[2+3] Cycloadditions between nitroalkenes and camphor-derived oxazoline N-oxides and radical denitration of the adducts

Article abstract of DOI:10.1055/s-2003-40191

[2+3] Cycloadditions between camphor-derived oxazoline N-oxide 2 and nitroalkenes 3a-f afforded stereoselectively adducts 4a-f. Radical denitration followed by acidic hydrolysis gave rise to anti-aldols 8a,b. The radical intermediate was also trapped by a suitable alkene, giving rise to a single stereoisomer.

Full text of DOI:10.1055/s-2003-40191

SPECIAL TOPIC
1419
[2+3] Cycloadditions Between Nitroalkenes and Camphor-Derived Oxazoline
N-Oxides and Radical Denitration of the Adducts
[2+3]
C
ycloadditio
r
ns Betw
n
een
N
itroalk
a
ene
s
and
C
a
u
mphor-Deri
d
ved
O
xazoline
N
-O
V
xides oituriez, Julien Moulinas, Cyrille Kouklovsky,* Yves Langlois*
Laboratoire de Synthèse Des Substances Naturelles Associé au CNRS, ICMMO, Bâtiment 410, Université de Paris-Sud, 91405 Orsay,
France
Fax +33(1)69154679; E-mail: cykouklo@icmo.u-psud.fr; E-mail: langlois@icmo.u-psud.fr
Received 28 April 2003
groups. Particularly, we were interested in the radical de-
Abstract: [2+3] Cycloadditions between camphor-derived oxazo-
nitration of nitro-substituted cycloadducts since [2+3] cy-
cloaddition reactions of oxazoline N-oxide 2 are limited in
line N-oxide 2 and nitroalkenes 3a–f afforded stereoselectively ad-
ducts 4a–f. Radical denitration followed by acidic hydrolysis gave
most cases to electron-deficient alkenes as dipolarophiles,
even the use of cyclopentadiene4 or intramolecular
cycloadditions5 can overcome the poor reactivity ob-
served with other alkenes. In this context, it appears that
cycloadditions between dipole 2 and nitroalkenes, fol-
lowed by denitration of the adducts should constitute an
equivalent of this type of cycloaddition between 2 and un-
functionalized alkenes (Scheme 2).
rise to anti-aldols 8a,b. The radical intermediate was also trapped
by a suitable alkene, giving rise to a single stereoisomer.
Key words: cycloaddition, asymmetric synthesis, radical
Introduction
In the recent years, we have investigated the asymmetric
[2+3] cycloaddition reaction between camphor-derived
oxazoline N-oxide 2 and various electron-deficient al-
kenes. This reaction proceeds in a highly regio- and stere-
oselective fashion, a single isomer often being obtained
via an endo-transition state.1,2 Oxidative cleavage of the
chiral auxiliary gives rise to enantiomerically pure -hy-
droxy aldehydes, which can be used as chirons for the
synthesis of natural products (Scheme 1); this reaction se-
quence has been applied, using either , -unsaturated es-
ters or nitriles, to the synthesis of pheromones, of
-
lactones and -lactams.3
Scheme 2
In the present article, we report several new examples of
asymmetric [2+3] cycloadditions between 2 and various
nitroalkenes, and a study of the stereoselective denitration
of the resulting adducts, as well as their transformation
into anti- -hydoxyesters.
Asymmetric [2+3] Cycloaddition Reaction with Ni-
troalkenes
Scheme 1
Recently, we have turned our attention to the cycloaddi-
tion reactions with nitroalkenes as dipolarophiles, because
of the high reactivity of these compounds, and the nitro
function can be transformed into various other functional
Previous results from this laboratory have shown that ni-
troalkenes display good reactivity in the asymmetric
[2+3] cycloaddition with dipole 2, the reaction occuring in
refluxing dichloromethane to give cycloadducts with
good yields and high selectivity.2 This reaction may be ex-
tended to the use of trisubstituted nitroalkenes, which
gives rise to cycloadducts without loss of reactivity or re-
gioselectivity.
Synthesis 2003, No. 9, Print: 03 07 2003.
Art Id.1437-210X,E;2003,0,09,1419,1426,ftx,en;C01403SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

1420
A. Voituriez et al.
SPECIAL TOPIC
Dipolarophiles used in the present study were nitroal-
kenes 3a–f which were either commercially available (3f)
or prepared according to known procedures.6,7 The chiral
dipole 2 was prepared in situ by reaction of hydroxylami-
no isoborneol hydrochloride 1 with trimethyl orthofor-
mate following the described procedure. After stirring for
4 hours at 45 °C, the nitroalkene (3 equiv) was added and
the reaction was followed by TLC (Scheme 3).
Figure 1 Principle effects in 1H NMR
These results illustrate the remarkable reactivity of ni-
troalkenes in the asymmetric [2+3] cycloaddition reaction
with dipole 2, as a great variety of substitution onto the
double bond is allowed, including alkyl or aryl substitu-
ents, without any loss of regio- or stereoselctivity.
Radical Denitration of Nitro Substituted Cyclo-
adducts
With cycloadducts 4a–f in hand, their radical denitration
was studied. This reaction has been throughly investigat-
ed,8 and is known to proceed under standard radical con-
ditions (Bu3SnH, AIBN) at high temperature (generally in
refluxing toluene), giving good yields with tertiary ni-
troalkenes as substrates, whereas secondary nitroalkenes
give low yields and conversions.9 The radical denitration
may be associated with inter- or intramolecular addition to
a radical acceptor.10
Cycloadducts 4a and 4b, when treated with excess tributyl
tin hydride and AIBN, underwent the radical denitration
under slightly milder conditions than described (refluxing
benzene) to give the unfunctionalized adducts 5a and 5b
in good yields and stereoselectivity. Compound 5a
(R2 = Ph) was obtained as a single stereoisomer, whereas
compound 5b (R2 = n-Bu) was obtained as a 9:1 mixture
of stereoisomers. 1H NMR analysis of the products (with
NOESY) showed inversion of configuration at the carbon
C3, the methyl substituent being in the endo position. Per-
forming the reaction at higher temperature resulted in par-
tial degradation of the reaction mixture, whereas the use
of bulkier hydride reagents (eg. Ph3SnH) did not improve
selectivity. When radical denitration of cycloadduct 4b
Scheme 3
Reaction conditions and results are summarized in
Table 1. As previously observed,2 cycloaddition reactions
between nitroalkenes 3a–f and oxazoline N-oxide 2 gave
in a regio- and stereoselective fashion endo adduct 4a–f
(major). The structure of adducts 4a–f were deduced after
NOE experiments as exemplified in adduct 4a, thus con-
firming the endo transition state of the cycloaddition reac-
tion (Figure 1).
Table 1 Compounds 4a–f Prepared
Entry
Alkene
Solvent
Time (h)
Adduct
Endo
Yield (%)
(Temp, °C)
/Exo
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
CH2Cl2
PhMe
18 (45)
18 (60)
18 (45)
18 (45)
18 (45)
2 (45)
4a
4b
4c
4d
4e
4f
>95/5
>95/5
84/16
>95/5
>95/5
>95/5
75
73
80
67
43
70
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Synthesis 2003, No. 9, 1419–1426 ISSN 1234-567-89 © Thieme Stuttgart · New York

SPECIAL TOPIC
[2+3] Cycloadditions Between Nitroalkenes and Camphor-Derived Oxazoline N-Oxides
1421
was perfomed with tributyltin deuteride, complete incor- radical intermediate with the isobutyronitrile radical
poration of deuterium on carbon C3 was observed, thus in- (Scheme 6).
dicating there was no hydride abstraction from the radical
intermediate during the radical-chain process. The stabil-
ity of the radical intermediate ( to an oxazolidine ring) is
note worthy (Scheme 4).
Scheme 6
These results demonstrate the efficiency of the asymmet-
ric [2+3] cycloaddition-radical denitration sequence for
the preparation of unfunctionalized cycloadducts 5 when
Scheme 4
trisubstitued nitroalkenes are used as dipolarophiles for
the cycloaddition reaction. The radical denitration occurs
with high stereoselectivity, leading to trans-alkyl- or aryl-
disubstituded cycloadducts. The synthetic utility of this
sequence was further demonstrated by the transformation
of compounds 5a,b into the known -hydroxy esters
8a,b.11,12 Accordingly, following previously described
conditions, compounds 5a,b were oxidized with excess
MCPBA. The resulting nitrone intermediates were hydro-
lyzed under acidic conditions to give -hydoxy aldehydes
7a,b, which were in turn oxidized to the corresponding
carboxylic acids. After diazomethane esterification, the -
hydroxy esters 8a and 8b were isolated in 29% and 34%
overall yield respectively (Scheme 7).
The stereoselectivity of this radical reaction may be ex-
plained by the formation of a bowl-shaped radical inter-
mediate 6, which undergoes attack by tin hydride from the
exo-face (convex face). Although the role of the substitu-
ent at carbon C2 is not clearly understood, its absence re-
sults in complete loss of selectivity, as illustred by the
radical denitration of cycloadduct 4c (Scheme 5).
Diastereo- and enantiomeric excess of esters 8a and 8b
were measured by NMR.11,12 The anti/syn ratio of 8a was
90:10 based on 13C NMR chemical shifts at 14.0 ppm and
45.2 ppm for the major anti-isomer and at 10.2 ppm and
43.3 ppm for the minor syn-isomer. In the presence of (+)
Eu(Hfc)3, the 1H NMR spectrum of 8a showed peaks for
the OMe group at 4.07 ppm (major anti-isomer) and 4.15
ppm (minor syn-isomer) respectively. The enantiomeric
purity of each isomer was found to be up to 98%. The
same analysis for compound 8b showed both diastereo-
and enantiomeric purities to be up to 98%.
Scheme 5
Results for the denitration of cycloadducts 4a–f are sum-
marized in Table 2. Tertiary nitroalkanes gave good
yields and stereoselectivity, whereas denitration of sec-
ondary nitroalkane 4f gave as expected low yields. Deni-
tration of cycloadduct 4d required a slow addition of tin
hydride and AIBN in order to prevent recombination of
Table 2 Denitration of Cycloadducts 4a–fa
Entry
Cycloadduct
R
R1
Product
5a
Yield%
70
dsd
90/10
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
Bu
Ph
H
Me
Me
Me
5b
95
>95/5
50/50
>95/5
>95/5
–
5c
48
-(CH2)4-
5d
69b
53
Bu
Bu
Ph
H
5e
5f
14c
a Conditions:Bu3SnH (2equiv), AIBN (1.2 equiv), benzene, reflux.
b AIBN was added over 10 h (syringe pump).
c In refluxing toluene, reaction gave 25% yield.
d Ratio was determined by NMR.
Synthesis 2003, No. 9, 1419–1426 ISSN 1234-567-89 © Thieme Stuttgart · New York

1422
A. Voituriez et al.
SPECIAL TOPIC
Scheme 8
Scheme 7
Tandem Radical Denitration-Cyclization Reaction
Having demonstrated the good stereoselectivity of the
radical denitration of nitro-substituted cycloadducts, we
attempted a tandem radical denitration-cyclization reac-
tion. This radical sequence has often been used for the
stereoselective preparation of cyclic compounds, and in-
volves the intramolecular addition of the radical onto an
activated double bound.13 The application of this se-
quence to a nitro-substituted cycloadducts therefore re-
quires the preparation of a dipolarophile with a
nitroalkene function and another electron-deficient dou-
ble bond. The known , -unsaturated ester 914 was there-
fore prepared and reacted with excess dipole 2 under
standard conditions (CH2Cl2, reflux), to give the cycload-
duct 10 as a single isomer in 70% yield (Scheme 8). The
reaction showed remarkable chemoselectivity since de-
spite being more substituted, only the nitroalkene function
reacts in the cycloaddition. No trace of cycloadduct with
the , -unsaturated ester was detected in the crude prod-
uct. Upon treatment of 10 with excess tin hydride and
AIBN in refluxing benzene, a 5-exo-trig cyclization oc-
cured, leading to the cyclopentane product 11 as a single
stereoisomer (70% yield). Extensive NMR analysis of
compound 11 (with COSY, NOESY and HSQC) proved
the syn relationship between the proton at carbon C2, the
methyl substituent at C3, and the proton at C2 , thus estab-
lishing the (3R,1 R) configurations for the newly created
stereogenic centers.
Scheme 9
Conclusion
A new asymmetric [2+3] cycloaddition-radical denitra-
tion sequence was developed for the preparation of un-
functionalized cycloadducts, formally resulting from
cycloaddition with simple alkenes. This sequence is effi-
cient when various trisubstituted nitroalkenes are used,
and shows excellent stereoselectivity, as a single isomer is
obtained in most cases. This sequence may also be associ-
ated with a radical cyclization process, as shown for the
preparation of compound 11, with complete stereocontrol,
thus allowing the formation of three contiguous stereo-
genic centers. The nitro function may therefore be consid-
ered as a removable activating group for cycloaddition
reactions; further methological studies as well as synthetic
applications of this sequence are currently in progress
The high stereoselectivity of this radical cyclization may
be explained considering steric interactions between the
ester function in the radical acceptor and the methyl sub-
stitutent on the radical, leading to an attack of the radical
on the Re-face of the double bond (Scheme 9); as ob-
served in the simple denitration reaction, the radical trap-
ping is exo-selective, leading to an inversion of the methyl
substituent at C3. These two factors account for the high
stereoselectivity of the 5-exo-trig radical cyclization of
the nitro compound 10.
Synthesis 2003, No. 9, 1419–1426 ISSN 1234-567-89 © Thieme Stuttgart · New York

SPECIAL TOPIC
[2+3] Cycloadditions Between Nitroalkenes and Camphor-Derived Oxazoline N-Oxides
1423
1H and 13C NMR spectra were recorded at 200, 250 or 400 MHz and
50, 62.5 or 100 MHz, respectively. Optical rotation were recorded
at 25 °C. Chromatographic purifications were performed on 230–
400 mesh silica gel (Merck 9385) using the indicated solvent sys-
tem. CH2Cl2 and trimethyl orthoformate were distilled from CaH.
Toluene was distilled from sodium metal. Et2O and THF were dis-
tilled from sodium metal/benzophenone ketyl. CHCl3 used for opti-
cal measurements was filtered through basic alumina before use. 2-
Nitropropene was prepared by dehydration (phthalic anhydride,
150 °C) of commercial 2-nitro-propanol8. 1-Nitro-hexene and 2-ni-
tro-hept-2-ene were prepared by Henry condensation (Al2O3) of ni-
tromethane and nitroethane with valeraldehyde, followed by
dehydration (PPh3, CCl4).7 All non-aqueous reactions were per-
formed under an argon atmosphere using oven-dried glassware.
1H NMR (250 MHz, CDCl3): = 7.29 (5 H, br s, ArH), 6.06 (1 H,
s), 5.06 (1 H, s), 4.13 (1 H, d, J = 8 Hz), 3.62 (1 H, d, J = 8 Hz), 2.16
(1 H, d, J = 5 Hz), 1.70–1.42 (4 H, m), 1.34 (3 H, s), 0.91, 0.87, 0.80
(9 H, 3 × s).
13C NMR (50 MHz, CDCl3): = 132.4, 128.9, 128.5, 126.5, 103.6,
97.5, 91.2, 80.7, 76.1, 49.3, 48.8, 45.7, 31.3, 25.4, 22.1, 19.1, 18.8,
10.7.
MS (CI, NH3): m/z = 359 (MH+).
HRMS: m/z calcd for C20H26N2O4, 358.18924; found, 358.18922.
(3S,3aS,4aS,5R,8S,8aR)-3-Nitro-3,5,10,10-tetramethyl-5,8-
methanooctahydro-2H-isoxazolo[3,2-b]benzoxazole (4c)
After the addition of 2-nitropropene (3c) the reaction was refluxed
in CH2Cl2 for 18 h. The crude product was purified by chromatog-
raphy. First to elute was 4c (Rf 0.35; yield 64%), followed by a
small amount of exo-adduct 5c (Rf 0.29; yield: 16%); combined
yield: 80%; [ ]D20 –202.1 (c 1.89, CHCl3).
1H NMR (250 MHz, CDCl3): = 4.94 (1 H, s), 4.73 (1 H, d, J = 10
Hz), 3.94 (1 H, d, J = 7.5 Hz), 3.79 (1 H, d, J = 10 Hz), 3.42 (1 H,
d, J = 7.5 Hz), 2.09 (1 H, d, J = 4.5 Hz), 1.78 (3 H, s), 1.80 and 1.65
(4 H, 2 × m), 0.87, 0.83 and 0.77 (3 s, 9 H, 3 × CH3).
Asymmetric [2+3] Cycloadditions Between Oxazoline N-Oxide
2 and Nitroalkenes 3a–f; General Procedure
A suspension of 3-hydroxylaminoisoborneol hydrochloride 1 (1
equiv) and powdered Ca(CO3)2 (l equiv) in either CH2Cl2 or toluene
(5ml/mmol) was heated at 45 °C with stirring and trimethyl ortho-
formate (4 equiv) was added via syringe. The mixture was stirred at
45 °C for 4 h then the nitroalkene 3 was added (4 equiv). The mix-
ture was stirred vigorously at the appropriate temperature and for
the appropriate time (see Table 1). The completion of the reaction
was monitored by TLC. After cooling to r.t., the mixture was fil-
tered through a plug of celite and the filtrate concentrated in vacuo.
The residue was purified by flash chromatography on silica gel
(10% EtOAc–heptane,1:9) to give the pure cycloadduct (except for
products 4b and 4e, vide infra).
13C NMR (62.5 MHz, CDCl3): = 102.8, 94.9, 91.4, 75.6, 72.1,
49.2, 48.9, 45.8, 31.4, 25.5, 22.8, 22.6, 18.9, 10.8.
Mass (CI NH3): m/z = 301 (MNH4 ), 283 (MH+);
+
Anal. Calcd for C14H22N2O4 (282.34244): C, 59.56; H, 7.85; N,
9.92. Found: C, 59.71; H, 8.11; N, 9.42.
(2S,3S,3aS,4aS,5R,8S,8aR)-3-Nitro 3,5,10,10-tetramethyl-5,8-
methanoperhydrobenzo[d]isoxazolo[3,2-b]benzoxazole (4d)
After the addition of 1-nitrocyclohexene (3d) the reaction was re-
fluxed in CH2Cl2 for 18 h to give the product 4d as a single stereo-
isomer; yield: 67%; [ ]D20 –163 (c 0.99, CHCl3).
1H NMR (250 MHz with COSY and NOESY, CDCl3): = 4.82 (1
H, s), 4.59 (1 H, s), 3.81 (1 H, d, J = 8 Hz), 3.41 (1 H, d, J = 8 Hz),
2.59 (1 H, d, J = 14 Hz), 1.96 (1 H, d, J = 5 Hz), 1.87 (1 H, m), 1.70–
1.50 (4 H, m), 1.36 (1 H, m), 1.31–1.20 (2 H, m), 094 (1 H, m),
0.90–0.80 (2 H, m), 0.75, 0.70, 0.65 (3 s, 9 H, 3 × CH3 ).
(2S,3S,3aS,4aS,5R,8S,8aR)-2-Butyl 3-nitro-3,5,10,10-tetrame-
thyl- 5,8-methanooctahydro-2H- isoxazolo[3,2-b]benzoxazole
(4a)
After the addition of 2-nitrohept-2-ene (3a) the reaction was heated
to 80 °C in toluene for 18 h to give the product 4a as a single stere-
oisomer; yield: 75%; [ ]D20 –172 (c 1.1, CHCl3).
1H NMR (250 MHz, CDCl3): = 4.96 (1 H, s), 4.77 (1 H, t, J = 6
Hz), 4.00 (1 H, d, J = 7.5 Hz), 3.45 (1 H, d, J = 7.5 Hz), 2.10 (1 H,
d, J = 4.5 Hz), 1.63 (3 H, s), 1.80–1.30 (10 H, m), 0.90 (3 H, t, J = 7
Hz), 0.90, 0.85 and 0.80 (9 H, 3 × s).
13C NMR (50 MHz, CDCl3): = 103.9, 95.9, 91.2, 79.6, 76.6, 49.3,
48.7, 45.6, 31.3, 28.2, 26.5, 25.4, 22.6, 22.1, 18.7, 17.8, 13.8, 10.7.
13C NMR (50 MHz, CDCl3): = 102.4, 94.5, 91.4, 77.8, 73.7, 49.5,
49.0, 45.5, 31.3, 30.5, 25.7, 23.4, 22.2, 21.2, 19.3, 18.7, 10.8.
MS (CI NH3): m/z = 345 (MH+).
MS (CI, NH3): m/z = 339 (MH+).
HRMS: m/z calcd for C17H26NaN2O4 (M + Na), 345.17983; found,
345.17903.
Anal. Calcd for C18H30N2O4 (338.22054): C, 63.88; H, 8.93; N,
8.28. Found: C, 64.23; H, 9.24; N, 8.41.
(2S,3S,3aS,4aS,5R,8S,8aR)-2-Butyl-3-nitro-3-phenyl-5,10,10-
trimethyl-5,8-methanooctahydro[2H]isoxazolo[3,2-b]benzox-
azole (4e)
(2S,3S,3aS,4aS,5R,8S,8aR)-3-Nitro 2-phenyl 3,5,10,10-tetrame-
thyl-5,8-methanooctahydro-2H-isoxazolo[3,2-b]benzoxazole
(4b)
After the addition of l-nitro-1-phenylhexene (3e) the reaction was
refluxed in CH2Cl2 for 2 h. Purification of the crude product was ac-
complished as for the purification of cycloadduct 4b to give the
product 4e as a single stereoisomer; yield: 43%; [ ]D20 –161 (c 1,
CHCl3).
1H NMR (250 MHz, CDCl3): = 7.29 (5 H, br s), 5.48 (1 H, s), 4.58
(1 H, d, J = 9 Hz), 3.89 (1 H, d, J = 8 Hz), 3.48 (1 H, d, J = 8 Hz),
2.09 (1 H, d, J = 5 Hz), 1.40–1.05 (10, m), 0.80 (3 H, s, Me-C2),
0.78, 0.75, 0.65 (3 s 9 H, 3 × CH3 ).
After addition of 2-nitro-1-phenylpropene (3b) the reaction was re-
fluxed in CH2Cl2 for 18 h. The crude product consists of an insepa-
rable mixture of cycloadduct 4b and excess dipolarophile.
Separation of both compounds was accomplished as follows: the
crude product was redissolved in a THF–water mixture (1:1, 5mL/
mmol). NaHCO3 (5 equiv to the starting dipolarophile) was added,
followed by hydroxylamine hydrochloride (5 equiv); gas evolution
was observed, and the yellow solution progressively faded to pale
yellow; after stirring for 24 h at r.t., THF was removed in vacuo, and
the mixture was extracted EtOAc (2 × 30 mL); the combined organ-
ic layers were washed with brine (50 mL), dried (Na2SO4), filtered,
and concentred in vacuo. The pure cycloadduct 4b was obtained as
a single isomer after chromatography;15 yield: 73%; [ ]D20 –161
(c 1.2, CHCl3).
13C NMR (50 MHz, CDCl3): = 133.5, 130.3, 128.4, 126.4, 103.6,
103.1, 91.1, 79.6, 79.0, 49.5, 49.1, 45.2, 31.3, 28.2, 27.4, 25.7, 22.4,
22.2, 13.8, 10.8;
MS (CI, NH3): m/z = 401 (MH+).
HRMS: m/z calcd for C23H32N2O4, 400.23621; found, 400.23623.
Synthesis 2003, No. 9, 1419–1426 ISSN 1234-567-89 © Thieme Stuttgart · New York

1424
A. Voituriez et al.
SPECIAL TOPIC
(2S,3S,3aS,4aS,5R,8S,8aR)-2-Butyl 3-nitro-5,10,10-trimethyl-
5,8-methanooctahydro[2H]isoxazolo[3,2-b]benzoxazole (4f)
After the addition of 1-nitrohexene (3f), the reaction was refluxed
in CH2Cl2 for 2 h to give the product 4f as a single stereoisomer;
yield: 70%; [ ]D20 –161 (c 1.47, CHCl3).
further 4 h before being cooled to r.t., CCl4 (1 mL) was added, and
the mixture was treated as usual. Purification of the crude product
by chromatography (EtOAc–heptane, 1:19) gave compound 5d as a
single stereoisomer; colorless oil; yield: 69% (85 mg); [ ]D20 –124
(c 0.34, CHCl3).
1H NMR (250 MHz, CDCl3): = 5.55 (1 H, d, J = 7 Hz), 4.80 (1 H,
dd, J = 7, 8 Hz), 4.65 (1 H, dt, J = 6, 8 Hz), 4.05 (1 H, d, J = 7.5 Hz),
3.45 (1 H, d, J = 7.5 Hz), 2.10 (1 H, d, J = 4.5 Hz), 1.80–1.30 (10
H, m), 0.90 (3 H, t, J = 7 Hz), 0.95, 0.88, 0.80 (3 s 9 H, 3 × CH3).
1H NMR (250 MHz, CDCl3): 5.27 (1 H, d, J = 4 Hz), 3.87 (1 H, d,
J = 8 Hz), 3.49 (1 H, d, J = 8 Hz), 3.21 (1 H, ddd, J = 2, 6, 13 Hz),
2.05 (1 H, d, J = 6 Hz), 2.00–0.80 (13 H, m), 0.96, 0.95, 0.81 (3 s,
9 H, 3 × CH3).
13C NMR (62.5 MHz, CDCl3): = 96.4, 92 4, 91.4, 78.0, 75.7, 49.1,
48.7, 45.8, 31.3, 30.6, 27.3, 25.2, 22.4, 22.0, 18.7, 13.7, 10.6.
13C NMR (50 MHz, CDCl3): = 100.2, 92.1, 79.6, 79.5, 53.7, 50.5,
49.8, 45.8, 32.5, 30.1, 26.7, 25.9, 24.7, 24.6, 23.0, 19.5, 11.8.
MS (CI, NH3): m/z = 325 (MH+).
MS (ESI): m/z = 300 (M + Na), 278 (MH+).
HRMS: m/z calcd for C17H28N2O4, 324.20489; found, 324.20491.
HRMS: m/z calcd for C17H27NaO2 (M + Na), 300.19386; found,
300.19385.
Radical Denitration of Cycloadducts 4a–e
AIBN (1.2 equiv) was added to a solution of the nitro cycloadduct
4 and Bu3SnH (2 equiv) in anhyd benzene (5 mL/mmol). The mix-
ture was stirred at reflux for 2 h, then cooled to r.t. Excess hydride
reagent was destroyed by the addition of CCl4 (1 mL), and this was
subsequently stirred for 20 min. The solvents were removed in vac-
uo (in a well ventilated hood) and the residue redissolved in EtOAc
(25 mL). Sat. aq KF solution was added and the mixture was stirred
for 30 min. The white precipitate was removed by filtration through
cotton wool, and the layers were separated. The organic layer was
washed with brine (25 mL), dried (Na2SO4), filtered and concentred
in vacuo. The crude product was purified by chromatography
(EtOAc–heptane, 1:9) to give the pure denitrated products 5.
Hydrolysis of Chiral Auxiliary
A solution of the denitrated cycloadduct 5a,b (1 mmol) in anhyd
Et2O (20 mL) was treated with MCPBA (4 mmol, 4 equiv). The col-
orless solution was stirred at r.t. After 1 h, excess peroxy reagent
was destroyed by the addition of an aq 5% NaHCO3–5% Na2S2O3
solution (25 mL) and the resulting mixture was stirred for 1 h. The
layers were separated, the organic layer was washed with 5%
NaHCO3 solution (15 mL), brine (15 mL), then dried (Na2SO4), fil-
tered and concentred in vacuo. The crude product was redissolved
in THF (10 mL), and a 2 N HCl solution (10 mL) was added. The
resulting pale yellow solution was stirred for 30 min, before being
diluted with H2O (15 mL), and extracted with EtOAc (3 × 20 mL).
The combined organic layer was washed with brine (50 mL), dried
(Na2SO4), filtered, and concentred in vacuo to give a crude mixture
of the -hydroxy-aldehyde 7 and the recovered chiral auxiliary.
(2S,3S,3aS,4aS,5R,8S,8aR)-2-Butyl-3,5,10,10-tetramethyl-5,8-
methanooctahydro[2H]isoxazolo[3,2-b]benzoxazole (5a)
Denitration of cycloadduct 4a according to the procedure described
above gives a 90:10 mixture of 5a and its exo isomer; yield: 70%.
1H NMR (250 MHz, CDCl3): = 5.14 (1 H, d, J = 6.9 Hz), 3.74 (1
H, d, J = 8 Hz), 3.41 (1 H, m), 3.25 (1 H, d, J = 8 Hz), 2.07 (1 H, d,
J = 5 Hz), 1.93 (1 H, ddq with J3-J3a = 6.9 Hz), 1.75–1.20 (10 H, m)
1.15 (3 H, d), 1.12 (3 H, t), 0.95, 0.80, 0.75 (3 s, 9 H, 3 × CH3).
13C NMR (50 MHz, CDCl3): = 100.8, 90.4, 82.8, 77.7, 50.1, 49.3,
46.9, 46.3, 32.3, 32.0, 28.8, 26.3, 23.5, 22.9, 19.6, 14.6, 11.7, 10.7.
MS (CI, NH3): m/z = 294 (MH+).
For the sake of characterization, the aldehyde 7 was transformed
into the corresponding methyl ester in a two-step sequence: the
crude aldehyde was redissolved in t-BuOH (8 mL), 2-methyl-2-
butene (3 mL) was added, followed by a freshly prepared aq 10%
NaClO2 –10% NaH2PO4 (4.5 mL). The solution was stirred at r.t.
for 1 h, then diluted with H2O (20 mL), and extracted with EtOAc
(4 × 20 mL). The combined organic layer was washed with brine
(50 mL), dried (Na2SO4), filtered, and concentred in vacuo. The
crude carboxylic acid was redissolved in aq NaHCO3 solution (50
mL) and extracted with Et2O (2 × 10 mL). The organic layer (con-
taining the recovered chiral auxiliary) was discarded, the aqueous
layer was acidified with 6 N HCl solution, and extracted with
EtOAc (4 × 20 mL). The combined organic extracts were washed
with brine (50 mL), dried (Na2SO4), filtered, and concentred in vac-
uo to give the pure carboxylic acid, which was redissolved in Et2O
(5 mL) and treated with etheral diazomethane until the yellow color
persisted. After concentration in vacuo, pure methyl ester 8 was ob-
tained.
(2S,3S,3aS,4aS,5R,8S,8aR)-2-Phenyl-3,5,10,10-tetramethyl-5,8-
methanooctahydro[2H]isoxazolo[3,2-b]benzoxazole (5b)
Denitration of cycloadduct 4b according to the described procedure
gives compound 5b as a single isomer; white solid; yield: 90%;
[ ]D20 –67 (c 0.47, CHCl3).
1H NMR (250 MHz, CDCl3): = 7.32 (5 H, br s), 5.33 (1 H, d,
J = 6.8 Hz), 4.34 (1 H, d, J = 10 Hz), 3.89 (1 H, d, J = 8 Hz), 3.46
(1 H, d, J = 8 Hz), 2.24 (1 H, ddq with J3-J3a = 6.8 Hz), 2.13 (1 H,
d, J = 5 Hz), 1.75–1.10 (4 H, m), 1.05, 0.85, 0.82 (3 s, 9 H, 3 × CH3).
(2S, 3S)-Methyl 3-hydroxy 2-methylheptanonate (8a)
This ester was prepared from denitrated cycloadduct 5a according
to the four-step sequence previously described; overall yield: 29%.
This product consists of a mixture of anti- and syn-isomers in a ratio
of 90:10.
13C NMR (50 MHz, CDCl3): = 137.3, 129.3, 128.4, 126.8, 100.2,
89.9, 84.7, 77.3, 50.1, 49.5, 48.8, 45.7, 31.7, 25.7, 22.2, 19.0, 11.0,
9.4;
MS (ESI): m/z = 336 (M + Na).
1H NMR (250 MHz, CDCl3): = 3.72 (3 H, s), 3.65 (1 H, m), 2.54
(1 H, dq, J = 7.5, 6.5 Hz), 1.60–1.28 (6 H, m), 1.22 (3 H, d, J = 7.5
Hz), 0.91 (3 H, t, J = 7 Hz).
HRMS: m/z calcd for C20H27NaNO2 (M + Na), 336.19380; found,
336.19395.
13C NMR (50 MHz, CDCl3): = 176.5, 73.3, 51.7, 45.2, 34.4, 37.6,
22.6, 14.3, 14.0; small peaks at 43.3 and 10.2 ppm are characteristic
of the minor syn-isomer.
Enantiomeric purity was checked by 1H NMR in the presence of tris
[3-(heptafluoropropyl)hydroxymethylene]-d-camphorato europi-
um. The chemical shifts for the OMe group at 4.07 ppm (major iso-
mer) and 4.15 ppm (minor isomer) are assigned as (2S,3S) and
(2S,3R,3aS,4aS,5R,8S,8aR) 3,5,10,10-tetramethyl-5,8-metha-
noperhydrobenzo[d]isoxazolo[3,2-b]benzoxazole (5d)
A solution of nitrated cycloadduct 4d (142 mg, 0.44 mmol) and
Bu3SnH (0.26 mL, 0.88 mmol, 2 equiv) in benzene (1 mL) was
stirred at reflux and a solution of AIBN (82 mg, 0.52 mmol, 1.2
equiv) in benzene (2.5 mL) was added with a syringe pump over 10
h. After completion of the addition, the solution was refluxed for a
Synthesis 2003, No. 9, 1419–1426 ISSN 1234-567-89 © Thieme Stuttgart · New York

SPECIAL TOPIC
[2+3] Cycloadditions Between Nitroalkenes and Camphor-Derived Oxazoline N-Oxides
1425
(2R,3S) isomers respectively. Chemical shifts for (2S,3R) and
(2R,3R) isomers are not detected.
Hz, C4-H), 3.64 (3 H, s, OMe), 3.23 (1 H, d, J = 8 Hz, C8a-H), 2.55
(1 H, dd, J = 5, 15 Hz, one of C1 -H), 2.34 (1 H, dd, J = 10, 15 Hz,
one of C1 -H), 2.06 (1 H, m, C2 -H), 2.02 (1 H, d, J = 5 Hz, C8-H),
1.86 (1 H, m, one of C3 -H), 1.75 (1 H, m, one of C4 -H), 1.67 (1 H,
m, one of C7), 1.61 (1 H, m, one of C4 -H), 1.46 (1 H, m, one of C3 -
H), 1.35 (1 H, m, one of C6-H), 1.28 (1 H, m, one of C7-H), 1.11 (3
H, s, Me-C3), 0.88 (1 H, m, one of C6-H), 0.94, 0.92, 0.77 (3 s, 9 H,
3 × CH3).
13C NMR (100 MHz, CDCl3) = 173.4 (CO), 100.9 (C3a), 90.6 (C2),
89.9 (C4a), 74.6 (C8a), 58.0 (C3), 51.8 (OMe), 49.0 (C8), 48.6 (C5),
46.7 (C2’), 46.2 (C10), 35.8 (C1 ), 31.9 (C6), 31.2 (C3 ), 29.7 (C4 ),
25.3 (C7), 21.1 (Me-C3), 22.3, 19.3, 10.9 (3 × CH3).
(2S, 3S)-Methyl 3-hydroxy 2-methylphenylpropionate (8b)
This ester was prepared from denitrated cycloadduct 5b according
to the four-step sequence previously described as a single isomer;
overall yield: 34%.
1H NMR (250 MHz, CDCl3): = 7.34 (5 H, br s), 4.73 (1 H, d,
J = 8.5 Hz), 3.71 (3 H, s), 2.90 (1 H, s, exchangeable with D2O),
2.83 (1 H, m), 1.00 (3 H, d, J = 7 Hz). In the presence of Eu(hfc)3,
the OMe signal shifts to 4.1 ppm, no other signal corresponding to
another enantiomer was detected.
MS (ESI): m/z = 217 (M + Na).
MS (ESI): m/z = 721.5 (2 M + Na), 372 (M + Na).
HRMS: m/z calcd for C11H14NaO3 (M + Na), 217.08398; found,
217.08046.
References
(2S,3S,3aS,4aS,5R,8S,8aR,1 E)-2-(1 -Methoxycarbonyl-
1 buten-4 -yl) 3-nitro 3,5,10,10-tetramethyl 5,8- methano oc-
tahydro[2H]isoxazolo[3,2-b]benzoxazole (10)
(1) Berranger, T.; Langlois, Y. J. Org. Chem. 1995, 60, 1720.
(2) Kouklovsky, C.; Dirat, O.; Berranger, T.; Langlois, Y.; Tran
Huu Dau, M.-E.; Riche, C. J. Org. Chem. 1998, 63, 5123.
(3) For a review: Dirat, O.; Kouklovsky, C.; Mauduit, M.;
Langlois, Y. Pure Applied Chem. 2000, 72, 1721.
(4) Berranger, T.; Langlois, Y. Tetrahedron Lett. 1995, 36,
5523.
Trimethylorthoformate (2.2 mL, 20 mmol, 8 equiv) was added to a
suspension of hydroxylamino isoborneol hydrochloride (1.1 g, 5
mmol, 2 equiv) and Ca(CO3)2 (500 mg, 5 mmol, 2 equiv) in CH2Cl2
(15 mL). The resulting suspension was stirred at reflux for 4 h, then
(2E,7E)-methyl 7-nitro-2,6-octadienoate (9) (504 mg, 2.5 mmol, 1
equiv), was added in one protion. The reaction mixture was stirred
at reflux for 16 h, then cooled to r.t. and filtered through a short pad
of celite, eluting with CH2Cl2. The filtrate was concentred in vacuo
and the crude product purified by chromatography on silica gel
(EtOAc–heptane, 3:1) to give the cycloadduct 10 as a single stere-
oisomer; yield: 70% (660 mg); [ ]D20 –129 (c 0.3, CHCl3).
(5) Kobayakawa, M.; Langlois, Y. Tetrahedron Lett. 1992, 33,
2353.
(6) Nitroalkenes 3a, 3e, and 3f were prepared in two steps,
Henry condensation in the presence of basic alumina,
followed by dehydration of the nitroalcohol by treatment
with PPh3–CCl4: (a) Ballini, R.; Chatagnani, R.; Petrini, M.
J. Org. Chem. 1992, 57, 2160. (b) Saikia, A. K.; Barua, N.
C.; Sharma, R. P.; Ghosh, A. C. Synthesis 1994, 685.
(7) Nitroalkene 3c was prepared by dehydration of
commercially available 2-nitropropanol with phthalic
anhydride: Ranganathan D., Bhushan Rao C., Ranganathan
S., Mehrotra A.K., Iyengar R.; J. Org. Chem.;1980, 45:
1185.
(8) (a) Ono, N.; Miyake, H.; Fuji, H.; Kaji, A. Tetrahedron Lett.
1984, 23, 3477. (b) Review: Ono, N.; Kaji, A. Synthesis
1986, 693. (c) For a tin-catalyzed procedure: Torno, J.;
Hays, D. S.; Fu, G. C. J. Org. Chem. 1998, 63, 5296.
(9) Recently Mioskowski and co-workers reported good yields
in the denitration of secondary N-2-nitroalkyl
IR (CHCl3): 3055, 2956, 1723, 1548, 1267, 1132, 1111, 738 cm–1.
1H NMR (400 MHz, CDCl3, with COSY and NOESY): = 6.90 (1
H, m, with J1 -J2 = 13 Hz, C2 -H), 5.83 (1 H, d, J1 -J2 = 13 Hz, C1 -
H), 4.94 (1 H, s, C3a-H), 4.71 (1 H, dd, J = 9, 4 Hz, C2-H), 3.93 (1
H, d, J = 8 Hz, C4a-H), 3.70 (3 H, s, OMe), 3.37 (1 H, d, J = 8 Hz,
C8a-H), 2.29 (2 H, m, 2 × C3 -H), 2.07 (1 H, d, J = 5 Hz, C8-H), 1.68
(3 H, m, 2 × C4 -H, one of C6-H), 1.61 (3 H, s, Me-C3), 1.37 (1 H,
m, one of C6-H), 0.92 (2 H, m, 2 × C7-H), 0.86, 0.80, 0.73 (3 s, 9 H,
3 × CH3).
13C NMR (62.5 MHz, CDCl3): = 166.4 (CO), 146.8 (C2 ), 121.8
(C1 ), 103.7 (C3a), 95.6 (C2), 91.1 (C4a), 78.4 (C8a), 76.6 (OMe), 53.3
(C3), 49.1 (C8), 48.6 (C5), 45.4 (C10), 31.1 (C6), 28.6, 25.3 (C3 , C4 ),
25.1 (C7), 22.0 (Me-C3), 18.5, 17.7, 10.6 (3 × CH3).
oxazolidinones: Leroux, M.-L.; Le Gall, T.; Mioskowski, C.
Tetrahedron: Asymmetry 2001, 12, 1817.
(10) For an example of intermolecular addition: Dupuis, J.;
Giese, B.; Hartung, J.; Leising, M.; Korth, H. G.; Sustmann,
R. J. Am. Chem. Soc. 1985, 107, 4332.
(11) Matteson, D. S.; Man, H. W. J. Org. Chem. 1994, 59, 5734.
(12) Gennari, C.; Colombo, L.; Bertolini, G.; Schimherna, G. J.
Org. Chem. 1987, 52, 2754.
(13) For reviews see inter alia: (a) Giese, B.; Kopping, B.;
Göbel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F.
Org. React. 1996, 48, 301. (b) Curran, D. P.; Porter, N. A.;
Giese, B. In Stereochemistry of Radical Reactions; VCH:
Weinheim, 1986. (c) Giese, B. In Radicals in Organic
Synthesis Formation of C-C Bonds; Pergamon: Oxford,
1986.
MS (ES): m/z = 417 (M + Na).
Cyclization Product 11
AIBN (82 mg, 0.5 eq.) and Bu3SnH (290 L, 1 mmol) were added
to a solution of nitro cycloadduct 10 (197 mg, 0.5 mmol) in benzene
(5 mL), and the colorless solution was stirred at reflux. After 1.5 h,
the reaction mixture was cooled to r.t., CCl4 (0.5 mL) was added and
the mixture treated as usual. After purification by chromatography
(EtOAc–heptane, 4:1), the cyclized product 11 was obtained as a
colorless oil that solidified on standing to give the product as a sin-
gle isomer; yield: 70% (122 mg); [ ]D20 –115.2 (c 1.1, CHCl3).
IR (CHCl3): 2958, 1732, 1457, 1438, 1090 cm–1.
1H NMR (400 MHz, CDCl3, with COSY, NOESY and HSQC):
4.92 (1 H, s, C3a-H), 4.20 (1 H, d, J = 4 Hz, C2-H), 4.09 (1 H, d, J = 8
=
(14) Denmark, S. E.; Senanayake, C. B. W. J. Org. Chem. 1993,
58, 1853.
Synthesis 2003, No. 9, 1419–1426 ISSN 1234-567-89 © Thieme Stuttgart · New York

1426
A. Voituriez et al.
SPECIAL TOPIC
(15)
Scheme 10 Note: this special purification procedure applies when-
ever phenyl-substituted nitroalkenes are used in the cycloaddition
(Scheme 10).
Synthesis 2003, No. 9, 1419–1426 ISSN 1234-567-89 © Thieme Stuttgart · New York