Synthesis and Iodocyclization of Homoallylic Hydroxylamines

Full text of DOI:10.1021/jo970544s

J . Org. Chem. 1997, 62, 5623-5626
5623
Sch em e 1
Syn th esis a n d Iod ocycliza tion of
Hom oa llylic Hyd r oxyla m in es
Andrea Fiumana, Marco Lombardo, and
Claudio Trombini*
Dipartimento di Chimica “G. Ciamician”,
Universita` di Bologna, via Selmi 2, I-40126 Bologna, Italy
Received March 24, 1997
The allylation of nitrogen derivatives of carbonyl
compounds such as imines and oximes,1 etc., has received
special attention due to the synthetic versatility of the
final homoallylic amines and their applications as chiral
modifiers or auxiliaries in asymmetric synthesis.
We recently reported the simple allylation of prochiral
and chiral nitrones with allylmagnesium chloride; the
resulting homoallylic N-hydroxylamines were exploited
in iodocyclization reactions to give 5-(iodomethyl)isox-
azolidines.2
We now wish to report that allylic zinc bromides
generated in situ from allylic bromides 1 and zinc powder
in THF regioselectively add to model aldonitrones 2 in
very good yields. The simple diastereoselectivity of
reactions involving crotylzinc bromide and the facial
selectivity displayed by allylzinc bromide toward the
N-benzylnitrone of glyceraldehyde were examined. Fi-
nally, homoallylic hydroxylamines 3 were O-silylated and
subjected to iodocyclization to 4 in order (i) to get
information about the syn/anti stereorelationship in
hydroxylamines 3 and (ii) to observe stereodirecting
effects of methyl substituents on the isoxazolidine-
forming reaction (Scheme 1). In a first set of experiments
(Table 1), we examined the allylation, crotylation, and
prenylation of O-benzyl glycolaldehyde N-benzylnitrone.
Reaction rates were found to be dependent on the
degree of substitution on the allylic moiety, as expected
on steric grounds (Table 1, entries 1, 2, and 6), the prenyl
complex being the least reactive. The crotyl complex
displayed an anti diastereoselectivity. Interesting ob-
servations were made when the reaction was carried out
in the presence of Et2AlCl (DEAC). Independent of
the order of addition, reaction rates tremendously in-
creased, the addition step could be carried out at much
lower temperature, and a reversed syn selectivity was
displayed (Table 1, entries 4 and 5). We also tested the
crotylation of benzaldehyde N-methylnitrone, and again,
we observed the inversion of simple diastereopreference
with and without DEAC. The results are reported in
Table 2. The syn selectivity displayed by DEAC could
be accounted for by the adoption of an acyclic anti-
Ta ble 1. Rea ction of O-Ben zyl Glycola ld eh yd e
N-Ben zyln itr on e w ith Allylic Zin c Com p lexes
entry 1 (method)a T (°C) t (h) productbt(%) syn/antic
1
2
3
4
5
6
7
8
allyl (A)
25
25
-40
-40
-40
25
0.5
3.5
4
1.5
1.5
24
1
1
3a (94)
3b (95)
3b (23)
3b (91)
3b (89)
3c (59)
3c (38)
3c (80)
crotyl (A)
crotyl (A)
crotyl (B)
crotyl (C)
prenyl (A)
prenyl (B)
prenyl (B)
1/4
1/5
4/1
4/1
-40
20
a
Method A involves the addition of the allylic zinc complex to
nitrone at the reported temperature. Method B involves the
addition of the allylic zinc complex to a preequilibrated mixture
of nitrone and DEAC. Method C involves the addition of nitrone
at -40 °C to a preequilibrated mixture of crotylzinc bromide and
b
DEAC. Isolated yield. c Determined by integral ratios in the
1H NMR of crude reaction mixture.
Ta ble 2. Rea ction of Ben za ld eh yd e N-Meth yln itr on e
w ith Cr otylzin c Br om id e
entry
methoda
T (°C)
t (h)
3d b (%)
syn/antic
1
2
3
A
A
B
25
-40
-40
24
24
1
80
traces
38
3/7
not det
9/1
a-c See corresponding footnotes in Table 1.
periplanar transition state (TS); this TS geometry ex-
plains the stereoconvergent syn selectivity in the addi-
tion of crotylstannanes to aldehydes in the presence of
Lewis acids, independent of the crotyl double bond
configuration.3 In the absence of DEAC, synclinal TS’s,
leading to the anti product, could be stabilized by
attractive interactions between nitrone oxygen and zinc
atom.3b
The last set of experiments was performed on (R)-
glyceraldehyde acetonide N-benzylnitrone (Table 3). Us-
ing allylzinc bromide, we observed a slightly higher
diastereofacial anti selectivity with respect to the previ-
ously reported allylmagnesium chloride2b (Table 3, entries
1 and 2). Again, an inversion of diastereopreference was
* To whom correspondence should be addressed: Tel.: 51-259513.
Fax: 51-259456. E-mail: trombini@ciam.unibo.it.
(1) Owing to the huge number of references on this topic, we only
refer to the most recent papers and to references therein: (a) Itsuno,
S.; Watanabe, K.; Ito, K.; El-Shehawy, A. A.; Sarhan, A. A. Angew.
Chem., Int. Ed. Engl. 1997, 36, 109. (b) Nakamura, H.; Iwama, H.;
Yamamoto, Y. J . Am. Chem. Soc. 1996, 118, 6641. (c) Nakamura, M.;
Hirai, A.; Nakamura, E. J . Am. Chem. Soc. 1996, 118, 8489. (d) Alvaro,
G.; Savoia, D. Tetrahedron: Asymmetry 1996, 7, 2083. (e) Alvaro, G.;
Boga, C.; Savoia, D.; Umani-Ronchi, A. J . Chem. Soc. Perkin Trans. 1
1996, 875. (f) Hanessian, S.; Yang, R.-Y. Tetrahedron Lett. 1996, 37,
5273. (g) Wang, D.-K.; Dai, L.-X.; Hou, X.-L.; Zhang, Y. Tetrahedron
Lett. 1996, 37, 4187. (h) Wang, J .; Zhang, Y.; Bao, W. Synth. Commun.
1996, 26, 2473. (i) Yanagisawa, A.; Ogasawara, K.; Yasue, K.;
Yamamoto, H. J . Chem. Soc., Chem. Commun. 1996, 367.
(2) (a) Mancini, F.; Piazza, M. G.; Trombini, C. J . Org. Chem. 1991,
56, 4246. (b) Dhavale, D. D.; Gentilucci, L.; Piazza, M. G.; Trombini,
C. Liebigs Ann. Chem. 1992, 1289.
(3) (a) Yamamoto, Y.; Yatagai, H.; Ishihara, Y.; Maeda, N.; Maruya-
ma, K. Tetrahedron 1984, 40, 2239. (b) Nishigaichi, Y.; Takuwa, A.;
Naruta, Y.; Maruyama, K. Tetrahedron 1993, 49, 7395.
S0022-3263(97)00544-6 CCC: $14.00 © 1997 American Chemical Society

5624 J . Org. Chem., Vol. 62, No. 16, 1997
Notes
Ta ble 3. Rea ction of (R)-Glycer a ld eh yd e Aceton id e
N-Ben zyln itr on e w ith Allylzin c Br om id e
Sch em e 2
entry
methoda
T (°C)
t (h)
3eb (%)
syn/antic
d
1a
2
3
-30
0
0
-40
2
1
0.5
0.5
90
92
88
80
44/56
25/75
58/42
65/35
A
B
B
4
a-c See corresponding notes to Table 1. Reaction carried out
with allylmagnesium chloride, taken from ref 2b.
d
decomposition than N-benzylhydroxylamine syn-3b and
was stereoselectively converted into 3,4-cis-4,5-trans-
isoxazolidine 4d . Noteworthy is that entry 6 repre-
sents the only iodocyclization experiment so far reported
by us in which a product coming from a 4-exo-trig ring
closure (Scheme 2, path B) has been observed. In fact,
we isolated, besides isoxazolidine 3,4-trans-4,5-trans-
4d coming from the normal 5-exo-trig mode (path A),
azetidine N-oxide 5d in 17% yield.
In conclusion, regiocontrolled allylation of nitrones
combined with the iodocyclization reaction of the result-
ing homoallylic hydroxylamines could offer an interesting
route to highly functionalized carbon frameworks. The
attainment of the best stereocontrol in this process is the
goal of our present studies.
Ta ble 4. Iod ocycliza tion Rea ction of O-Silyla ted
Hyd r oxyla m in es 3 P r om oted by NIS
entry
substrate
t (h)
productsa (%)
1
2
3
3a
2
3
3
3,5-cis-4a (41) + 3,5-trans-4a (50)
4b (traces)
3,4-trans-4,5-trans-4b (56) +
3,4-trans-4,5-cis-4b (19)
3,5-trans-4c (41)d
syn-3bb
anti-3bc
4
5
6
3c
4
3
3
syn-3d e
anti-3d f
3,4-cis-4,5-trans-4d (55)
3,4-trans-4,5-trans-4d (58)
a
b
Isolated yields. Reaction carried out on an 80% enriched
mixture of the reported isomer. c Reaction carried out on an 80%
d
enriched mixture of the reported isomer.
No trace of 3,5-cis
isomer was observed and isolated. e Reaction carried out on a 90%
enriched mixture of the reported isomer. f Reaction carried out
on a 70% enriched mixture of the reported isomer.
Exp er im en ta l Section
recorded in the presence of DEAC, even though the
absolute level of stereoselectivity was not impressive. An
analogous reversal of facial stereoselection had previously
been reported by Dondoni in the addition of nucleophiles
such as 2-lithiothiazole,4 2-lithiofuran,5 and simple Grig-
nard reagents6 to chiral nitrones in the presence of
DEAC.
Gen er a l Meth od s. All reactions were carried out in oven-
dried glassware under an atmosphere of dry argon. All re-
agents were commercially available and were used without
further purification, unless otherwise stated. 1H and 13C NMR
were recorded at 300 and 75 MHz, respectively, using tetra-
methylsilane as an internal standard. Melting points are
uncorrected.
Glycola ld eh yd e N-Ben zyln itr on e. 2-(Benzyloxy)ethanal
(1.0 g, 6.7 mmol) and N-benzylhydroxylamine, freshly freed from
the hydrochloride (1.07 g, 6.7 mmol), were allowed to react in
CH2Cl2 (5 mL) at 20 °C overnight. After solvent evaporation
and recrystallization (cyclohexane:ether), the pure nitrone (1.71
A classical solution to the assignment of the relative
stereochemistry of contiguous centers requires their
incorporation on the ring system of a 5- or 6-membered
cyclic derivative. The iodocylization reaction of products
3 to isoxazolidines 4 not only allowed us to establish the
syn/anti stereorelationships of 3b and 3d by inspecting
coupling constants and NOE effects7 on H-3 and H-4 of
4 but also gave interesting information about the effect
of methyl groups on the ring closure process. The
reactions were promoted by N-iodosuccinimide (NIS) in
chloroform at 0 °C. The results are summarized in Table
4. Hydroxylamine 3a afforded the expected mixture of
3,5-cis and 3,5-trans products on the basis of previous
results on related hydroxylamines (Table 4, entry 1).2a
Interestingly, the presence of two methyl groups on 3c
completely inhibited the formation of the 3,5-cis product
(Table 4, entry 4). As far as homoallylic hydroxylamines
3b and 3d are concerned, the methyl group confers a
marked preference for the formation of the 4,5-trans
isoxazolidines, which are the sole products in entries 5
and 6 (Table 4) and the major one in entry 3 (Table
4). In general, products possessing the 3,4-cis-4,5-cis
stereochemistry were never detected; in particular, hy-
droxylamine syn-3b underwent only oxidative decomposi-
tion into a plethora of unidentified products upon stand-
ing with NIS.8 On the other hand, N-methylhydrox-
ylamine syn-3d proved to be less sensitive to oxidative
1
g, 97%) was obtained as a white solid: mp 95-96 °C; H NMR
(CDCl3) δ 4.48 (d, J ) 4.1 Hz, 2H), 4.54 (s, 2H), 4.87 (s, 2H),
6.79 (t, J ) 4.1 Hz, 1H), 7.32-7.40 (m, 10H); 13C NMR (CDCl3)
δ 66.1, 69.0, 73.8, 127.9, 128.0, 128.5, 129.0, 129.2, 129.6, 132.0,
137.1, 137.4. Anal. Calcd for C16H15NO2: C, 75.26; H, 6.72; N,
5.49. Found: C, 75.31; H, 6.58; N, 5.33.
P r ep a r a tion of Allylic Zin c Br om id e Solu tion s. To a
suspension of activated zinc powder9 (1.1 g, 16.8 mmol) in
anhydrous THF (5 mL) was added a solution of allyl bromide
(0.36 mL, 4.2 mmol) in THF (2 mL) at 0 °C. The heterogeneous
mixture was allowed to reach rt and stirred for 2 h. After
filtration through a glass frit under argon, the resulting solu-
tion of organozinc complex was titrated10 and directly used for
the addition reaction. For the preparation of crotyl- and
prenylzinc bromide solutions, the corresponding allylic bromide
was stirred with zinc at 0 °C for 3 h, so avoiding a Wurtz-type
side reaction.
N-Hydr oxy-N-ben zyl-1-(ben zyloxy)-4-pen ten -2-am in e (3a).
Meth od A (Ta ble 1, En tr y 1). A solution of allylzinc bromide
(5 mL, 0.6 M, 3 mmol) was added to glycolaldehyde N-benzylni-
trone (383 mg, 1.5 mmol) dissolved in THF (2 mL), and the
solution was stirred at rt for 30 min. The reaction mixture was
quenched with aqueous NaHCO3, filtered (Celite), and extracted
(8) In three different experiments we got untractable reaction
mixtures; after thiosulfate quenching, we identified
a significant
amount of benzaldehyde. We believe that oxidation might convert the
starting N-benzyl group into a C-phenyl nitrone, which undergoes
hydrolysis to benzaldehyde on aqueous workup.
(9) A number of methods for the activation of zinc or for the in situ
preparation of active forms of zinc are available; see, for example (a)
Rieke, R. D.; Hanson, M. V. Tetrahedron 1997, 53, 1925. (b) Erdik, E.
Tetrahedron 1987, 43, 2203. For our purposes, activation was simply
carried out by heating zinc powder (J anssen) at about 300 °C with a
heat gun for 5 min under argon.
(4) Dondoni, A.; Franco, S.; J unquera, F.; Merchan, F. L.; Merino,
P.; Tejero, T.; Bertolasi, V. Chem. Eur. J . 1995, 1, 505.
(5) Dondoni, A.; J unquera, F.; Merchan, F. L.; Merino, P.; Tejero,
T. Synthesis 1994, 1450.
(6) Merchan, F.; Merino, P.; Rojo, P.; Tejero, T.; Dondoni, A.
Tetrahedron: Asymmetry 1996, 7, 667.
(7) The following ranges of NOE values were observed: cis H-3/H-4
and cis H-4/H-5 5-8%; trans H-3/H-4 and trans H-4/H-5 <2%; cis H-4/
CH2I and cis H-4/CH2OBn 3-5%.
(10) An aliquot of allylic zinc bromide solution was quenched with
1 N HCl, and zinc was titrated by EDTA.

Notes
J . Org. Chem., Vol. 62, No. 16, 1997 5625
with ether (3 × 5 mL). The combined organic layers were dried
(Na2SO4) and concentrated at reduced pressure. Hydroxylamine
3a was obtained as a yellow oil (420 mg, 94%) after purifica-
tion using flash chromatography (cyclohexane:ethyl acetate
95/5). 3a : 1H NMR (CDCl3) δ 2.36 (dt, J ) 7.6/14.3 Hz, 1H),
2.52 (dt, J ) 6.0/14.3 Hz, 1H), 3.07 (ddt, J ) 4.2/6.0/7.6 Hz, 1H),
3.63 (dd, J ) 4.2/10.1 Hz, 1H), 3.78 (dd, J ) 6.0/10.1 Hz, 1H),
3.97 (s, 2H), 4.54 (s, 2H), 5.03-5.12 (m, 2H), 5.19 (br s, 1H),
5.86 (ddt, J ) 6.0/7.6/13.8 Hz, 1H), 7.28-7.40 (m, 10H); 13C
NMR (CDCl3) δ 32.8, 60.7, 64.9, 69.4, 73.2, 116.5, 127.1, 127.6,
dry CH2Cl2 (5 mL), and the reaction mixture was stirred at rt
overnight. Hexane (2 mL) was added, and the solution was
filtered (Celite) and evaporated under reduced pressure to afford
silylated hydroxylamine (442 mg, 86%) as a dense oil.11 The
product was dissolved in CHCl3 (5 mL), the solution was cooled
at 0 °C, and NIS (540 mg, 2.4 mmol) was added. After being
stirred in the dark for 2 h at 0 °C, the reaction was quenched
with aqueous Na2S2O3, and the aqueous layer was extracted with
CHCl3 (3 × 5 mL). cis-4a (208 mg, 41%) and trans-4a (254 mg,
50%) were separated using flash chromatography eluting with
cyclohexane/ethyl acetate 95:5. 3,5-cis-4a : oil; 1H NMR (CDCl3)
δ 1.92 (dt, J ) 6.2/12.7 Hz, 1H), 2.66 (dt, J ) 7.9/12.7 Hz, 1H),
3.13 (dd, J ) 8.4/9.6 Hz, 1H), 3.29 (dd, J ) 5.0/9.6 Hz, 1H), 3.29-
3.38 (m, 1H), 3.49 (dd, J ) 5.8/9.6 Hz, 1H), 3.57 (dd, J ) 6.9/9.6
Hz, 1H), 3.99 (d, J ) 13.8 Hz, 1H), 4.12 (d, J ) 13.8 Hz, 1H),
4.39 (m, 1H), 4.49 (d, J ) 12.0 Hz, 1H), 4.55 (d, J ) 12.0 Hz,
1H), 7.22-7.40 (m, 10H); 13C NMR (CDCl3) δ 8.1, 38.3, 61.5, 65.0,
71.8, 73.3, 76.6, 127.2, 127.7, 128.2, 128.4, 128.8, 136.2, 139.8.
Anal. Calcd for C19H22NO2I: C, 53.89; H, 5.24; N, 3.31.
128.2, 128.4, 129.2, 136.0, 138.2, 138.4. Anal. Calcd for C19H23
-
NO2: C, 76.72; H, 7.80; N, 4.71. Found: C, 76.92; H, 7.75; N,
4.83.
Meth od B (Ta ble 1, En tr y 4). Nitrone (383 mg, 1.5 mmol)
and DEAC (∼1.8 M in hexane, 0.82 mL) in THF (2 mL) were
equilibrated at -40 °C for 20 min. At the same temperature, a
solution of crotylzinc bromide (6 mL, 0.5 M, 3 mmol) was added,
and the reaction mixture was stirred for 1.5 h.
Meth od C (Ta ble 1, En tr y 5). A solution of crotylzinc
bromide (5 mL, 0.16 M, 0.8 mmol) was treated with DEAC (0.21
mL, 0.8 mmol) at -40 °C for 30 min. Solid nitrone (100 mg,
0.39 mmol) was added at -40 °C, and stirring was continued
for 1.5 h.
N-Hyd r oxy-N-ben zyl-1-(ben zyloxy)-3-m eth yl-4-p en ten -
2-a m in e (3b). The product was obtained as a solid mixture of
the two syn/ anti isomers having the same Rf on silica gel. The
following spectroscopic data were drawn from the enriched
mixtures obtained in entries 3 and 4 of Table 1. syn-3b: 1H
NMR (CDCl3) δ 1.17 (d, J ) 6.8 Hz, 3H), 2.54-2.67 (m, 1H),
2.82 (ddd, J ) 3.0/5.8/8.7 Hz, 1H), 3.75 (dd, J ) 3.0/10.2 Hz,
1H), 3.87 (dd, J ) 5.8/10.2 Hz, 1H), 3.92 (d, J ) 13.7 Hz, 1H),
4.16 (d, J ) 13.7 Hz, 1H), 4.53 (s, 2H), 4.99 (ddd, J ) 0.7/1.9/
10.2, 1H), 5.05 (ddd, J ) 1.0/1.9/17.2, 1H), 5.32 (br s, 1H), 5.79
(ddd, J ) 8.3/10.2/17.2 Hz, 1H), 7.20-7.42 (m, 10H); 13C NMR
(CDCl3) δ 18.1, 38.8, 61.3, 68.9, 73.4, 80.9, 114.5, 127.1, 127.7,
128.3, 128.4, 128.7, 130.3, 135.7, 139.1, 141.8. anti-3b: 1H NMR
(CDCl3) δ 1.08 (d, J ) 6.8 Hz, 3H), 2.52-2.67 (m, 1H), 2.89 (ddd,
J ) 3.2/5.7/7.4 Hz, 1H), 3.73 (dd, J ) 3.2/10.2 Hz, 1H), 3.78 (dd,
J ) 5.7/10.2 Hz, 1H), 3.88 (d, J ) 13.9 Hz, 1H), 4.15 (d, J )
13.9 Hz, 1H), 4.56 (s, 2H), 5.00-5.07 (m, 2H), 5.39 (br s, 1H),
5.97 (ddd, J ) 7.7/10.3/17.1 Hz, 1H), 7.21-7.38 (m, 10H); 13C
NMR (CDCl3) δ 17.4, 38.4, 60.6, 67.1, 69.6, 73.2, 113.3, 127.0,
127.6, 128.1, 128.2, 128.4, 129.4, 138.3, 138.9, 142.8. Anal. (of
a purified mixture of syn-3b /anti-3b in a 4:1 ratio) Calcd for
Found: C, 53.96; H, 4.98; N, 3.28. 3,5-trans-4a : oil;
1H NMR
(CDCl3) δ 2.18 (dt, J ) 7.8/12.7 Hz, 1H), 2.30 (dt, J ) 7.3/12.7
Hz, 1H), 3.15 (dd, J ) 8.0/9.9 Hz, 1H), 3.30 (dd, J ) 4.7/9.9
Hz, 1H), 3.27-3.34 (m, 1H), 3.53 (d, J ) 5.5 Hz, 2H), 4.01
(d, J ) 13.7 Hz, 1H), 4.12 (br dq, J ) 4.7/7.7 Hz, 1H), 4.24 (d, J
) 13.7 Hz, 1H), 4.52 (s, 2H), 7.26-7.41 (m, 10H); 13C NMR
(CDCl3) δ 8.3, 38.6, 62.7, 64.4, 71.3, 73.4, 76.6, 127.2, 127.6,
127.7, 128.2, 128.4, 129.1, 135.5, 137.9. Anal. Calcd for
C
19H22NO2I: C, 53.89; H, 5.24; N, 3.31. Found: C, 53.72; H,
5.12; N, 3.47.
2-Ben zyl-3-[(ben zyloxy)m eth yl]-5-(iod om eth yl)-4-m eth -
ylisoxa zolid in e (4b). 3,4-trans-4,5-trans-4b: oil; 1H NMR
(CDCl3) δ 1.24 (d, J ) 6.8 Hz, 3H), 2.09-2.26 (m, 1H), 2.85 (dt,
J ) 5.6/11.7 Hz, 1H), 3.28 (d, J ) 6.4 Hz, 2H), 3.59 (d, J )
5.6 Hz, 2H), 3.82 (q, J ) 6.4 Hz, 1H), 3.94 (d, J ) 14.0 Hz, 1H),
4.31 (d, J ) 14.0 Hz, 1H), 4.53 (s, 2H), 7.22-7.40 (m, 10H);
13C NMR (CDCl3) δ 8.0, 18.2, 47.2, 61.7, 71.1, 73.2, 73.3, 82.6,
127.0, 127.5, 127.6, 128.1, 128.4, 128.7, 137.8, 137.9. Anal.
Calcd for C20H24NO2I: C, 54.91; H, 5.53; N, 3.20. Found: C,
54.65; H, 5.61; N, 3.37. 3,4-trans-4,5-cis-4b: oil; 1H NMR (CDCl3)
δ 1.09 (d, J ) 7.1 Hz, 3H), 2.40-2.51 (m, 1H), 2.79-2.85 (m,
1H), 3.07 (dd, J ) 7.8/10.0 Hz, 1H), 3.18 (dd, J ) 6.2/10.0
Hz, 1H), 3.52-3.57 (m, 2H), 3.98 (d, J ) 14.0 Hz, 1H), 4.24-
4.34 (m, 1H), 4.26 (d, J ) 14.0 Hz, 1H), 4.51 (d, J ) 12.0 Hz,
1H), 4.55 (d, J ) 12.0 Hz, 1H), 7.27-7.40 (m, 10H); 13C NMR
(CDCl3) δ 1.3, 13.5, 42.3, 62.9, 71.6, 72.6, 73.4, 79.2, 127.2, 127.6,
127.7, 128.2, 128.4, 129.3, 137.4, 137.9. Anal. Calcd for
C
20H25NO2: C, 77.12; H, 8.10; N, 4.50. Found: C, 77.36; H, 8.04;
N, 4.21.
N -H y d r o x y -N -b e n zy l-1-(b e n zy lo x y )-3,3-d im e t h y l-4-
C
20H24NO2I: C, 54.91; H, 5.53; N, 3.20. Found: C, 55.12; H,
p en ten -2-a m in e (3c): Oil; 1H NMR (CDCl3) δ 1.10 (s, 3H), 1.14
(s, 3H), 2.83 (dd, J ) 3.5/6.9 Hz, 1H), 3.69 (dd, J ) 3.5/10.3 Hz,
1H), 3.95 (d, J ) 13.7 Hz, 1H), 4.15 (dd, J ) 6.9/10.3 Hz, 1H),
4.24 (d, J ) 13.7 Hz, 1H), 4.51 (br s, 1H), 4.54 (d, J ) 11.8 Hz,
1H), 4.60 (d, J ) 11.8 Hz, 1H), 4.96 (dd, J ) 1.4/10.7 Hz, 1H),
4.99 (dd, J ) 1.4/17.5 Hz, 1H), 5.98 (dd, J ) 10.7/17.5 Hz, 1H),
7.25-7.42 (m, 10H); 13C NMR (CDCl3) δ 24.4, 26.1, 40.7, 64.0,
66.6, 72.8, 73.2, 111.1, 126.9, 127.5, 127.6, 128.2, 128.4, 129.1,
138.4, 139.2, 146.8. Anal. Calcd for C21H27NO2: C, 77.49; H,
8.37; N, 4.31. Found: C, 77.71; H, 8.56; N, 4.62.
5.58; N, 3.14.
2-Ben zyl-3-[(b en zyloxy)m et h yl]-5-(iod om et h yl)-4,4-d i-
m eth ylisoxa zolid in e (4c). 3,5-trans-4c: oil; 1H NMR (CDCl3)
δ 1.13 (s, 6H), 3.06 (d, J ) 6.6 Hz, 1H), 3.34 (dd, J ) 6.6/11.2
Hz, 1H), 3.65 (d, J ) 15.3 Hz, 1H), 3.75 (d, J ) 11.2 Hz, 1H),
3.88 (dd, J ) 4.4/11.0 Hz, 1H), 4.13 (t, J ) 11.0 Hz, 1H), 4.22
(dd, J ) 4.4/11.0 Hz, 1H), 4.26 (d, J ) 15.3 Hz, 1H), 4.46 (d, J
) 11.8 Hz, 1H), 4.51 (d, J ) 11.8 Hz, 1H), 7.21-7.38 (m, 10H);
13C NMR (CDCl3) δ 27.7, 37.5, 45.8, 59.3, 69.5, 72.6, 72.9, 73.8,
126.6, 127.6, 127.8, 127.9, 128.1, 128.5, 137.5, 139.2. Anal.
Calcd for C21H26NO2I: C, 55.86; H, 5.81; N, 3.10. Found: C,
55.73; H, 5.92; N, 3.14.
N -Me t h y l-r-(1-m e t h y l)-2-p r o p e n y lb e n ze n e m e t h a n -
a m in e (3d ). The product was obtained as a mixture of the two
syn/anti isomers having the same Rf on silica gel. The following
spectroscopic data were drawn from the enriched mixtures
obtained in entries 1 and 3 of Table 2. syn-3d : 1H NMR (CDCl3)
δ 0.95 (d, J ) 6.9 Hz, 3H), 2.53 (s, 3H), 3.00-3.08 (m, 1H), 3.41
(d, J ) 2.2 Hz, 1H), 4.95-5.00 (m, 2H), 5.75-5.87 (m, 1H), 7.26-
7.35 (m, 5H); 13C NMR (CDCl3) δ 17.6, 39.2, 46.3, 78.8, 114.6,
127.4, 127.8, 128.5, 129.6, 137.5, 140.4. anti-3d : 1H NMR
(CDCl3) δ 0.85 (d, J ) 6.8 Hz, 3H), 2.44 (s, 3H), 2.90-2.99 (m,
1H), 3.38 (s, 1H), 4.73 (br s, 1H), 5.05 (ddd, J ) 0.6/1.9/10.2 Hz,
1H), 5.13 (ddd, J ) 0.9/1.9/17.1, 1H), 5.87 (ddd, J ) 8.6/10.2/
17.1, 1H), 7.25-7.40 (m, 5H); 13C NMR (CDCl3) δ 16.9, 40.7, 45.4,
77.9, 113.5, 127.4, 127.8, 128.4, 128.7, 137.0, 143.2. Anal. (of a
purified mixture of syn-3d /anti-3d in a 7:3 ratio) Calcd for
5-(Iod om eth yl)-2,4-d im eth yl-3-p h en ylisoxa zolid in e (4d ).
3,4-cis-4,5-trans-4d : oil; 1H NMR (CDCl3) δ 0.76 (d, J ) 7.3 Hz,
3H), 2.53 (ddq, J ) 5.7/7.3/8.3 Hz, 1H), 2.68 (s, 3H), 3.33 (dd, J
) 5.7/10.4 Hz, 1H), 3.38 (dd, J ) 5.7/10.4 Hz, 1H), 3.72 (q, J )
5.7 Hz, 1H), 3.77 (d, J ) 8.3 Hz, 1H), 7.20-7.40 (m, 5H); 13C
NMR (CDCl3) δ 7.2, 15.8, 44.0, 48.1, 76.2, 83.7, 127.5, 128.2,
128.3, 136.8. Anal. Calcd for C12H16NOI: C, 45.42; H, 5.09; N,
4.42. Found: C, 45.38; H, 5.24; N, 4.46. 3,4-trans-4,5-trans-
1
4d : oil; H NMR (CDCl3) δ 1.18 (d, J ) 6.8 Hz, 3H), 2.38 (ddq,
J ) 5.7/6.8/9.3 Hz, 1H), 2.55 (s, 3H), 3.10 (d, J ) 9.3 Hz, 1H),
3.41 (dd, J ) 7.7/9.7 Hz, 1H), 3.48 (dd, J ) 5.7/9.7 Hz, 1H), 3.96
(dt, J ) 5.7/7.7 Hz, 1H), 7.28-7.40 (m, 5H); 13C NMR (CDCl3) δ
9.3, 16.9, 43.3, 54.1, 82.4, 83.1, 127.8, 128.1, 128.7, 137.5. Anal.
C
12H17NO: C, 75.34; H, 8.96; N, 7.33. Found: C, 75.38; H, 8.84;
N, 7.52.
2-Ben zyl-3-[(ben zyloxy)m eth yl]-5-(iod om eth yl)isoxa zo-
(11) All the O-silylated hydroxylamines, contrary to starting hy-
droxylamines, are easily analyzed by GC-MS and show the charac-
teristic fragment due to the loss of the allylic moiety from the molecular
ion.
lid in e (4a ). Gen er a l P r oced u r e for t h e Iod ocycliza t ion
Rea ction . Imidazole (190 mg, 2.8 mmol) and TMSCl (0.36 mL,
2.8 mmol) were added to a solution of 3a (420 mg, 1.4 mmol) in

5626 J . Org. Chem., Vol. 62, No. 16, 1997
Notes
Calcd for C12H16NOI: C, 45.42; H, 5.09; N, 4.42. Found: C,
45.48; H, 5.02; N, 4.51.
Anal. Calcd for C12H16NOI: C, 45.42; H, 5.09; N, 4.42. Found:
C, 45.36; H, 5.17; N, 4.48.
2-(Iod om eth yl)-1,3-d im eth yl-4-p h en yla zetid in e 1-Oxid e
(5d ). Oil; 1H NMR (CDCl3) δ 1.22 (d, J ) 6.8 Hz, 3H), 2.31 (ddq,
J ) 5.8/6.8/8.8 Hz, 1H), 2.70 (q, J ) 5.8 Hz, 1H), 2.91 (s, 3H),
3.31 (dd, J ) 5.8/10.4 Hz, 1H), 3.37 (dd, J ) 5.8/10.4 Hz, 1H),
4.81 (d, J ) 8.8 Hz, 1H), 7.30-7.42 (m, 5H); 13C NMR (CDCl3)
δ 8.0, 16.4, 46.2, 54.3, 76.4, 106.8, 127.2, 128.7, 129.0, 135.4.
Ack n ow led gm en t. We thank the University of
Bologna (funds for selected topics) and Italian CNR for
financial support.
J O970544S