The stereochemistry of 1,3-dipolar cycloaddition of internally H-bonded chiral methylenenitrones

Article abstract of DOI:10.1016/j.tet.2007.06.067

A study of diastereoselectivity in the cycloaddition reactions of a series of mono- and disubstituted alkenes with two chiral, internally H-bonded methylenenitrones has been carried out. The high degree of stereochemical control in the presence of anhydro

Full text of DOI:10.1016/j.tet.2007.06.067

Tetrahedron 63 (2007) 9134–9145
The stereochemistry of 1,3-dipolar cycloaddition of internally
H-bonded chiral methylenenitrones
*
Shaikh A. Ali and Muhammad Z. N. Iman
Chemistry Department, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia
Received 7 April 2007; revised 6 June 2007; accepted 21 June 2007
Available online 27 June 2007
Abstract—A study of diastereoselectivity in the cycloaddition reactions of a series of mono- and disubstituted alkenes with two chiral, in-
ternally H-bonded methylenenitrones has been carried out. The high degree of stereochemical control in the presence of anhydrous magne-
sium bromide has been explained in terms of a metal chelated transition state. Intramolecular cycloaddition involving a methylenenitrone
containing an alkene moiety linked to a nitrogen gave a stereoselective addition product.
Ó 2007 Elsevier Ltd. All rights reserved.
H
R
O
H
R
H
R
R
1. Introduction
N
Ph
N
Ph
N
Ph
O
H
O
Among a plethora of functional groups, the nitrone function-
ality has etched a place of distinction in organic synthesis.
Remarkable regio-, stereo-, face-, and chemoselectivity
along with efficient incorporation of multiple stereocenters
have made nitrone cycloaddition reactions an attractive and
efficient key step in the synthesis of a great many natural
products of biological interest.1 In recent years, focus has
been shifted toward asymmetric nitrone cycloaddition reac-
tions; enantioselective,2 catalytic enantioselective,3 and
diastereoselective4 synthetic methodologies, as well as
metal-assisted stereocontrol5 have been reported. The effi-
cacy of a diastereoselective approach using a chiral nitrone
very much depends on the ability of the chiral auxiliary to
effectively transfer chirality to the newly created stereocen-
ters. The poor selectivity observed6 in the cycloaddition reac-
tions of the chiral nitrone 1 may be attributed to its
conformational flexibility by virtue of easy N–C bond rota-
tion (Scheme 1). However, intramolecularly H-bonded ni-
trone 2, or its tightly metal-chelated form 3, severely
restricts the bond rotation, thereby allowing the incoming
alkenes to experience two different faces of the nitrone.
Approach of the alkenes toward the less hindered face of
the nitrone increases the diastereoselectivity.7,8 The chiral
auxiliary in 2 is receiving increasing attention owing to its
easy reductive cleavage from the cycloadduct 4, so as to pro-
vide a simple and efficient access to 5 to synthetically impor-
tant 1,3-aminoalcohols 6.
Metal
Me
O
2
O
3
1
R
R
3
5
N
O
HN
H2N
Ph
R'
O
R'
R'
O
O
H
H
4
6
5
Me
Me
H
H
H
H
O
H
H
O
Ph
N
Ph
N
N
O
H
O
Metal
H
Me
O
7
O
8
9
Scheme 1.
Even though the nitrone cycloaddition reactions of C,N-di-
substituted nitrones have been studied in great detail,1 the
chemistry of chiral (or even achiral) N-substituted nitrones
(i.e., methylenenitrones) has only been investigated to a lim-
ited extent.7,9 Here we report a systematic study detailing the
regio- and stereochemical features associated with the cyclo-
addition of the chiral internally H-bonded methyleneni-
trones 7 and 9 onto a series of mono- and 1,1-disubstituted
alkenes. The study would indeed provide a composite pic-
ture that reflects the scope and limitations associated with
the addition reactions of the methylenenitrones. In order to
make the nitrones more versatile, we would also like to
explore an intramolecular nitrone cycloaddition reaction in-
volving an N-alkenylnitrone that may be obtained by linking
Keywords: Nitrone cycloaddition; Asymmetric induction; Lewis acid cata-
lyst; Diastereoselection.
* Corresponding author. Fax: +966 3 860 4277; e-mail: shaikh@kfupm.
edu.sa
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.067

S. A. Ali, M. Z. N. Iman / Tetrahedron 63 (2007) 9134–9145
9135
an alkene moiety to the oxygen atom of the hydroxyl group
in the nitrone 7.
the b-face of the nitrone, while the H on the stereocentre re-
mains on the a-face (Scheme 3). While both the ‘a-exo (R)
approach’ (i.e., the approach of the alkene with exo-oriented
R group toward the a-face of the nitrone) and ‘b-endo (R)
approach’ of the alkene would lead to the same diastereo-
mer with ‘RR’ configuration, the ‘a-endo (R)’ and ‘b-exo
(R)’ approaches give the other diastereomer having ‘RS’
configuration. The face selectivity in the addition reaction
of methylenenitrones, like 7, cannot be determined since,
for instance, the formation of the ‘RR’ diastereomer is the
combined outcome of approach of the alkene to both faces
of the nitrone. Likewise, the stereoselectivity in each face
(exo/endo ratio) cannot be determined, since each diastereo-
mer can be obtained by both the exo and endo mode
of attack. This problem does not arise in the case of
C-substituted chiral nitrones, since their addition reactions
would create three chiral centers, and as such, each of the
approaches would generate a different diastereomer, thus
allowing the determination of face selectivity as well as
stereoselectivity of each face. For the current nitrone 7, it
can be presumed that the a-face of the nitrone will be pref-
erentially attacked, and the steric interactions would then
dictate the exo mode of approach. In line with this reasoning,
the 1-hexene cycloaddition resulted in the formation of the
major adduct 12a predominantly via ‘a-exo (R) approach’.
In the presence of MgBr2, the metal chelation imparts better
stability to the face than the H-bonded form, thereby leading
to a better face selectivity.
2. Results and discussion
The stereochemical details of the addition of the nitrone 7
onto several monosubstituted alkenes (Scheme 2) along
with the reaction temperatures, solvent, isolated yield, and
composition of diasteroemeric cycloadducts are given in
Table 1.
H
H
3
3
R
+
5
5
Ph
+ Ph
Ph
N
N
N
O
H
H
R
O
O
R
OH
OH
O
7
11
12
13
CH2O
a, R = (CH2)3CH3
f, R = CH2OH
g, R = CH2OSitBuMe2
h, R = CH2CH2OH
b, R = Ph
Ph
NHOH
c, R = CHO
d, R = CO2Me
i, R = CH2CH2OSitBuMe2
j, R = CH2CH2CH2OH
H
O
t
e, R = CO2 Bu
10
Scheme 2.
Reaction of nitrone 7 with 1-hexene gave a mixture of dia-
stereomers 12a and 13a in a ratio of 77:23, while the ratio
was improved to 85:15 in the presence of anhydrous
MgBr2. The nitrone 7 is expected to be internally H-bonded
as shown in Scheme 1. This would place the phenyl group on
H
R
H
- endo (R)
β
Ph
S
N
R
O
R
H
R
β - exo (R)
OH
Ph
Ph
O
R
R
N
Table 1. Regio- and stereochemistry of the cycloaddition of the nitrone 7
with monosubstituted alkenes 11
N
H
H
O
O
R
R
Ph
α - exo (R)
N
R
O
Alkene Temp Time Solvent Lewis
(ꢀC) (h)
Isolated Diastereomeric
yields (%) ratio (12:13)
H
H
O
H
11
acida
OH
R
H
a
105
65
8 Toluene None
48 CH2Cl2 MgBr2
90
77
77:23
85:15
α
- endo (R)
H
R
b
0
25
50
75
65
144 CHCl3 None
72 CHCl3 None
65
75
90
78:22
76:24
73:27
79:21
86:14
Scheme 3.
6
CHCl3 None
24 CHCl3 BF3$OEt2 75
24 CH2Cl2 MgBr2
Styrene undergoes addition to give 12b and 13b in a ratio of
73:27 at 50 ꢀC. At lower reaction temperatures of 25 and
0 ꢀC, the ratio is changed slightly in favor of the major iso-
mer; decreasing temperature is expected to make the H-
bonding more effective in arresting conformational change
to the open form by C–N bond rotation. However, there
was only a slight improvement in the diastereoselectivity.
The diastereoselectivity is further improved in the presence
of Lewis acids. Based on the earlier discussion, the major ad-
duct is obtained via ‘a-exo (R) approach’; steric factor of the
phenyl group in styrene is known10 to overwhelm any possi-
ble secondary orbital interactions in an endo approach.
92
c
65
6
CHCl3 None
65
44:56
d
0
25
50
65
65
144 CHCl3 None
72 CHCl3 None
64
74
86
44:56
48:52
46:54
38:62
62:38
6
CHCl3 none
24 CHCl3 BF3$OEt2 85
6
6
6
CHCl3 Ti(OiPr)4 83
e
f
65
CHCl3
85
56:44
85
40
Toluene None
83
90
62:38
4:96b
24 CH2Cl2 MgBr2
g
105
12 Toluene None
88
75:25
h
105
65
8 Toluene None
48 CH2Cl2 MgBr2
93
91
70:30
89:11
The reaction of nitrone 7 with acrolein and methyl acrylate
gave a diastereomeric mixture of 12c, 13c and 12d, 13d, re-
spectively; in each case a slight excess of the endo adduct 13
is obtained via ‘a-endo (R) approach’. While the cycloaddi-
tion favors the formation of 13d in the presence of
BF3$OEt2, the stereoselectivity is reversed with Ti(OiPr)4.
i
105
12 Toluene None
90
82:18
j
105
65
8 Toluene None
48 CH2Cl2 MgBr2
92
93
73:27
91:9
a
In the presence of 1 equiv of Lewis acid as described in Section 3.3.
Work taken from Ref. 7.
b

9136
S. A. Ali, M. Z. N. Iman / Tetrahedron 63 (2007) 9134–9145
The addition of the nitrone 7 with tert-butyl acrylate gave the
diastereomers 12e and 13e in a 56:44 ratio; a slight excess of
the exo adduct 12e demonstrates the steric hindrance of the
tert-butyl group. To confirm the stereochemistry, adduct
13d was subjected to X-ray crystallographic analysis; the
ORTEP representation is shown in Figure 1. Complete
stereochemical analysis was carried out by conversion of
the tert-butyl acrylate adducts 12e, 13e into methyl acrylate
adducts 12d, 13d by ester exchange with methanol/HCl. The
stereochemistry of the acrolein adducts 12c, 13c was corre-
lated with that of the methyl acrylate adducts 12d, 13d by
their conversions to the alcohol adducts 12f and 13f.
Allyl alcohol (11f), 3-buten-1-ol (11h), and 4-penten-1-ol
(11j) appear to undergo cycloadditions in the presence of
MgBr2 with much higher diastereoselection to give 12f/
13f, 12h/13h, 12j/13j, respectively, in a ratio of 4:96,7
89:11, and 91:9. It is interesting to note the change in stereo-
selection in this series of alkenes differing in the length sep-
arating the OH and alkene functionality. The configuration
of the overwhelmingly predominant adduct 13f is consistent
with a magnesium-chelated endo approach of the CH2OH
group of the allyl alcohol from the less hindered face of
the nitrone7,8 as depicted in A (Fig. 3). However, the transi-
tion state, for the higher homologs of allyl alcohol, as de-
picted in B is expected to give cycloadducts (12h or 12j)
via exo-mode of attack by the alkene. This was indeed ob-
served experimentally; the study thus provided information
on the effect of the intervening length between the alkene
and hydroxyl moiety on the stereoselection.
Addition reactions of nitrone 7 with allyl alcohol (11f), 3-
buten-1-ol (11h), and 4-penten-1-ol (11j) afforded 12f,
12h, and 12j, respectively, as the major adducts via ‘a-exo
(R) approach’ (Scheme 3). Among these three alcohols, allyl
alcohol gave the largest proportion of a-endo (R) adduct 13f.
The higher tendency of the allyl moiety than 3-butenyl for
the endo approach is also demonstrated in the addition reac-
tions of tert-butyldimethylsilyl allyl ether 11g and tert-
butyldimethylsilyl 3-butenyl ether 11i; the adduct ratio
changes from 75:25 for 12g/13g to 82:18 for 12i/13i. Signif-
icant preference for the endo approach observed in the addi-
tion of allyl ether and alcohols may be attributed to the
stabilizing interaction between the nitrogen atom of the
nitrone LUMO with the oxygen lone pair of the alkene
(Fig. 2).10,11
Next, we pursued the cycloaddition of nitrone 7 with a num-
ber of 1,1-disubstituted alkenes 14 (Scheme 4). The results
of our stereochemical analysis are summarized in Table 2.
The addition of methacrolein 14a to the nitrone 7 gave the
hemiacetals 15a0 and 16a0 instead of the expected adducts
15a and 16a (in the aldehyde form). We were able to isolate
one of the hemiacetals—presumably the 15a0—in pure form.
The configuration of adducts was correlated to the methallyl
alcohol adducts 15d and 16d by NaBH4 reduction of the
crude cycloaddition products. The ratio of the isomers 15a
and 16a was determined to be 66:34, respectively. For the
favorable secondary orbital interactions, the aldehyde group
is assumed to have the endo orientation in 15a, formed via
‘a-endo (CHO) approach’.
The cycloaddition of 7 with methyl methacrylate 14b at
50 ꢀC gave a separable mixture of 15b and 16b in a ratio
of 86:14. The favorable secondary orbital interactions place
the ester in the endo orientation in 15b. The cycloaddition at
0 and 25 ꢀC gave the adducts 15b and 16b in a ratio of 90:10
and 87:13, respectively. The ratio is slightly changed at
lower temperatures in favor of the major isomer, presumably
as a result of more effective H-bonding in reducing confor-
mational change to the open form by C–N bond rotation.
The stereochemistry of adducts was correlated to the meth-
allyl alcohol adducts 15d and 16d by lithium aluminum
hydride reduction of the crude cycloaddition products. Addi-
tion of nitrone 7 with tert-butyl methacrylate 14c gave a
non-separable mixture of cycloadducts 15c and 16c in a ratio
of 87:13. The adducts 15c and 16c were converted into the
methyl methacrylate adducts 15b and 16b by ester exchange
with methanol. The addition reaction of nitrone 7 onto
Figure 1. ORTEP drawing of 13d.
C
R
R
N
O
Br
Br
N
N
O
C
Mg
Mg
H
H
R
C
O
O
O
O
H
O
O
H
H
H
A
B
(CH2)n
Figure 2. Stabilizing interaction between nitrogen in nitrone LUMO and
oxygen lone pair of the alkene.
Figure 3. Metal chelated transition states for the cycloaddition reactions.

S. A. Ali, M. Z. N. Iman / Tetrahedron 63 (2007) 9134–9145
9137
H
H
R1
R2
R1
3
3
+
Ph
5
5
Ph
R1
R2
N
Ph
N
N
+
O
H
R2
O
O
OH
OH
O
7
14
15
16
a, R1= Me; R2 = CHO
d, R1= Me; R2 = CH2OH
e, R1= Me; R2 = CH2OSitBuMe2
f, R1= R2 = CO2Me
b, R1= Me; R2 = CO2Me
c, R1= Me; R2 = CO2 Bu
t
Me
Me
Me
5
5
Ph
Ph
Ph
N
N
N
OH
OH
O
O
O
CHO
C
'
C
'
5
5
H
H
O
OH
O
15a
15a'
16a'
Scheme 4.
Table 2. Stereochemistry of cycloadditiona of the nitrone 7 with 1,1-disub-
stituted alkenes 14
dimethyl methylenemalonate 14f gave the cycloadduct 15f
as the sole regiomer in an excellent yield.
Alkene Temp Solvent Lewis
(ꢀC)
Isolated Diastereomeric
yields (%) ratio (15:16)
14
acid
The results discussed above are in general agreement with
the Frontier orbital treatment of the nitrone 1,3-dipolar cy-
cloadditions.12 In the case of mono- as well as 1,1-disubs-
tituted alkenes, the nitrone (HOMO)–alkene (LUMO)
contribution does not offer any regiochemical preference,
since the nitrone HOMO has a similar magnitude of orbital
coefficients at both the nitrogen and carbon terminals. How-
ever, the nitrone (LUMO)–alkene (HOMO) prefers the for-
mation of 5-substituted regioisomers by uniting the larger
terminal coefficients in the transition state (Fig. 4).13
a
65
CHCl3
None
93
66:34
b
0
25
50
65
CHCl3
CHCl3
CHCl3
CHCl3
None
None
None
53
87
80
90:10
87:13
86:14
86:14
BF3$OEt2 84
c
65
CHCl3
None
85
87:13
d
90
65
Toluene None
CH2Cl2 MgBr2
82
95
67:33
97:3
e
110
50
Toluene None
74
90
58:42
100
f
CHCl3
None
Next, we studied the cycloaddition behavior of another inter-
nally H-bonded chiral methylenenitrone 9 with several
mono- (11) and di-substituted alkenes (14) (Scheme 5).
The stereochemical analyses of these additions are summa-
rized in Table 3. Cycloaddition of 1-hexene (11a) with ni-
trone 9 gave a mixture of the cycloadducts 18 and 19 in
a ratio of 95:5. The reaction of nitrone 9 with styrene
(11b) afforded a non-separable mixture of adducts 20 and
21 in a ratio of 96:4. The major isomer in each case is as-
signed the configuration with an exo-oriented n-butyl/or
a
Duration of reaction: 6 h in the absence of Lewis acid (except for 14e the
reaction was run for 12 h), and 24 h in the presence of Lewis acid.
conjugated 1,1-disubstituted alkenes 14 gave better stereo-
selectivity than their monosubstituted counterparts 11 as a
result of a marked preference for the ‘a-endo (–C]O) ap-
proach’. While for the stereoselection in monosubstituted
alkenes, the steric factor (H vs R) and secondary orbital
interactions operate in opposite directions, the secondary or-
bital interaction is the dominant player in 14 since the steric
differences between ‘Me’ and ‘–C]O’ are very minimal.
LUMO
E (ev)
~+ 3
R2
Reaction of nitrone 7 with methallyl alcohol 14d gave a non-
separable mixture of cycloadducts 15d and 16d in a ratio of
67:33. Significant change in the stereoselection was ob-
served when this addition reaction was carried out in the
presence of anhydrous MgBr2; the isomers 15d and 16d
were obtained in a 97:3 ratio. The configuration of the major
adduct is based on a transition state similar to that depicted
in A (Fig. 3); overwhelming preference of the CH2OH group
to assume endo orientation is manifested. The addition of si-
lylether alkene 14e afforded cycloadducts 15e and 16e in
a 58:42 ratio; the stereochemistry of the cycloadducts was
correlated to the methallyl alcohol adducts 15d and 16d by
their conversion into the corresponding alcohols. As dis-
cussed before, significant preference for the endo-approach
of the CH2O– moieties is attributed to the stabilizing interac-
tion as depicted in Figure 2. Reaction of nitrone 7 with
~+1
+ 0.3
R1
R
N
Z
Z
R
R
R2
R
N
R1
~- 8
- 8.7
HOMO
~-10
R
N
5
O
Figure 4. A qualitative representation of the energies and orbital coeffi-
cients of methylenenitrone and alkene Frontier orbital energies of nitrone
and mono- and 1,1-disubstituted alkenes.

9138
S. A. Ali, M. Z. N. Iman / Tetrahedron 63 (2007) 9134–9145
phenyl as expected via a sterically favored transition state
with an exo-disposition of the alkene substituent. The addi-
tion of methyl acrylate (11d) to the nitrone 9 gave 22 and 23
in a ratio of 65:35. The stereochemistry of the major adduct
22 was confirmed by X-ray crystallographic analysis; the
ORTEP representation is shown in Figure 5. The reaction
of the nitrone 9 with methyl methacrylate (14b) afforded
a mixture of adducts 24 and 25 in a ratio of 66:34. Addition
of the nitrone 9 with dimethyl methylenemalonate 14f gave
cycloadduct 26 as the sole regiomer as expected.
b face of nitrone 9 is indeed very crowded thereby leading to
the preferential attack on the a face with exo-disposition of
the alkene substituents. A similar trend is observed in the ad-
dition of methyl acrylate (11d); while nitrone 7 afforded 12d
and 13d in a 0.9:1 ratio; the corresponding ratio for the reac-
tion of nitrone 9 to give 22 and 23 was found to be 1.9:1. The
results reemphasize the dominance of steric factor over sec-
ondary orbital interactions in the additions of the nitrone 9.
Finally, we studied the intramolecular nitrone–alkene cyclo-
addition reaction involving chiral nitrone 28 having an alkene
moiety linked to the nitrogen atom (Scheme 6). While intra-
molecular cycloadditions of C-alkenylnitrones, having an
alkene moiety attached to the C-terminal, have been widely
studied, the addition reaction of the N-alkenylnitrone is
very limited.4c The synthesis of nitrone 28 is not so straight-
forward; instead we pursued a protection–deprotection
chemistry of the nitrone functionality. Adducts derived
from the addition reaction of a highly polarized alkene like
dimethylmethylene malonate are known to undergo facile
cycloreversion.10 The cycloadduct 15f was converted into
its acrylate ester 27. It is gratifying to see the adduct 27
undergo cycloreversion, followed by intramolecular cycload-
dition of the intervening alkenenitrone 28, to give the single
bicyclic adduct 29. The configuration of adduct is corrobo-
rated by spectral analyses including COSY NMR and also
by conversion into the known methyl acrylate adduct 13d. In-
spection of the molecular models indicates the favorable tran-
sition state involving the alkene in an ‘endo (R)-approach’.
Me
Me
Me
Me
H
H
O
NHOH
N
CH2=O
O
O
H
H
Me
Me
9
17
Me
Me
Me
Me
R2
R1
R1
R2
3
3
5
5
R2
R1
N
N
O
+
O
O
O
11/or 14
H
H
Me
Me
11a
11b
11d
14b
14f
18 R1=H, R2= (CH2)3CH3
20 R1=H, R2= Ph
19
21
23
25
22 R1=H, R2= CO2Me
24 R1=CO2Me, R2= Me
26 R1=R2= CO2Me
Scheme 5.
O
CO2Me
CO2Me
CO2Me
CO2Me
The results indicate that the additions of nitrone 9 onto nor-
mal monosubstituted alkenes are more diastereoselective
than the additions of the nitrone 7. For example, while the
addition of nitrone 7 to 1-hexene (11a) and styrene (11b)
gave the diastereomers 12 and 13 in a ratio of 3.35:1 and
2.70:1, respectively, the corresponding ratio for the addition
of nitrone 9 leading to the diastereomers 18/19 and 20/21 be-
came 24:1 and 19:1, respectively. In an H-bonded form, the
Ph
Ph
N
N
ClCCH=CH2
pyridine
120 °C
O
O
OH
O
27
15f
O
H
H
Ph
Ph
Ph
MeOH/H+
N
N
O
N
O
O
CO2Me
H
H
OH
13d
O
O
O
O
Table 3. Regio- and stereochemistry of the cycloadditiona of the nitrone 9
with mono- 11 and di-substituted alkenes 14
+
29
28
MeO2C
CO2Me
14f
Alkene
11/14
Temp
(ꢀC)
Solvent
Isolated
yields (%)
Diastereomeric
ratio
Scheme 6.
11a
11b
11d
14b
14f
107
65
55
50
50
Toluene
CHCl3
CHCl3
CHCl3
CHCl3
79
81
85
88
79
(18/19) 95:5
(20/21) 96:4
(22/23) 65:35
(24/25) 66:34
(26) —
A systematic study of asymmetric reactions of two chiral
methylenenitrones with several mono- and di-substituted
alkenes has been carried out. The diastereoselection observed
in our study reflects the scope and limitation inherent in these
important cycloaddition reactions. Remarkable stereoselec-
tivity observed in the intramolecular reaction (28/29)
paves the way to explore reactions involving nitrone–
alkenes differing in structure and intervening spacer length
between the nitrogen and the alkene moieties.
a
Duration of reaction: 8 h.
3. Experimental
3.1. General
Elemental analysis was carried out on a EuroVector Elemen-
tal Analyzer Model EA3000. All mps are uncorrected. IR
Figure 5. ORTEP drawing of 22.

S. A. Ali, M. Z. N. Iman / Tetrahedron 63 (2007) 9134–9145
9139
spectra were recorded on a Perkin–Elmer 16F PC FTIR
signals. (Found: C, 72.0; H, 9.2; N, 5.6. C15H23NO2 requires
C, 72.25; H, 9.30; N, 5.62%.) nmax (neat) 3420, 2929, 2864,
1456, 1378, 1048, 852, 758 and 701 cmꢁ1; dH (CDCl3,
+20 ꢀC) 0.91 (3H, t, J 6.8 Hz), 1.00–1.90 (7H, m), 2.31
(1H, m), 2.75 (1H, m), 2.98 (1H, m), 3.45 (1H, m), 3.71
(1H, dd, J 3.3, 11.6 Hz), 3.85 (1H, dd, J 3.3, 7.7 Hz), 4.09
(1H, dd, J 7.7, 11.6 Hz), 4.29 (1H, m), 7.30 (5H, m). Non-
overlapping signals of the minor isomer 13a were displayed
at d 2.47 (1H, m), 3.75 (1H, dd, J 3.3, 7.7 Hz).
1
spectrometer. H and 13C NMR spectra were measured in
CDCl3 using TMS as internal standard on a JEOL LA
500 MHz spectrometer. Silica gel chromatographic separa-
tions were performed with Silica gel 100 from Fluka Chemie
AG (Buchs, Switzerland). Paraformaldehyde, 1-hexene, sty-
rene, allyl alcohol, 3-buten-1-ol, 4-penten-1-ol methyl
acrylate, methyl methacrylate, methylallyl alcohol, m-
chloroperbenzoic acid (70% purity), D(ꢁ)-a-phenylglycinol
(i.e., (R)-phenylglycinol), hydroxylamine hydrochloride
from Fluka were used as received. All solvents were of re-
agent grade. Dichloromethane was passed through alumina
before use. MgBr2 was prepared freshly by reaction of
Mg with 1,2-dibromoethane. Alkanols were silylated using
tBuMe2SiCl in the presence of imidazole in DMF. All
reactions were carried out under N2.
3.2.2. Cycloaddition of nitrone 7 with styrene (11b). The
crude mixture of cycloadducts was purified by chromato-
graphy over silica using ether/hexane as eluant to give
a non-separable mixture of the cycloadducts 12b and 13b
(1.21 g, 90%) as a colorless liquid in a ratio of 73:27 as
determined by integration of the C5(H) signals. (Found: C,
75.6; H, 6.9; N, 5.1. C17H19NO2 requires C, 75.81; H,
7.11; N, 5.20%.) nmax (neat) 3417, 3061, 3029, 2881,1603,
1493, 1454, 1360, 1310, 1179, 1028, 950, 913, 847, 760,
and 703 cmꢁ1; dH (CDCl3, +20 ꢀC) broad NMR signal be-
tween d 2.2–5.5 ppm due to relatively slow nitrogen inver-
sion. The proton signals for the individual isomers, as
detailed below, are extracted from the spectrum of the
non-separable mixture.
The chiral hydroxylamine (R)-3-hydroxyamino-2-phenyl-
ethanol (10) was prepared in 80% yield according to the
literature procedures;14,15 mp 68–68.5 ꢀC (methanol/ether);
[a]2D3 ꢁ62 (c 2.00, methanol). The chiral 3-(hydroxyamino)-
borneol (17) was prepared as described.16,17
3.2. General procedure for the cycloaddition reactions
In all the cycloadditions involving electron deficient conju-
gated alkenes, a mixture of the hydroxylamine 10
(5 mmol), paraformaldehyde (7.5 mmol), and a solvent
(15 cm3) was stirred in a closed flask at 50 ꢀC for 4 h to
generate the nitrone 7. The nitrone solution was then treated
with MgSO4 (1 g) and the alkene. The conjugated alkene
was not added prior to the formation of the nitrone in order
to avoid any Michael addition of the hydroxylamine. For the
additions involving normal alkenes, all the reactants were
added in the beginning, and the reaction mixture was directly
heated at the specified temperatures (Tables 1–3). The al-
kenes used, with the amounts in mmol given in parentheses,
were as follows: 1-hexene (30), styrene (20), acrolein (12),
methyl acrylate (15), tert-butyl acrylate (10), allyl alcohol
(25), tert-butyldimethylsilyl allyl ether 11g (8), 3-buten-
1-ol (15), tert-butyldimethylsilyl 3-butenyl ether 11i (8),
4-penten-1-ol (12), methyl methacrolein (8), methyl methac-
rylate (15), tert-butyl methacrylate (10), methallyl alcohol
(20), tert-butyldimethylsilyl 2-methyl-2-propenyl ether 14e
(10), and dimethyl methylenemalonate 14f (6). The reaction
temperatures, time, solvent used, composition of adducts,
and isolated yields are given in Tables 1 and 2. The reaction
mixture was filtered, evaporated to remove the solvent and
excess alkene (if volatile) to give crude residues containing
the cycloadducts, which were then purified and analyzed.
Major isomer 12b: dH (CDCl3, ꢁ40 ꢀC) 2.20 (1H, m), 2.77
(1H, m), 2.98 (1H, m), 3.28 (1H, m), 3.70 (1H, OH), 3.76
(1H, m), 4.05 (1H, m), 4.22 (1H, m), 5.39 (1H, dd, J 6.6,
8.1 Hz), 7.40 (10H, m). C5(H) signal for minor invertomer
appear at 4.97 ppm (t, J 7.5 Hz) in a ratio of 95:5; dC
(CDCl3, ꢁ40 ꢀC) 38.74, 53.94, 68.73, 70.83, 78.93, 128.8
and 129.8, 137.68 and 140.59. (TMS: 0.0; CDCl3 middle
carbon: 77.1). The spectrum also revealed the presence of
weak signals for the minor invertomer.
Minor isomer 13b: dH (CDCl3, ꢁ40 ꢀC) 2.10 (1H, m), 2.60
(1H, m), 2.65 (1H, m), 3.15 (1H, m), 3.55 (1H, m), 3.70 (1H,
OH), 4.00 (1H, m), 4.17 (1H, m), 5.16 (1H, dd, J 6.9,
8.1 Hz), 7.4 (10H, m). C5(H) signal for minor invertomer
of minor isomer appear at 4.72 ppm (t, J 7.1 Hz) in a ratio
of 92:8; dC (CDCl3, ꢁ40 ꢀC) 36.26, 55.07, 68.42, 74.17,
80.22, and overlapping signals of aromatic carbons (TMS:
0.0; CDCl3 middle carbon: 77.1). In addition to these sig-
nals, signals for the minor invertomer can also be seen in
the spectrum.
The above cycloaddition reaction was repeated at 0 and
25 ꢀC using the hydroxylamine 10 (38 mg, 0.25 mmol).
The yields and ratio of the diastereomers are given in the
Table 1.
The nitrone (9)–alkene (11/14) reactions were carried out in
a similar way as described above using the hydroxylamine
17 instead of 10. The reaction temperatures, time, solvent
used, composition of adducts, and isolated yields are given
in Table 3.
3.2.3. Cycloaddition of nitrone 7 with acrolein (11c), and
sodium borohydride reduction of cycloadducts 12c and
13c to 12f and 13f. The crude mixture of cycloadducts
12c and 13c in methanol (5 cm3) was treated with NaBH4
(150 mg) and stirred at 20 ꢀC for 1 h. After removal of the
solvent by a gentle stream of N2, the reaction mixture was
taken up in a saturated K2CO3 solution (7 cm3), and ex-
tracted with CH2Cl2 (3ꢂ10 cm3). The combined organic
layers were dried (Na2SO4), concentrated and the residual
liquid was purified by silica gel chromatography using
ether/methanol (95:5) as the eluant to give a non-separable
mixture 12f and 13f (65%) in a ratio of 44:56, respectively,
3.2.1. Cycloaddition of nitrone 7 with 1-hexene (11a). The
crude mixture of cycloadducts was purified by chromato-
graphy over silica using ether/hexane mixture as eluant to
give a non-separable mixture of isomers 12a and 13a as a col-
orless liquid (1.13 g, 90%) in a ratio of 77:23, respectively, as
1
determined by integration and peak heights of several H

9140
S. A. Ali, M. Z. N. Iman / Tetrahedron 63 (2007) 9134–9145
as determined by integration of non-overlapping proton sig-
nals (vide infra: Section 3.2.4) at d 2.08 (1H, m), 2.31 (1H,
m) for the major isomer 13f, and at d 2.14 (2H, m) for minor
isomer 12f.
C, 64.5; H, 7.7; N, 6.1. C12H17NO3 requires C, 64.55; H,
7.67; N, 6.27%.) nmax (neat) 3300, 3031, 2922, 2862,
1449, 1035, 754 and 701 cmꢁ1; dH (CDCl3, +20 ꢀC) 2.14
(2H, m), 2.25–3.50 (4H, br), 3.59–3.87 (4H, m), 4.10 (1H,
m), 4.24 (1H, m), 7.31 (5H, m).
3.2.4. Cycloaddition of nitrone 7 with methyl acrylate
(11d), and lithium aluminum hydride reduction of cyclo-
adducts 12d and 13d to 12f and 13f. The crude mixture of
cycloadducts was chromatographed over silica using ether/
hexane as eluant to give the minor isomer 12d (476 mg,
38%) as a colorless liquid. Continued elution afforded a
mixture of 12d and 13d (239 mg, 19%) and finally the major
isomer 13d (369 mg, 29%) as colorless needles. The dia-
stereomeric ratio of 12d and 13d was found to be around
46:54, respectively, as determined by integration of several
3.2.5. Cycloaddition of nitrone 7 with tert-butyl acrylate
(11e), and conversion of cycloadducts 12e and 13e into
methyl acrylate adducts 12d and 13d. The crude mixture
of cycloadducts was purified by chromatography over silica
using ether/hexane as eluant to give the non-separable ad-
ducts 12e and 13e as a colorless liquid in 85% yield. (Found:
C, 65.4; H, 7.8; N, 4.6. C16H23NO4 requires C, 65.51; H,
7.90; N, 4.77%.) nmax (neat) 3470, 3060, 2976, 2929,
2876, 1732, 1602, 1454, 1368, 1292, 1234, 1157, 1077,
915, 843, 732 and 704 cmꢁ1; dH (CDCl3, +20 ꢀC) 1.51
(9H, s), 2.30–2.50 (2H, m), 2.80–3.00 (1H, m), 3.20–3.60
(1H, br), 3.72–3.77 (1H, m), 3.94–4.20 (2H, m), 4.40–4.55
(1H, m), 7.32 (5H, m).
1
proton signals in H NMR spectrum of the crude reaction
mixture. The stereochemistry of the major isomer 13d was
assigned by X-ray diffraction analysis.
Compound 12d: (Found: C, 61.9; H, 6.9; N, 5.5. C13H17NO4
requires C, 62.14; H, 6.82; N, 5.57%.) nmax (neat) 3491,
3061, 3029, 2952, 2850, 1740, 1603, 1493, 1406, 1350,
1290, 1211, 1083, 937, 826, 760, and 703 cmꢁ1; dH
(CDCl3, +20 ꢀC) 2.41 (1H, m), 2.55 (1H, m), 2.99 (1H,
m), 3.28 (1H, m), 3.76 (1H, m), 3.79 (3H, s), 3.95 (2H,
m), 4.67 (1H, m), 7.33 (5H, m).
A mixture of the tert-butyl acrylate adducts 12e and 13e
(50 mg, 0.153 mmol) in 5:1 methanol/HCl (1 cm3) was
stirred at 20 ꢀC for 6 h. After removal of the methanol the re-
sidual liquid was taken up into CH2Cl2 (15 cm3) and washed
with 5% K2CO3 (5 cm3). The organic layer was dried
(Na2SO4) and concentrated to give a mixture of methyl
acrylate adducts 12d and 13d as a colorless liquid. The H
NMR spectrum as analyzed before (Section 3.2.4) revealed
isomers 12d and 13d in a ratio of 56:44, respectively.
1
Compound 13d: mp 63–63.5 ꢀC (CH2Cl2/hexane). (Found:
C, 62.0; H, 6.7; N, 5.6. C13H17NO4 requires C, 62.14; H,
6.82; N, 5.57%.) nmax (KBr) 3481, 3088, 3063, 3024,
2982, 2942, 2904, 2876, 1740, 1496, 1452, 1433, 1364,
1316, 1299, 1279, 1209, 1172, 1111, 1081, 1057, 1023,
948, 915, 864, and 758 cmꢁ1; dH (CDCl3, +20 ꢀC) 2.41
(1H, m), 2.43 (1H, m), 2.91 (2H, m), 3.30 (1H, br, OH),
3.75 (1H, m), 3.80 (3H, s), 3.96 (1H, dd, J 4.0, 7.6 Hz),
4.17 (1H, dd, J 7.6, 11.2), 4.56 (1H, m), 7.30 (5H, m).
3.2.6. Cycloaddition of nitrone 7 with allyl alcohol (11f).
The crude mixture of cycloadducts was purified by chroma-
tography over silica using ether/methanol (95:5) as eluant to
give a non-separable mixture of the cycloadducts 12f and 13f
(83%) as a colorless liquid. Major and minor isomers were
found to be in a ratio of 62:38 as determined by integration
of non-overlapping proton signals at d 2.08 (1H, m), 2.31
(1H, m) for the major isomer, and at d 2.14 (2H, m) for the
minor isomer (IR and CHN analysis for 12/13f are given
in Section 3.2.4 vide supra).
The above cycloaddition reaction was repeated at 0 and
25 ꢀC for a duration of 6 and 3 days, respectively, to afford
the cycloadducts in 64 and 74% yields. The ratio of the
12d and 13d at 0 and 25 ꢀC were found to be 44:56 and
48:52, respectively.
3.2.7. Cycloaddition of nitrone 7 with tert-butyldimethyl-
silyl allylether (11g), and conversion of 12g and 13g to 12f
and 13f. The crude mixture of cycloadducts was purified by
chromatography over silica using 80:20 hexane/ether as elu-
ant to give adduct 12g (893 mg) as a colorless liquid, fol-
lowed by a mixture of adducts 12g/13g (298 mg).
Continued elution afforded 13g (296 mg,) as a colorless liq-
uid. The overall isolated yield was thus determined to be
88%. Spectral analysis of the crude as well as the separated
fractions revealed the presence of the 12g and 13g in a ratio
of 75:25, respectively, as determined by the integration and
peak heights of several proton signals (belonging to
SitBuMe2) of the crude as well as separated fractions.
To a stirred solution of 12d (100 mg, 0.40 mmol) in ether
(15 cm3) was added lithium aluminum hydride (100 mg,
2.7 mmol) at room temperature. The reaction was complete
in 10 min as indicated by TLC experiment (silica, ether). To
the reaction mixture was added water (0.1 g), 10% NaOH so-
lution (0.1 g), and water (0.4 g). The mixture was stirred for
1 h and was then decanted and the residue washed with
CH2Cl2. The organic layer was dried (Na2SO4), concen-
trated, and purified by silica gel chromatography using
a 95:5 CH2Cl2/methanol as the eluant to give 12f as a color-
less liquid (85 mg, 95%). (Found: C, 64.4; H, 7.6; N, 6.3.
C12H17NO3 requires C, 64.55; H, 7.67; N, 6.27%.) nmax
(neat) 3300, 3060, 3026, 2920, 1602, 1492, 1453, 1270,
1188, 1034, 870, 846, 759 and 701 cmꢁ1; dH (CDCl3,
+20 ꢀC) 2.08 (1H, m), 2.31 (1H, m), 2.40–3.50 (5H, br),
3.64 (1H, m), 3.75 (2H, m), 4.09 (1H, m), 4.43 (1H, m),
7.35 (5H, m).
Major isomer 12g: (Found: C, 63.8; H, 9.3; N, 4.0.
C18H31NO3Si requires C, 64.05; H, 9.26; N, 4.15%.) nmax
(neat) 3440, 3064, 3029, 2958, 2928, 2852, 1492, 1461,
1415, 1388, 1361, 1254, 1188, 1102, 939, 837, 778 and
701 cmꢁ1; dH (CDCl3, +20 ꢀC) 0.093 (6H, s), 0.90 (9H, s),
1.92 (1H, m), 2.26 (1H, m), 2.68 (1H, m), 2.96 (1H, m),
3.11 (1H, m), 3.62 (1H, m), 3.70 (2H, m), 3.82 (1H, d, J
7.3 Hz), 4.10 (1H, dd, J 7.65, 11.6 Hz), 4.48 (1H, m), 7.30
The above procedure was repeated with 13d to give the cor-
responding 13f (81 mg, 91%) as a colorless liquid. (Found:

S. A. Ali, M. Z. N. Iman / Tetrahedron 63 (2007) 9134–9145
9141
(5H, m); dC (CDCl3, +20 ꢀC) (ꢁ)5.39 (2C), 18.22, 25.81
(3C), 29.86, 53.30, 64.71, 68.61, 71.63, 78.16, 128.00
(3C), 128.60 (2C), 138.32.
The cycloadduct 12i was hydrolyzed in methanolic HCl as
before (Section 3.2.7) to obtain the alcohol 12h as a colorless
liquid in an almost quantitative yield. (Found: C, 65.6; H,
8.3; N, 5.8. C13H19NO3 requires C, 65.80; H, 8.07; N,
5.90%.) nmax (neat) 3338, 3058, 3032, 2949, 2866, 1452,
1057, 869, 760 and 703 cmꢁ1; dH (CDCl3, +20 ꢀC) 1.92
(3H, m), 2.38 (1H, m), 2.5–3.3 (3H, m), 3.80 (5H, m),
3.83 4.07 (1H, dd, J 7.0, 11.6 Hz), 4.52 (1H, m), 7.32 (5H,
m); dC (CDCl3, +20 ꢀC) 33.14, 37.23, 53.66, 59.70, 68.12,
72.15, 75.66, 128.15 (3C), 128.71 (2C), 138.10.
Minor isomer 13g: (Found: C, 63.9; H, 9.4; N, 3.9.
C18H31NO3Si requires C, 64.05; H, 9.26; N, 4.15%.) nmax
(neat) 3440, 3060, 3030, 2953, 2928, 2857, 1493, 1454,
1388, 1360, 1255, 1104, 1063, 1019, 938, 838, 778 and
701 cmꢁ1; dH (CDCl3, +20 ꢀC) 0.092 (3H, s), 0.10 (3H, s),
0.92 (9H, s), 1.99 (1H, m), 2.15 (1H, m), 2.44 (1H, m),
2.96 (1H, m), 3.60–3.80 (5H, m), 4.10 (1H, dd, J 7.3,
11.3 Hz), 4.20 (1H, m), 7.30 (5H, m); dC (CDCl3, +20 ꢀC)
(ꢁ)5.39 (2C), 18.22, 25.81 (3C), 29.86, 53.30, 64.71,
68.61, 71.63, 78.16, 128.00 (3C), 128.60 (2C), 138.32.
3.2.10. Cycloaddition of nitrone 7 with 4-penten-1-ol
(11j). The crude mixture of cycloadducts was purified by
chromatography over silica using 95:5 ether/methanol mix-
ture as eluant to give non-separable mixture of isomers 12j
and 13j as a colorless liquid (1.15 g, 92%). Spectral analysis
of adducts revealed the presence of 12j and 13j in a ratio of
73:27, respectively, as determined by integration of several
1H signals. One of the C(4)H of the major isomer 12j
appeared at d 2.36 while the corresponding proton for the
minor isomer 13j appeared at 2.23 ppm. The following
non-overlapping 13C signals of the minor isomer 13j were
picked up from the spectrum of the adduct mixture and the
known spectrum of 12j (vide infra: Section 3.3.3); dC
(CDCl3, +20 ꢀC) 29.29, 31.31, 33.52, 54.30, 62.28, 68.20,
74.16, 78.51, 128.01 (3C), 128.58 (2C), 138.16.
The separated adducts 12g and 13g were hydrolyzed to their
corresponding alcohols 12f and 13f, respectively, in near
quantitative yields. For instance, a solution of 12g
(100 mg) in MeOH/HCl (5:1) (1 cm3) was stirred at 20 ꢀC
for 10 min. Removal of the solvent, basification (K2CO3),
followed by extraction with CH2Cl2 afforded the hydrolyzed
product 12f.
3.2.8. Cycloaddition of nitrone 7 with 3-buten-1-ol (11h).
The crude mixture of cycloadducts was purified by chroma-
tography over silica using 95:5 ether/methanol as eluant to
give a non-separable mixture of isomers 12h and 13h as
a colorless liquid (1.10 g, 93%). Spectral analysis revealed
the presence of 12h and 13h in a ratio of 70:30, respectively,
3.2.11. Cycloaddition of nitrone 7 with methyl methacro-
lein (14a), and conversion of 15a and 16a into 15d and
16d. Half of the crude mixture of cycloadducts was purified
by chromatography over silica using 1:1 ether/hexane as el-
uant to give the hemiacetal 15a0 (200 mg, 34%) as colorless
needles; mp 156.0–157.0 ꢀC. (Found: C, 66.1; H, 7.3; N, 5.8.
C13H17NO3 requires C, 66.36; H, 7.28; N, 5.95%.) nmax
(KBr) 3122, 2997, 2968, 2932, 2900, 2876, 2843, 1604,
1494, 1452, 1375, 1311, 1289, 1185, 1153, 1100, 1034,
996, 940, 878, 760 and 712 cmꢁ1; aldehyde absorption
was not observed; dH (CDCl3, +20 ꢀC) 1.39 (3H, s), 1.86
(1H, ddd, J 2.8, 9.0, 12.0 Hz), 2.67 (1H, dt, J 12.4,
8.7 Hz), 3.06 (1H, d, J 4.3 Hz, OH, exchangeable), 3.27
(1H, ddd, J 2.90, 8.85, 11.4 Hz), 3.60 (1H, dt, J 11.1,
8.9 Hz), 3.80 (2H, m), 3.91 (1H, dd, J 5.2, 9.8 Hz), 4.69
(1H, d, J 4.3 Hz), and 7.30 (5H, m); on D2O exchange the
signal at d 3.06 disappeared, while the signal at d 4.69 col-
lapsed into a singlet. The spectrum revealed the presence
of a trace amount of an aldehyde by displaying a signal at
d 9.62 ppm. The spectra also revealed the presence of a minor
hemiacetal by displaying a signal of the methyl proton as
a singlet at d 1.41 ppm. The ratio of the two hemiacetals
was found to be 90:10, however, after D2O exchange the ra-
tio was changed to 64:36; dC (CDCl3, +20 ꢀC) 21.66, 32.38,
58.67, 68.06, 74.72, 89.46, 100.89, 126.97 (2C), 129.28,
128.44 (2C), 140.60. The 13C signals for the minor hemiacetal
were also observed. The non-overlapping signals of the
minor hemiacetal were as follows: 1.41 (3H, s), 2.02 (1H, dd,
J 8.1, 11.8 Hz), 2.55 (1H, m), 3.01 (1H, d J 7.05 Hz, OH
exchangeable), 3.19 (1H, m), 3.45 (1H, m), 4.07 (2H, m),
4.37 (1H, dd, J 10.6, 13.4 Hz), 4.91 (1H, d, J 7.05 Hz).
1
as determined by integration of several H signals. The
C(5)H of 12h and 13h appeared at d 4.51 and 4.23 ppm, re-
spectively. One of the C(4)H of the major isomer 12h ap-
peared at d 2.38 while the corresponding proton for the
minor isomer 13h appeared at 2.28 ppm. The following
non-overlapping 13C signals of the minor isomer was picked
up from the spectrum of the mixture (vide infra: Section
3.2.9); dC (CDCl3, +20 ꢀC) 33.78, 37.72, 54.01, 60.10,
74.21.
3.2.9. Cycloaddition of nitrone 7 with tert-butyldimethyl-
silyl 3-butenyl ether (11i), and conversion of 12i into 12h.
The crude mixture of cycloadducts was purified by chroma-
tography over silica using 5:2 hexane/ether as eluant to give
adduct 12i (410 mg) as a colorless liquid, followed by a mix-
ture of adducts 12i/13i (1.17 g). The overall isolated yield
was thus determined to be 90%. One of the C(4)H of the
major isomer 12i appeared at d 2.36 while the corresponding
proton for the minor isomer 13i appeared at 2.19 ppm. The
C(5)H of 12i and 13i appeared at d 4.47 and 4.20 ppm, re-
spectively. Spectral analysis of the crude as well as the sep-
arated fractions revealed the presence of the 12i and 13i in
a ratio of 82:18, respectively.
Major isomer 12i: (Found: C, 64.8; H, 9.3; N, 3.9.
C19H33NO3Si requires C, 64.91; H, 9.46; N, 3.98%.) nmax
(neat) 3300, 3027, 2950, 2856, 1462, 1385, 1253, 1096,
930, 836, 777 and 701 cmꢁ1; dH (CDCl3, +20 ꢀC) 0.07
(6H, s), 0.90 (9H, s), 1.55–2.0 (4H, m), 2.36 (1H, m), 2.73
(1H, m), 3.00 (1H, m), 3.7 (3H, m), 3.83 (1H, dd, J 3.1,
7.6 Hz), 4.09 (1H, dd, J 7.6, 11.6 Hz), 4.47 (1H, m), 7.32
(5H, m); dC (CDCl3, ꢁ30 ꢀC) (ꢁ) 5.50 (2C), 18.29, 25.81
(3C), 33.23, 37.61, 53.25, 59.92, 69.05, 70.88, 74.59,
127.78 (2C), 128.07, 128.69 (2C), 137.89.
Another half of the crude mixture of cycloadducts in meth-
anol (3 cm3) was reduced with NaBH4 as before (Section
3.2.3) to give, after chromatographic purification, the

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S. A. Ali, M. Z. N. Iman / Tetrahedron 63 (2007) 9134–9145
corresponding mixture of alcohol 15d and 16d as a colorless
liquid (550 mg, 93%) in a ratio of 66:34, respectively, as
determined by integration of the non-overlapping signals
at d 1.83 ppm (1H, major isomer) and d 1.93 ppm (1H, minor
isomer). The stereochemistry was confirmed by comparison
to the spectrum of the pure alcohols 15d and 16d (vide infra:
Section 3.2.12).
+20 ꢀC) 1.32 (3H, s), 1.66 (1H, m), 1.93 (1H, m), 2.38
(1H, m), 2.56 (1H, m), 3.00 (2H, m), 3.20–3.80 (4H, br),
4.09 (1H, m), 7.30 (5H, m). dC (CDCl3, +20 ꢀC) 22.78,
35.76, 55.47, 68.35, 71.20, 74.43, 83.01, 127.88, 128.31
(2C), 128.77 (2C), 138.10.
3.2.13. Cycloaddition of nitrone 7 with tert-butyl meth-
acrylate (14c). The crude mixture of cycloadducts was pu-
rified by chromatography over silica using using ether/
hexane as eluant to give the non-separable adducts 15c and
3.2.12. Cycloaddition of nitrone 7 with methyl methacry-
late (14b), and conversion of 15b and 16b into 15d and
16d. The crude mixture of cycloadducts was purified by
chromatography over silica using 1:1 ether/hexane as eluant
to give the cycloadduct 16b (117 mg, 9%). Continued
elution afforded a mixture of 15b and 16b (57 mg, 4%),
and finally the isomer 15b (886 mg, 67%) as a colorless
liquid. The total isolated yield for the addition reaction
was thus found to be 80%. The diastereomeric ratio of 15b
and 16b was found to be around 86:14, respectively.
1
16c as a colorless liquid in 85% yield. The H NMR spec-
trum of the crude as well as the purified mixture revealed
the presence of two isomers. The C(5)-Me methyl proton ap-
peared as a singlet at d 1.49 (major) and d 1.50 (minor),
while the tert-butyl proton appeared at d 1.52 (major) and
d 1.53 (minor) in a ratio of 87:13, respectively. The major
isomer was assigned to the stereochemistry as depicted in
15c because of its similarity to the major adduct 15b in their
1H NMR spectral data. 15c/16c mixture, colorless liquid.
(Found: C, 66.3; H, 8.1; N, 4.5. C17H25NO4 requires C,
66.43; H, 8.20; N, 4.56%.) nmax (neat) 3466, 3062, 3030,
2978, 2935, 2876, 1728, 1454, 1369, 1290, 1143, 1063,
931, 846, 758 and 702 cmꢁ1. Major isomer 15c displayed
the following signals: dH (CDCl3, +20 ꢀC) 1.49 (3H, s),
1.52 (9H, s), 2.01 (1H, m), 2.68 (1H, m), 2.92 (2H, m),
3.73 (1H, dd, J 3.50, 11.45 Hz), 3.94 (1H, dd, J 5.05,
8.40 Hz), 4.18 (1H, dd, J 8.1, 11.45), 4.18 (1H, m) and
7.30 (5H, m). The adducts 15c and 16c were converted
into the methyl methacrylate adducts 15b and 16b by ester
exchange with methanol using procedure as described in
Section 3.2.5.
Major isomer 15b: (Found: C, 63.2; H, 7.2; N, 5.3.
C14H19NO4 requires C, 63.38; H, 7.22; N, 5.28%.) nmax
(neat) 3497, 2952, 2850, 1732, 1602, 1493, 1452, 1373,
1285, 1205, 1144, 983, 919, 848, 761 and 703 cmꢁ1; dH
(CDCl3, +20 ꢀC) 1.52 (3H, s), 2.04 (1H, m), 2.73 (1H, m),
2.90 (1H, m and 1H OH), 3.50 (1H, m), 3.65 (1H, m),
3.80 (3H, s), 3.95 (1H, m), 4.18 (1H, m) and 7.30 (5H, m);
13C spectrum is broad and complicated due to slow nitrogen
inversion.
Minor isomer 16b: (Found: C, 63.4; H, 7.1; N, 5.2.
C14H19NO4 requires C, 63.38; H, 7.22; N, 5.28%.) nmax
(neat) 3494, 2953, 2847, 1737,1494, 1452, 1407, 1372,
1286, 1199, 1125, 1063, 979, 933, 842, 761 and 703 cmꢁ1
;
3.2.14. Cycloaddition of nitrone 7 with methallyl alcohol
(14d). The crude mixture of cycloadducts was purified by
chromatography over silica using CH2Cl2/methanol (97:3)
as eluant to give a non-separable mixture of alcohols 15d
and 16d as a colorless liquid (973 mg, 82%) in a ratio of
67:33 as determined by integration of the C(5) methyl sin-
dH (CDCl3, +20 ꢀC) 1.55 (3H, s), 2.03 (1H, m), 2.50 (1H,
m), 2.74 (1H, m), 2.93 (1H, m), 3.50 (1H, br, OH), 3.74
(1H, m), 3.81 (3H, s), 3.88 (1H, m), 3.99 (1H, m) and 7.30
(5H, m); dC (CDCl3, ꢁ30 ꢀC) 23.21, 38.47, 52.85, 53.43,
67.10, 71.67, 81.89, 127.92 (2C), 128.03, 128.48 (2C),
138.16, 175.87.
1
glets. The H NMR spectrum of the mixture of 15d and
16d was compared with that of the pure isomer 15d (vide
supra: Section 3.2.12).
The above cycloaddition reaction was repeated at 0 and
25 ꢀC for duration of 6 and 3 days, respectively, to give
the adducts 15b and 16b in 53 and 87% yields. Integration
of several proton signals in 1H NMR spectrum in CDCl3 in-
dicated the ratio of the isomers.
3.2.15. Cycloaddition of nitrone 7 with tert-butyldime-
thylsilyl 2-methyl-2-propenyl ether (14e). The crude mix-
ture of cycloadducts was separated by chromatography over
silica using 9:1 hexane/ether as eluant to give 16e (460 mg),
followed by a mixture of 15e and 16e (243 mg) and finally,
15e (597 mg). The isomers 15e and 16e (colorless liquid,
74%) were formed in a ratio of 58:42, respectively, as deter-
mined by proton NMR analyses of the crude as well as sep-
arated fractions.
The pure adducts 15b and 16b was reduced with lithium alu-
minum hydride as before (vide supra). The alcohols were pu-
rified by chromatography using CH2Cl2/methanol (97:3) as
eluant to give 15d (90 mg, 93%) and 16d (40 mg, 90%) as
colorless liquids. Compound 15d: (Found: C, 65.6; H, 8.1;
N, 5.8. C13H19NO3 requires C, 65.80; H, 8.07; N, 5.90%.)
nmax (neat) 3380, 3060, 3030, 2973, 2932, 2876, 1603,
1493, 1452, 1374, 1309, 1269, 1061, 893, 760, 735 and
703 cmꢁ1; dH (CDCl3, +20 ꢀC) 1.26 (3H, br s), 1.83 (1H,
m), 2.40 (1H, m), 2.60–3.30 (4H, br), 3.52 (1H, m), 3.61
(1H, m), 3.71 (1H, m), 3.92 (1H, m), 4.09 (1H, m), 7.30
(5H, m); dC (CDCl3, +20 ꢀC) 23.99, 35.07, 54.04, 79.28,
68.71, 72.15, 85.00, 128.08 (3C), 128.63 (2C), 138.10.
Compound 16d: (Found: C, 65.7; H, 8.0; N, 5.8.
C13H19NO3 requires C, 65.80; H, 8.07; N, 5.90%.) nmax
(neat) 3381, 3064, 3031, 2973, 2931, 2876, 1494, 1453,
1376, 1116, 1060, 889, 841, 760 and 703 cmꢁ1; dH(CDCl3,
Major isomer 15e: (Found: C, 64.6; H, 9.4; N, 3.8.
C19H33NO3Si requires C, 64.91; H, 9.46; N, 3.98%.) nmax
(neat); 3443, 3062, 3030, 2954, 2930, 2857, 1493, 1462,
1411, 1390, 1362, 1310, 1255, 1102, 938, 897, 838, 778
and 701 cmꢁ1; dH (CDCl3, +20 ꢀC) 0.10 (6H, s), 0.93 (9H,
s), 1.30 (3H, s), 1.83 (1H, m), 2.22 (1H, m), 2.69 (1H,
m), 2.99 (1H, m), 3.56 (2H, AB, J 10.1 Hz), 3.70 (1H, m),
3.83 (1H, m), 4.06 (1H, dd, J 7.5, 11.5 Hz), 7.30 (5H,
m); dC (CDCl3, +20 ꢀC) (ꢁ)5.49, (ꢁ)5.39, 18.25, 23.90,
25.84 (3C), 36.10, 54.04, 68.00, 68.45, 73.18, 83.90,
127.90 (2C), 128.11, 128.52 (2C), 138.49.

S. A. Ali, M. Z. N. Iman / Tetrahedron 63 (2007) 9134–9145
9143
Minor isomer 16e: (Found: C, 64.7; H, 9.3; N, 4.0.
C19H33NO3Si requires C, 64.91; H, 9.46; N, 3.98%.) nmax
(neat); 3440, 3063, 3030, 2958, 2930, 2857, 1493, 1460,
1410, 1391, 1363, 1311, 1254, 1101, 938, 899, 838, 777
and 701 cmꢁ1; dH (CDCl3, +20 ꢀC) 0.08 (3H, s), 0.09 (3H,
s), 0.91 (9H, s), 1.35 (3H, s), 1.84 (1H, m), 2.05 (1H, m),
2.45-3.10 (3H, m), 3.38-3.85 (4H, m), 4.04 (1H, dd, J 7.7,
11.4 Hz), 7.30 (5H, m); dC (CDCl3, +20 ꢀC) (ꢁ)5.46 (2C),
18.22, 23.56, 25.64 (3C), 36.48, 54.42, 68.24, 69.14,
73.72, 83.16, 127.98 (3C), 128.55 (2C), 138.46.
(5H, m); dC (CDCl3, ꢁ30 ꢀC) 11.4, 21.1, 21.3, 27.2, 32.6,
37.9, 46.7, 49.0, 49.6, 54.2, 74.3, 78.2, 80.3, 125.8 (2C),
127.4, 128.5 (2C), 143.1.
3.2.19. Cycloaddition of nitrone 9 with methyl acrylate
(11d). The crude mixture of cycloadducts was purified by
chromatography over silica using 1:4 ether/hexane as eluant
to afford the major and minor cycloadducts 22 and 23
(1.20 g, 85%) as a non-separable mixture of isomers. Crys-
tallizations from hexane/ether afforded the major cycload-
duct 22 as colorless needles. The diastereomeric ratio of
22 and 23 was found to be around 65:35, respectively. The
stereochemistry of the major isomer 22 was assigned by
X-ray diffraction analysis.
The cycloadducts 15e and 16e were hydrolyzed in meth-
anolic HCl as before (Section 3.2.7) to obtain the alcohols
15d and 16d, respectively, in an almost quantitative yield.
3.2.16. Cycloaddition of nitrone 7 with dimethyl methyl-
enemalonate (14f). The crude cycloadduct was purified by
chromatography over silica using ether/hexane as eluant to
give adduct 15f as a colorless liquid (1.39 g, 90%). (Found:
C, 58.2; H, 6.2; N, 4.4. C15H19NO6 requires C, 58.25; H,
6.19; N, 4.53%.) nmax (neat) 3491, 3030,2956, 2885, 1746,
1453, 1436, 1285, 1204, 1110, 761 and 704 cmꢁ1; dH
(CDCl3, +20 ꢀC) 2.70–3.20 (4H, br m), 3.70–4.20 (4H br
m, including OH), 3.83 (3H, s), 3.84 (3H, s), 7.30 (5H, m);
dC (CDCl3, +20 ꢀC) 36.24, 53.33, 53.46, 66.93, 72.30,
85.37, 91.18, 128.28, 128.69 (2C), 128.93 (2C), 138.18,
168.60, 169.14.
Major isomer 22: mp 78–78.5 ꢀC (hexane/ether). (Found: C,
63.7; H, 8.9; N, 4.8. C15H25NO4 requires C, 63.58; H, 8.89;
N, 4.94%.) nmax (KBr) 3506, 2952, 1742, 1444, 1362, 1221,
1080, and 813 cmꢁ1; dH (CDCl3, +20 ꢀC) 0.78 (3H, s), 0.99
(3H, s), 1.07 (2H, m), 1.11 (3H, s), 1.46 (1H, m), 1.72 (2H,
m), 2.51 (1H, m), 2.61 (1H, m), 2.83 (2H, d, J 6.7 Hz), 3.32
(1H, m), 3.71 (1H, d, J 6.4 Hz), 3.76 (3H, s), 4.04 (1H, OH),
4.56 (1H, m); dC (CDCl3, ꢁ30 ꢀC) 11.4, 21.0, 21.5, 27.3,
32.5, 32.7, 46.7, 49.2, 49.9, 52.3, 52.7, 73.67, 73.73, 80.4,
173.7. The following 1H NMR signals for the minor isomer
23 was extracted from the spectrum of the mother liquor,
which was rich in the minor isomer 23: 0.78 (3H, s), 0.96
(3H, s), 1.12 (3H, s), 3.74 (3H, s), 4.53 (1H, m).
3.2.17. Cycloaddition the nitrone 9 with 1-hexene (11a).
The crude mixture of cycloadducts was purified by chroma-
tography over silica using 1:4 ether/hexane as eluant to give
a non-separable mixtures of the cycloadducts 18 and 19
(1.11 g, 79%) as a colorless liquid in a ratio of 95:5 as deter-
mined by the peak heights of major and minor methyl sin-
glets of the camphor moiety. (Found: C, 72.4; H, 11.0; N,
4.8. C17H31NO2 requires C, 72.55; H, 11.10; N, 4.98%.)
nmax (neat) 3344, 2955, 2929, 2876, 1460, 1386, 1370,
1289, 1120, 1096, 1073 and 1005 cmꢁ1; (CDCl3, +20 ꢀC)
0.78 (3H, s), 0.89 (3H, t, J 7.0 Hz), 0.97 (3H, s), 1.17 (3H,
s), 1.00–1.78 (11H, m), 1.91 (1H, m), 2.34 (1H, m), 2.66
(1H, m), 2.76 (1H, m), 3.29 (1H, m), 3.59 (1H, m), 3.64
(1H, m), 4.10 (1H, m). Methyl singlet for the minor isomer
was observed at 0.82, 0.99 and 1.09 ppm. The peak height of
these signals was used to calculate the ratio of isomers as
95:5; dC (CDCl3, 20 ꢀC) 11.32, 13.99, 21.20, 21.67, 22.56,
27.24, 28.44, 33.00, 34.63, 35.76, 46.74, 49.12, 49.97,
53.62, 74.38, 76.89, 80.65.
3.2.20. Cycloaddition of nitrone 9 with methyl methacryl-
ate (14b). The crude mixture of cycloadducts was purified
by chromatography over silica using 1:4 ether/hexane as el-
uant to give the mixture of minor isomer 25 (346 mg, 23%)
contaminated with a small percentage of major isomer. Con-
tinued elution afforded the major isomer 24 (959 mg, 65%)
contaminated by a minor portion of minor isomer. Repeated
chromatography was unable to separate the two isomers
since they have very close Rf values. The diastereomeric ra-
tio of 24 and 25 was found to be around 66:34, respectively,
as determined by integration of several methyl proton sig-
nals in 1H NMR spectrum of the crude reaction mixture.
Major isomer 24: (Found: C, 64.4; H, 9.2; N, 4.7.
C16H27NO4 requires C, 64.62; H, 9.15; N, 4.71%.) nmax
(neat) 3547, 2952, 1736, 1458, 1391, 1369, 1291, 1201,
1121, 1074, 984, 828, and 750 cmꢁ1; dH (CDCl3, +20 ꢀC)
0.78 (3H, s), 0.96 (3H, s), 1.17 (3H, s), 1.46 (1H, m), 1.53
(3H, s), 1.60 (2H, m), 1.70 (2H, m), 2.22 (1H, m), 2.82
(3H, m), 3.31 (2H, m), 3.67 (1H, m), 3.75 (3H, s).
3.2.18. Cycloaddition of nitrone 9 with styrene (11b). The
crude mixture of cycloadducts was purified by chromato-
graphy over silica using 1:4 ether/hexane as eluant to give
a non-separable mixture of the cycloadducts 20 and 21
(1.22 g, 81%) as a colorless liquid. Major and minor isomer
were found in a ratio of 96:4 as determined by integration of
C5(H) signal of 20 appearing at d 5.13 (major) and that of 21
at d 5.01 (minor). (Found: C, 75.5; H, 8.9; N, 4.6.
C19H27NO2 requires C, 75.71; H, 9.03; N, 4.65%.) nmax
(neat) 3536, 3062, 3028, 2951, 1604, 1492, 1454, 1391,
1368, 1291, 1242, 1216, 1120, 1099, 1067, 1025, 990,
974, 943, 809, 760, and 700 cmꢁ1; dH (CDCl3, +20 ꢀC)
0.78 (3H, s), 0.97 (3H, s), 1.06 (2H, m), 1.20 (3H,s), 1.47
(1H, m), 1.75 (2H, m), 2.36 (1H, m), 2.74 (1H, m), 2.90
(2H, m), 3.49 (2H, m), 3.67 (1H, m), 5.14 (1H, m), 7.31
Minor isomer 25: (Found: C, 64.5; H, 9.1; N, 4.8.
C16H27NO4 requires C, 64.62; H, 9.15; N, 4.71%.) nmax
(neat) 3540, 2953, 2876, 1745, 1479, 1454, 1392, 1370,
1355, 1289, 1201, 1098, 985, 963, 829, and 753 cmꢁ1; dH
(CDCl3, +20 ꢀC) 0.76 (3H, s), 0.98 (3H, s), 1.05 (2H, m),
1.09 (3H, s), 1.30 (1H, m), 1.49 (3H, s), 1.68 (2H, m),
2.08 (1H, ddd, J 1.9, 9.0, 11.0 Hz), 2.60 (1H, app q,
J 8.9 Hz), 2.81 (2H, m), 3.28 (1H, t, J 8.1), 3.72 (1H, d,
J 6.4 Hz), 3.75 (3H, s).
3.2.21. Cycloaddition of nitrone 9 with dimethyl methyl-
enemalonate (14f). The crude cycloadduct was purified by
chromatography over silica using ether/hexane as eluant to

9144
S. A. Ali, M. Z. N. Iman / Tetrahedron 63 (2007) 9134–9145
give adduct 26 as colorless crystals (79%); mp 131–132.0 ꢀC
(ether). (Found: C, 59.7; H, 8.0; N, 4.0. C17H27NO6 requires
C, 59.81; H, 7.97; N, 4.10%.) nmax (KBr) 3515, 2958, 2881,
1753, 1440, 1290, 1270, 1216, 1095, 1003, 926, 828, and
771 cmꢁ1; dH (CDCl3, +20 ꢀC) 0.77 (3H, s), 0.97 (3H, s),
1.07 (2H, m), 1.10 (3H, s), 1.45 (1H, m), 1.70 (2H, m),
2.70 (1H, m), 2.86 (2H, m), 2.94 (1H, m), 3.37 (1H, m),
3.67 (1H, m), 3.74 (1H, m), 3.79 (3H, s), 3.81 (3H, s); dC
(CDCl3, 20 ꢀC) 11.36, 21.11, 21.54, 27.39, 32.90, 36.90,
46.93, 49.30, 50.39, 53.26, 53.45, 53.51, 74.51, 80.63,
84.42, 167.15, 170.19.
943, 851, 759, 734 and 702 cmꢁ1; dH (CDCl3, +20 ꢀC)
1.60–190 (5H, m), 2.35 (1H, m), 2.74 (1H, m), 2.99 (1H,
m), 3.70 (3H, m), 3.83 (1H, dd, J 3.4, 7.4 Hz), 4.06 (1H,
dd, J 7.1, 11.4 Hz), 4.34 (1H, m), 7.30 (5H, m), the 2H for
OHs are spread out in the range 2–3.5 ppm; dC (CDCl3,
+20 ꢀC) 29.29, 31.31, 33.52, 53.31, 62.36, 68.20, 71.45,
77.30, 128.01 (3C), 128.58 (2C), 138.16.
3.3.4. Cycloaddition of nitrone 7 with methylallyl alcohol
(14d). As described in Section 3.3.1, the addition reaction
was carried out using hydroxylamine 10 (1.0 mmol) and
methylallyl alcohol (1.1 mmol) in the presence of 1 equiv
of MgBr2 at 65 ꢀC for 24 h. After usual work up, the residual
liquid was purified by silica gel chromatography using
CH2Cl2/MeOH (95:5) as eluant to give a non-separable mix-
ture of alcohols 15d and 16d as a colorless liquid (95%). The
1H NMR spectrum revealed the presence of 15d and 16d in
a ratio of 97:3, respectively. The ratio was determined by
integration of the C(5)-methyl singlets as before (Section
3.2.12).
3.3. Cycloaddition of nitrone 7 in the presence of MgBr2
3.3.1. Cycloaddition of nitrone 7 with 1-hexene (11a). To
a solution of hydroxylamine 10 (153 mg, 1.0 mmol) in
dichloromethane (20 cm3), was added paraformaldehyde
(34 mg, 1.13 mmol) and the mixture was stirred in a closed
vessel under N2 at 65 ꢀC for 2 h. Thereafter, the solution was
cooled to room temperature and the volume of the solution
was reduced to 5 cm3 by gently blowing N2 at 40 ꢀC. This
process is expected to remove moisture (H2O) by evapora-
tion along with CH2Cl2. Then MgBr2 (184 mg, 1.0 mmol)
was added to the solution. The resulting suspension was
stirred at 20 ꢀC for 15 min after, which 1-hexene
(4.0 mmol) was added. The reaction mixture was then stirred
at 65 ꢀC in the closed vessel under N2 for 48 h. During the
reaction, a precipitate of magnesium salts was observed. Af-
ter the elapsed time, the reaction mixture was cooled to room
temperature and was taken up in 10% K2CO3 (20 cm3) and
extracted with CH2Cl2 (3ꢂ20 cm3). The combined organic
layers were dried (Na2SO4), concentrated, and purified by
silica gel chromatography using ether/hexane mixture as el-
uant to give a non-separable mixture of isomers 12a and 13a
as a colorless liquid (192 mg, 77%). The ratio of 12a and 13a
3.4. Conversion of adduct 15f into its acrylate ester 27
To a solution of the adduct 15f (1.00 g, 3.23 mmol) and pyr-
idine (10 mmol) in CH2Cl2 (passed through Al2O3)
(100 cm3) under N2 was added drop wise (ca. 2 min) acrolyl
chloride (6 mmol) at 0 ꢀC. The reaction mixture was stirred
at 20 ꢀC for 1 h. TLC experiment (silica, hexane/ether) was
carried out to determine the completion of reaction. (If
incomplete, a further amount of acrolyl chloride/pyridine
has to be added.) The reaction mixture was washed with
aqueous NaHCO3 (20 cm3). The aqueous layer was reex-
tracted with dichloromethane (2ꢂ25 cm3). The combined
organic layers was dried, concentrated, and purified by chro-
matography using 4:1 hexane/ether mixture as the eluant to
give the ester 27 (926 mg, 79%) as a colorless liquid.
(Found: C, 59.3; H, 5.9; N, 3.8. C18H21NO7 requires C,
59.50; H, 5.83; N, 3.85%.) nmax (neat) 3032, 3004, 2955,
2849, 1745, 1720, 1634, 1494, 1454, 1435, 1407, 1284,
1192, 1105, 991, 918, 810, 761, and 703 cmꢁ1; dH
(CDCl3, +20 ꢀC) 2.60–3.10 (4H, m), 3.80 (3H, s), 3.83
(3H, s), 4.08 (1H, app t, J 6.0 Hz), 4.50 (1H, dd, J 7.0,
11.0 Hz), 4.74 (1H, m), 5.73 (1H, d, J 10.4 Hz), 6.01 (1H,
dd, J 10.4, 17.3 Hz), 6.26 (1H, d, J 17.3 Hz), 7.30 (5H, m).
1
was found to be 85:15, respectively, as determined by H
NMR spectroscopic analysis (vide supra).
3.3.2. Cycloaddition of nitrone 7 with 3-buten-1-ol (11h).
As described in Section 3.3.1, the addition reaction was
carried out using hydroxylamine 10 (307 mg, 2.0 mmol)
and 3-buten-1-ol (2.0 mmol) in the presence of 1 equiv of
MgBr2 at 65 ꢀC for 48 h. After usual work up the residual
liquid was purified by chromatography over silica using
95:5 ether/methanol as eluant to give a non-separable mix-
ture of isomers 12h and 13h as a colorless liquid (430 mg,
91%). The ratio of 12h and 13h was found to be 89:11, re-
3.5. Cycloreversion of acrylate ester 27 to alkenenitrone
28, and its intramolecular cycloaddition to 29. Conver-
sion of 29 into 13d
1
spectively, determined by H NMR spectroscopic analysis
as before (Section 3.2.9).
A solution of acrylate ester 27 (500 mg, 1.38 mmol) in anhy-
drous toluene (400 cm3) was heated to 120 ꢀC in a closed
vessel for 30 h. After removal of the toluene by distillation
using a 25 cm Vigreux column, the residual liquid was chro-
matographed over silica using a 2:1 hexane/ether to give the
intramolecular cycloaddition product 29 as colorless crystals
(127 mg, 42%); mp 157–158 ꢀC (CH2Cl2/ether). (Found: C,
65.6; H, 5.9; N, 6.4. C12H13NO3 requires C, 65.74; H, 5.98;
N, 6.39%.) nmax (KBr) 3059, 2992, 2960, 2886, 1728, 1460,
1404, 1334, 1262, 1239, 1181, 1086, 1047, 1014, 900, 791,
754 and 703 cmꢁ1; dH (CDCl3, +20 ꢀC) 2.68 (1H, m), 2.92
(1H, m), 3.16 (1H, m), 3.25 (1H, m), 3.98 (1H, d, J
12.2 Hz), 4.08 (1H, d, J 9.5 Hz), 5.05 (1H, d, J 9.8 Hz),
5.07 (1H, dd, J 6.5, 9.8 Hz), 7.35 (5H, m); dC (CDCl3,
3.3.3. Cycloaddition of nitrone 7 with 4-penten-1-ol (11j).
As described in Section 3.3.1, the addition reaction was car-
ried out using hydroxylamine 10 (230 mg, 1.5 mmol) and 4-
penten-1-ol (1.5 mmol) in the presence of 1 equiv of MgBr2
at 67 ꢀC for 48 h. After usual work up the residual liquid was
purified by chromatography over silica using 97:3 dichloro-
methane/methanol as eluant to give a non-separable mixture
of isomers 12j and 13j as a colorless liquid (350 mg, 93%).
The ratio of 12j and 13j was found to be 91:9, respectively,
1
determined by H NMR spectroscopic analysis as before.
(Found: C, 66.7; H, 8.3; N, 5.4. C14H21NO3 requires C,
66.91; H, 8.42; N, 5.57%.) nmax (neat) 3380, 3060, 2941,
2871, 1493, 1452, 1376, 1357, 1328, 1275, 1177, 1060,

S. A. Ali, M. Z. N. Iman / Tetrahedron 63 (2007) 9134–9145
9145
+20 ꢀC) 34.60, 55.44, 70.88, 73.69, 79.63, 127.65 (2C),
128.62, 128.91 (2C), 137.43, 172.54.
7. Hanselmann, R.; Zhou, J.; Ma, P.; Confalone, P. N. J. Org.
Chem. 2003, 68, 8739–8741.
8. Zhao, Q.; Han, F.; Romero, D. L. J. Org. Chem. 2002, 67,
3317–3322.
The adduct 29 (20 mg) on treatment with 5:1 methanol/HCl
(1 cm3) at 20 ꢀC for overnight, followed by work up as
described before (Section 3.2.5) afforded the adduct 13d in
almost quantitative yield.
9. (a) Ali, S. A.; Hassan, A.; Wazeer, M. I. M. Spectrochim. Acta,
Part A 1995, 51, 2279–2287; (b) Wazeer, M. I. M.; Ali, S. A.
Canad. J. Appl. Spectro. 1995, 40, 53–60; (c) Hassan, A.;
Wazeer, M. I. M.; Perzanowski, H. P.; Ali, S. A. J. Chem.
Soc., Perkin Trans. 2 1997, 411–418; (d) Fornefeld, E. J.;
Pike, A. J. J. Org. Chem. 1979, 44, 835–839.
Acknowledgements
10. (a) Ali, S. A.; Wazeer, M. I. M. J. Chem. Soc, Perkin Trans. 1
1988, 597–605; (b) Ali, S. A.; Khan, J. H.; Wazeer, M. I. M.
Tetrahedron 1988, 44, 5911–5920.
11. Micheli, C. De.; Invernizzi, A. G.; Gandolfi, R. Tetrahedron
Lett. 1975, 16, 2493–2496.
The facilities provided by the King Fahd University of Petro-
leum and Minerals, Dhahran, are gratefully acknowledged.
We thank Dr. M. B. Fettouhi for X-ray structure determina-
tion, and Mr. M. Arab for recording NMR spectra.
12. (a) Huisgen, R. J. Org. Chem. 1976, 41, 403–419; (b) Fukui, K.
Acc. Chem. Res. 1971, 4, 57–64; (c) Sustmann, R. Pure Appl.
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