Faulks, S.;Sharp, I. Aust. J.
Chem. 1977, 30, 1855.
17. For the corresponding methyl ester see Ref. 6.
18. Grundmann, C.;Grunanger, P. The Nitrile Oxides;Springer:
Berlin, 1971. Torsell, K. B. G. Nitrile Oxides, Nitrones and
Nitronates in OrganicSynthesis ;VCH: New York, 1988.
19. Ukaji, Y.;Sada, K.;Inomata, K. Chem. Lett. 1993, 1847.
Ukaji, Y.;Sada, K.;Inomata, K. Chem. Lett. 1993, 1227.
13. Yoshida, Y.;Ukaji, Y.;Fujinami, S.;Inomata, K. Chem. Lett.
1998, 1023.
14. Perrin, D. D.;Armarego, W. L. F.;Perrin, D. R. Puri®cation of
Laboratory Chemicals;3rd ed.;Pergamon: Oxford, 1988.
15. Li, X. PhD Thesis, University of Wales, Bangor, 1995.
16. Baird, M. S.;Hussain, H. H.;Nethercott, W. J. Chem. Soc.,