The regio- and stereo-chemistry of 1,3-dipolar cycloaddition of a chiral methylenenitrone to 1,2-disubstituted alkenes

Article abstract of DOI:10.3184/030823408X287087

A study of regio- and stereo-selectivity in the cycloaddition reactions of a series of symmetrical and unsymmetrical 1,2-disubstituted alkenestothechiral, internally H-bonded N-(2-hydroxy-1-phenyl)methylenenitrone, has been carried out. The regioselectivity observed in the addition reactions is explained in terms of frontier orbital interactions. The alkenes having a hydroxymethyl substituent at the allylic position are found to undergo regio- as well as highly stereo-selective cycloaddition reactions in the presence of anhydrous magnesium bromide.

Full text of DOI:10.3184/030823408X287087

38 RESEARCH PAPER
JANUARY, 38–47
JOURNAL OF CHEMICAL RESEARCH 2008
The regio- and stereo-chemistry of 1,3-dipolar cycloaddition of a chiral
methylenenitrone to 1,2-disubstituted alkenes
Shaikh A. Ali* and Muhammad Z.N. Iman
Chemistry Department, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia
A study of regio- and stereo-selectivity in the cycloaddition reactions of a series of symmetrical and unsymmetrical
1,2-disubstituted alkenes to the chiral, internally H-bonded N-(2-hydroxy-1-phenyl)methylenenitrone, has been carried
out. The regioselectivity observed in the addition reactions is explained in terms of frontier orbital interactions.
The alkenes having a hydroxymethyl substituent at the allylic position are found to undergo regio- as well as highly
stereo-selective cycloaddition reactions in the presence of anhydrous magnesium bromide.
Keywords: dipolar cycloddition, asymmetric induction, Lewis acid catalyst, diastereoselection, chiral methylenenitrone
The nitrone-alkene cycloaddition reaction is the best method
H
R
O
H
R
H
R
for constructing isoxazolidines in high yields.1,2 Remarkable
regio-, stereo-, face- and chemo-selectivity along with efficient
incorporation of multiple stereocentres in a single step
have made nitrone cycloaddition a powerful tool in organic
synthesis. In recent years, asymmetric nitrone cycloaddition
reactions3-7 leading to optically active isoxazolidines have
received considerable attention and have been reviewed by
various authors.8-13 A cyclic nitrone having a chirogenic centre
embedded in the ring skeleton allows an alkene to approach
the energetically favourable face of the nitrone. Even though
a chiral acyclic nitrone (e.g. 1) could allow an approaching
alkene to choose between the faces, poor stereoselectivity is
observed14 in its cycloadditions and this has been attributed
to its conformational flexibility by virtue of easy N–C bond
rotation (Scheme 1). However, the conformational mobility
is somewhat or completely arrested in the intramolecularly
H-bonded (R)-chiral nitrone 2 or its tightly metal-chelated
form 3. As a result, the nitrone 2 is receiving increasing
attention owing to its efficacy in transferring chirality to the
newly created stereocentres of the resulting isoxazolidines
N
Ph
N
Ph
N
Ph
O
H
O
Metal
Me
O
2
O
3
1
R
R
3
5
N
O
H2N
Ph
R'
O
H
R'
O
H
4
5
Scheme 1
temperatures, isolated yield, and composition of the isomeric
cycloadducts are given in Table 1.
While the reaction of nitrone 2 with methyl cinnamate (7a)
gave a mixture of isomers 8a–11a in a ratio of 73:8:13:6, the
in intramolecular15,16 (having
R
containing an alkene
moiety), as well as intermolecular15,17 (R = H, alkyl) cyclo-
addition reactions. Another important advantage that is bound
to make the nitrone 2 a very popular reactant, is the
facile reductive cleavage of the chiral auxiliary as well as
N–O bond of the isoxazolidine 4 thereby providing simple and
efficient access to a variety of synthetically important chiral
1,3-aminoalcohols 5.
Table 1 Regio- and stereo-chemistry of the cycloadditiona,b of
the nitrone 2 to trans-disubstituted alkenes 7
Alkene 7 Temp Time
Lewis
Acid
Isolated
yields/%
Isomeric
ratio
(8:9:10:11)
/°C
/h
Although the nitrone cycloaddition reactions of C,N-
disubstituted nitrones with various kind of alkenes have
been studied in great detail,1,2 the chemistry of N-substituted
nitrones (i.e. methylenenitrones) with mono- and 1,1-
disubstituited alkenes has only been investigated to a limited
extent.15,17,18-21 The reactions involving methylenenitrones
and 1,2-disubstituted alkenes are scarcely even mentioned
a
b
c
90
90
90
80
80
90
85
90
65
90
65
65
8
8
None
None
None
BF3.OEt2
ZnCl2
None
None
None
MgBr2
None
MgBr2
None
87
85
84
60
65
82
90
89
96
79
76
91
73:8:13:6
76:7:12:5
57:9:18:16
59:13:15:13
58:14:17:11
53:9:22:16
32:26:19:23
38:7:45:10
0: 0: 9:91
50:13:30:7
19:81:0:0
(8h = 10h)/
(9h = 11h)
70:30
(8i = 10i)/
(9i = 11i)
80:20
6:94
56:24:13:7
4:96:0:0
8
12
12
8
6
8
48
8
48
12
d
e
f
in the literature.19 Most recently, we have reported17
a
systematic study detailing the regio- and stereo-chemical
features associated with the cycloaddition of the chiral
methylenenitrone 2 (R = H) to a series of mono- and 1,1-
disubstituted alkenes. In our continuing study involving
methylenenitrones we report herein the cycloaddition of chiral
methylenenitrone 2 (R = H) to trans and cis-1,2-disubstituted
alkenes [(7) and (12) respectively] so as to provide a composite
picture that reflects the scope and limitations associated with
the addition reactions of the methylenenitrone.
g
h
i
105
12
None
92
65
105
65
36
12
36
12
MgBr2
None
MgBr2
None
74
89
88
73
j
k
105
(8a = 10k)/
(9k = 11k)
75:25
Results and discussion
The stereochemical details of the addition of nitrone 2 to
several trans-alkenes (7) (Scheme 2) along with the reaction
aIn toluene in the absence of Lewis acid catalyst. bIn the
presence of one equivalent of Lewis acid in CH2Cl2 except for
the addition reaction of alkene 7c in toluene.
* Correspondent. E-mail: shaikh@kfupm.edu.sa
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JOURNAL OF CHEMICAL RESEARCH 2008 39
R2
R2
R1
3
5
Ph
Ph
Ph
+
N
N
R1
O
O
R2
H
H
OH
OH
8
+
9
+
R1
Ph
N
O
H
7
R1
R2
O
R1
R2
3
2
5
+
Ph
N
N
O
O
CH2O
OH
OH
Ph
NHOH
10
11
a, R1 = Ph; R2 = CO2Me
g, R1 = CH2OH; R2 = CO2Me
h, R1 = R2 = CO2Me
H
O
t
b, R1 = Ph; R2 = CO2 Bu
c, R1 = Me; R2 = CO2Me
i, R1 = R2 = CH2OH
6
t
d, R1 = Me; R2 = CO2 Bu
j, R1 = CH2OH; R2 = CH2OSitBuMe2
e, R1 = Me; R2 = CHO
f, R1 = Me; R2 = CH2OH
k, R1 = R2 = CH2OSitBuMe2
Scheme 2
addition of t-butyl cinnamate (7b) afforded adducts 8b–11b
in a ratio of 76:7:12:5, respectively. The stereochemistry
of the t-butyl cinnamate adducts 8b–11b was correlated with
the methyl cinnamate adducts 8a–11a by ester exchange
with methanol/HCl. The structures of the regioisomers
were assigned on the basis of characteristic chemical shifts
of C(5)Hs (Experimental). The nitrone 2 is expected to be
internally H-bonded as shown in Scheme 3. This would
place the phenyl group on the b-face of the nitrone, while the
H on the stereocentre remains on the a-face. While both
the ‘a-exo (R1 = Ph) approach’ (i.e. the approach of the
alkene with exo-oriented R1 group toward the a-face of the
nitrone) and ‘b-endo (R1) approach’ of the alkene would
lead to the same diastereomer 8, the ‘a-endo (R1)’ and
‘b-exo (R1)’ approaches give the other diastereomer 9.
The face selectivity in the addition reaction of methylene-
nitrones, such as 2, cannot be determined since, for instance,
the formation of the diastereomer 8 is the combined outcome
of the approach of the alkene to both faces of the nitrone.
Likewise, the stereoselectivity in each face (exo/endo
ratio) cannot be determined, since each diastereomer can
be obtained by both the exo and endo mode of attack. This
problem does not arise in the case of N,C-disubstituted
chiral nitrones, since their regioselective addition reactions
with disubstituted alkenes would create four chiral centres,
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 2, it can be presumed that the a-face
of the nitrone will be preferentially attacked, and the steric
interactions would then dictate the exo (R1 = Ph) mode of
approach while the secondary orbital interactions would
augment the stereoselection by allowing CO2R (i.e. R2) endo-
oriented in the transition state. In line with this reasoning,
the trans-cinnamate cycloadditions resulted in the formation
of major adduct 8a and 8b predominantly via ‘a-exo (R1)
R2
R2
R1
R2
Ph
b - endo (R1)
N
R
R1
O
R1
b - exo (R1)
OH
9
Ph
H
Ph
R
R2
R
N
N
H
R1
O
O
Ph
a - exo (R1)
N
R
O
O
H
R1
H
R2
O
R2
OH
a - endo (R1)
8
R1
Scheme 3
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40 JOURNAL OF CHEMICAL RESEARCH 2008
approach’, while its minor stereoisomer 9a and 9b is the
product of ‘a-endo (R1) approach’. For the formation of the
corresponding regiosomers 10 and 11, the Scheme 3 has to
be modified with the positions of R1 and R2 reversed. In the
cinnamate additions, the major regioisomer was assigned the
stereochemistry as depicted in 11 obtained via ‘a-exo (R2
=CO2R) approach’ as a result of unfavourable steric hindrance
in the transition state (vide infra).
trans-Crotonates 7c and 7d underwent additions to give 8c–
11c and 8d–11d in ratios of 57:9:18:16 and 53:9:22:16,
respectively. The cycloaddition of 7c in the presence of
Lewis acid catalysts BF3.Et2O or ZnCl2 did not change the
isomeric compositions (Table 1). The stereochemistry of
the t-butyl crotonate adducts 8d–11d was correlated to the
methyl crotonate adducts 8c–11c by ester exchange with
methanol/HCl. Based on the earlier discussion, the major
adduct 8c was obtained via ‘a-exo (R1) approach’ (Scheme 3).
The stereochemistry of the isomers 8c–11c was confirmed
by lithium aluminum hydride (LAH) reduction to trans-
crotyl alcohol (7f) adducts 8f–11f (vide infra). The addition
reaction of trans-crotonal (7e) was also found to be non
regioselective; the cycloadducts 8e–11e were obtained in
a ratio of 32:26:19:23, respectively. The configuration of
adducts 8e–11e was correlated by NaBH4 reduction to trans-
crotyl alcohol (7f) adducts 8f–11f.
While the methylenenitrone–crotonate addition reaction is
scarcely mentioned in the literature, in one such cycloaddition
the achiral N-benzylmethylenenitrone gave a mixture of
regiomers having ester functionality attached to the C(4)
and C(5) in a ratio of 67:33, respectively.22 Recently, the
reaction of N-tetrahydropyran-2-ylmethylenenitrone with
methyl cinnamate (7a) has been reported23 to undergo
regioselective addition to give a single adduct having an
ester functionality attached to the C(4) of the isoxazolidine.
The report contradicts our findings: the methylenenitrone-
cinnamate or -crotonate cycloadditions in this work are found
to be non-regioselective; the preferred regioisomers (8 and
9) were the ones having the electron-withdrawing carbonyl
groups attached to the C(4) of the isoxazolidines. The results
discussed above are in general agreement with the frontier
orbital treatment of the nitrone 1,3-dipolar cycloadditions.24-30
In the case of cinnamates and more so in the case of crotonates,
both the HOMO–LUMO combinations do not offer any clear-
cut regiochemical preference since the nitrone as well as the
alkene HOMO orbitals have a similar magnitude of orbital
coefficients at both the oxygen and carbon terminals of the
methylenenitone31.32 and carbon terminals of the alkenes
(Fig. 1).33 As such a mixture of regioisomers is expected to
be formed in the addition reactions of methylene nitrones with
1,2-disubstituted alkenes. Based on the small differences in
the orbital coefficients, one may conclude that the nitrone
(HOMO)-crotonate (LUMO) or nitrone (LUMO)-cinnamate
(HOMO) prefer the formation of C(4)CO2R regioisomers by
uniting the larger terminal coefficients in the transition state
(Fig. 1).31,32
The stereochemistry of the minor regioisomers 10b/11b
and 10d/11d was correlated by using the similarity in the
chemical shift values of their tBu protons in toluene-d6; while
t
the Bu protons of 10b and 11b appeared at d 1.36 and 1.32,
the corresponding signals for 10d and 11d were displayed at
d 1.37 and 1.35, respectively. The major adduct was assigned
the stereochemistry as in 8a or 8b with endo-oriented R2 (i.e.
CO2R) as a result of favourable secondary orbital interactions.
The stereoisomeric preference for the endo-oriented CO2R
in isomers 8 over exo-oriented CO2R in 9 was found to be
much higher than that in their regioisomeric counterparts 10
and 11 (Table 1). As is evident from Table 1, while the ratio of
8a (endo-CO2Me) and 9a is 73:8, that of 10a and 11a (endo-
CO2Me) is found to be 13:6. A look at the corresponding
transition states A and B might reveal the reasons for the
differences in the exo/endo ratios (Figure 2). The oxygen
terminal of the nitrone apparently becomes a part of the six-
membered ring as a result of the H-bonding. The increased
steric encumbrance of the oxygen-terminal in the presence
of H-bonding thereby encourages the substituent (CO2Me) to
have a greater endo preference via transition state A rather
than via B. In the transition state A involving the H-bonded
nitrone, the OMe group does not experience steric crowding
as much as in transition state B where the OMe group will
be subjected to non-bonded repulsions with the substituent at
the nitrogen. The results thus revealed that an endo-oriented
group is better tolerated at the carbon terminal of the nitrone
than at the oxygen terminal. This is clearly demonstrated in
the addition reaction of crotyl alcohol (7f) which gave 8f–11f
in a ratio of 38:7:45:10. The regiochemical preference is
lost in this addition reaction owing to the presence of ‘normal’
substituents (i.e. CH3 vs. CH2OH) at both ends of the alkene;
a regioisomeric mixture of 8f/9f and 10f/11f was obtained in
ratio of 45:55. The formation of major regiomers 8f (endo-
CH2OH) and 10f (endo-Me), both having a substituent at C(4)
LUMO
E (ev)
- 0.43
RO2C
RO2C
~+1
Me
+ 0.3
Ph
R
N
0.46
0.44
- 0.55
RO2C
RO2C
R
N
Ph
Me
0.34
- 8.7
0.66
~- 10.1
HOMO
R
N
O
CO2R
Me
Fig. 1 A qualitative representation of the frontier orbital energies and coefficients of methylenenitrone and a 1,2-disubstituted
alkene.
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JOURNAL OF CHEMICAL RESEARCH 2008 41
Ph
Ph
N
N
H
OMe
O
H
O
O
O
O
8
11
O
C
R
MeOC
R
A: a–endo(CO2Me)
B: b–endo(CO2Me)
Fig. 2 Steric effects and secondary orbital interactions in the transition states.
endo-oriented, is a result of the preferred endo orientation of
the alkene substituent at the carbon terminal of the nitrone in
the transition states.
to afford 8g–11g in a ratio 0:0:19:81, respectively. If the
assignment of the regio- and stereochemistry is correct,
then a mixture of adducts 8g–11g in a ratio of 50:13:30:7
is expected to give, after LAH reduction, the triols 8i and 9i
in a ratio of (50 + 30):(13 + 7), respectively, as a result of
the following conversions: (8g, 10g)→ 8i; and (9g, 11g)→
9i. The formation of triols 8i and 9i in a ratio of ~80:20
provides evidence of the correctness of the assignment of the
stereochemistry of adducts 8g–11g. Likewise, the mixture of
adducts 10g and 11g (obtained via MgBr2-catalysed reaction)
in a 19:81 ratio was converted into 8i and 9i in a ratio of
~19:81 as expected.
Next, we pursued the cycloaddition reaction of symmetrical
trans-alkenes so as to eliminate the regiochemeical
complication. Thus the addition reaction of nitrone 2 with
dimethyl fumarate (7h) and trans-but-2-en-1,4-diol (7i) gave
a mixture cycloadducts 8h, 9h and 8i, 9i, respectively, in a
ratio of 70:30 and 80:20. The major adducts (i.e. 8h and
8i) were obtained via ‘a-exo (R1) approach’ (Scheme 3).
The stereochemistry of the fumarate adducts 8h and 9h
was correlated by LAH reduction to adducts 8i and 9i.
The stereoselectivity of the addition of trans-diol 7i was
dramatically reversed in the presence of MgBr2; adducts 8i
and 9i were obtained in a ratio of 6:94, respectively. While
the addition of unsymmetrical silyloxy alkeneol 7j gave the
cycloadducts 8j–11j in a ratio of 56:24:13:7, the symmetrical
disilyloxy alkene 7k afforded 8k and 9k in a ratio of 75:25,
respectively. The ratio of 80:20 for the regioisomers (8j + 9j)
vs. (10j + 11j) validates the earlier discussion that the alkene
carbon bearing the bulkier CH2OSitBuMe2 substituent prefers
to be away from the oxygen terminal and attaches itself to
the carbon terminal of the nitrone. The stereochemistry of
the mono- and di-silyloxy adducts was confirmed by their
conversion into adducts 8i and 9i by treatment with MeOH/
HCl. The formation of 8i and 9i in a ratio of ~69:31 from
the above mixture of 8j–11j (in a ratio of 56:24:13:7) as a
result of the following conversions: (8j, 10j)→ 8i; and (9j,
11j)→ 9i, provided further evidence of the correctness of the
assignment of the stereochemistry. The regio- as well as stereo-
Effective utilisation of the cycloaddition reactions under
study, however, demands a better regio- as well as stereo-
selectivity than has been observed so far. In search of a better
selectivity and proof for the stereochemistry assigned so far,
we next studied the cycloaddition of several trans-alkenes
containing hydroxy groups at the allylic position in the
presence of MgBr2. As documented in the recent literature,15-17
the magnesium-chelated endo approach of the CH2OH group
of the allyl alcohol from the less hindered face of the nitroneas
depicted in C afforded D and E (X = Y = H) in a ratio of 96:4
(Fig. 3).15 Likewise, methallyl alcohol gave the cycloadducts
D and E (X = Me, Y = H) in a 97:3 ratio.17 It is gratifying to
see that the metal-chelated transition state is equally effective
in controlling regio- as well as stereo-selection in the addition
reaction of a trans-alkeneol like crotyl alcohol 7f. The ratio of
38:7:45:10 for adducts 8f–11f in the absence of MgBr2 was
changed to 0:0:9:91 in the presence of MgBr2; a complete
reversal of the regiochemistry has thus been achieved. The
configuration of the overwhelmingly predominant adduct 11f
is consistent with a magnesium-chelated endo approach of
the CH2OH group of the crotyl alcohol from the less hindered
face of the nitrone as depicted in C (X = H, Y = Me) (Fig. 3).
This reaction was particularly helpful in establishing the
stereochemistry of the addition products of alkenes 7c–7f
since the stereochemistry of adducts was correlated with
each other by chemical conversions (vide supra). The 1H
NMR spectroscopic analysis was helpful in determining
the regioisomeric distributions. The C(5)Me protons of
cycloadducts 8 and 9, obtained from the addition reactions
of alkenes 7c, 7d and 7f, invariably appeared downfield by
virtue of being closer to the ring oxygen, while the C(4)Me of
the regioisomeric 10 and 11 appeared upfield.
While the addition reaction of nitrone 2 with trans-methyl
g-hydroxycrotonate (7g) was found to be non-regioselecetive
as expected, giving adducts 8g–11g in a ratio of 50:13:30:7,
the reaction became regioselective in the presence of MgBr2
Y
Y
3
3
X
Br
N
5
5
Ph
Ph
N
N
OH
Y
+
O
O
OH
Mg
H
X
O
O
OH
OH
O
X
H
C
D
E
X=Y=H;
X= Me; Y=H; (D/E) = 97:3
X= H; Y = Me; (11f/10f) i.e. (D/E) = 91:9
(D/E) = 96:4
Fig. 3 Metal-chelated transition state for the cycloaddition reactions.
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42 JOURNAL OF CHEMICAL RESEARCH 2008
selectivity of the addition of silyloxy alkeneol 7j was changed
in the presence of MgBr2; adducts 8j–11j were obtained in
a ratio of 4:96:0:0, respectively. The configuration of the
overwhelmingly predominant adduct 9j is consistent with the
magnesium-chelated endo approach of the CH2OH toward
the less hindered face of the nitrone (Fig. 3). As before, the
mixture of adducts 8j and 9j (obtained via MgBr2-catalysed
reaction) in a 4:96 ratio was converted into 8i and 9i in a ratio
of ~4:96 as expected.
Finally, we studied the cycloaddition of nitrone 2 with
several cis-alkenes 12. The stereochemical details along with
the reaction temperatures, isolated yield, and composition
of isomeric cycloadducts are given in Table 2 (Scheme 4).
The addition of dimethyl maleate 12a afforded adducts 13a
and 14a in a ratio of 40:60, which was changed to 53:47
in the presence of MgBr2. The emergence of 14a as the
major product certifies the dominance of secondary orbital
interaction over steric effects in dictating the stereochemical
outcome of the reaction. The addition of cis-diol 12b in the
absence and presence of MgBr2 afforded 13b and 14b in a
ratio of 48:52 and 20:80, respectively. The metal-chelated
transition state thus confirmed the stereochemistry of
14b as having endo-oriented hydroxymethyl substituents.
The stereochemistry of dimethyl adducts 13a and 14a was
correlated to adducts 13b and 14b by LAH reduction. While
the addition of the unsymmetrical monosilyloxy alkene 12c
in the absence of MgBr2 afforded adducts 13c–16c in a ratio
of 55:23:15:7, the addition reaction in the presence of
MgBr2 became regioselective to give the adducts in a ratio of
20:80:0:0. The addition of symmetrical disilyloxyalkene 12d
gave the adducts 13d and 14d in a ratio of 72:28, while the
ratio became 90:10 in the presence of MgBr2 in a low yielding
reaction. The stereochemistry of adducts from the addition
reaction of alkenes 12c and 12d as correlated to that of alkene
12b by treatment with MeOH/HCl. The formation of triols
13b and 14b in a ratio of ~70:30 from the above mixture of
13c–16c (in a ratio of 55:23:15:7), provides further evidence
of the correctness of the assignment of the stereochemistry
of adducts 13c–16c as a result of the following conversions:
(13c, 15c)→ 13b; and (14c, 16c)→ 14b.
While the use of 1H NMR coupling constant using
the Karplus equation is highly successful in assigning
configuration of six-membered rings, such applications often
do not work well with isoxazolidines or any five-membered
ring systems. The configuration of the isoxazolidines in
the current work is indeed very complex to elucidate with
any certainty. The complexity arises from the fact that the
relatively slow nitrogen inversion makes the proton signals
broader at ambient temperature. The five-membered ring does
not have the well-defined conformation of six-membered
systems. The constantly changing conformation (half chair/
envelope/near planar), flap of the envelope, as well as
configuration (owing to nitrogen inversion), make it a rather
difficult task to deduce the configuration of the isoxazolidines.
Table 2 Regio- and stereo-chemistry of the cycloadditiona,b of the nitrone 2 to cis-disubstituted alkenes 12
Alkene 12
Temp/°C
Time/h
Lewis Acid
Isolated yields/%
Isomeric ratio (13:14:15:16)
(13a = 15a)/14a = 16a)
a
85
65
12
36
None
MgBr2
90
45
40:60
53:47
(13b = 15b)/14b = 16b)
48:52
a
c
95
65
105
65
6
None
MgBr2
None
93
72
92
84
36
12
48
20:80
55:23:15:7
20:80:0:0
MgBr2
(13d = 15d)/14d = 16d)
d
105
65
12
48
None
MgBr2
89
8
72:28
90:10
aIn toluene in the absence of Lewis acid catalyst. bIn the presence of one equivalent of Lewis acid in CH2Cl2.
R2
R2
R1
3
5
Ph
+
Ph
N
N
R1
O
O
H
H
R2
R1
OH
OH
13
14
+
Ph
N
O
H
+
R1
12
O
R1
R2
3
R2
2
5
+
Ph
Ph
N
N
O
O
OH
OH
15
16
a, R1 = R2 = CO2Me
b, R1 = R2 = CH2OH
c, R1 = CH2OH; R2 = CH2OSitBuMe2
d, R1 = R2 = CH2OSitBuMe2
Scheme 4
PAPER: 07/4939

JOURNAL OF CHEMICAL RESEARCH 2008 43
t-butyldimethylsilyl chloride (5.72 g, 38 mmol). The reaction mixture
was stirred under N2 at 20°C for 6 h, and then taken up in ether
(40 cm3) and washed with water (4 ¥ 15 cm3). The organic layer was
dried, concentrated and chromatographed using chloroform as eluant
to give the disilylated trans-1,4-di-t-butyldimethylsilyloxybut-2-ene
(7k) as a colourless liquid (2.30 g, 32%); (Found: C, 60.4; H, 11.3.
C16H36O2Si2 requires C, 60.69; H, 11.46%.); nmax (neat) 2953, 2889,
2857,1467, 1367, 1254, 1129, 1044, 998, 968, 935, 839 and 776 cm-1;
dH (CDCl3) 0.068 (12H, s), 0.91 (18H, s), 4.18 (4H, d, J = 2.5 Hz),
5.76 (2H, t, J = 2.3 Hz); dC (CDCl3) –5.2, 18.4, 26.0, 63.3, 129.3.
Continued elution with 20:1 CHCl3/methanol afforded the trans-4-
t-butyldimethylsilyloxybut-2-en-1-ol (7j) (1.94 g, 42%); (Found: C,
59.5; H, 11.1. C10H22O2Si requires C, 59.35; H, 10.96%.); nmax (neat)
3347, 2931, 2857,1466, 1380, 1255, 1129, 1096, 1061, 1007, 906,
839, and 778 cm-1; dH (CDCl3) 0.078 (6H, s), 0.92 (9H, s), 1.98 (1H,
br, OH), 4.14 (2H, dd, J = 1.3, 5.2 Hz), 4.19 (2H, dd, J = 1.6, 3.1 Hz),
5.79 (1H, ttd, J = 1.2, 4.6, 15.3 Hz), 5.86 (1H, ttd, J = 1.5, 5.2, 15.3 Hz);
dC (CDCl3) –5.3, 18.4, 25.9, 63.0, 63.1, 129.0, 130.8.
The measurement of NOE is of not much help in this situation.
All the isoxazolidines in this work are liquids and as such
X-ray diffraction analysis cannot be carried out. Added to
these difficulties was the fact that most of the adducts were
non-separable; a few were separated with great difficulty.
It is important to know that the disubstititued alkenes in
this study, like the monosubstituted ones,17 gave the major
products via exo-oriented transition state at the N-terminal of
the nitrone 2. The endo-oriented C(5)H of the isoxazolidines
derived from the additions of monosubstituted alkenes, are
known17 to appear downfield in compare to that of the exo-
oriented C(5)H. Further evidence of the correctness of the
assignment of configuration in this work is based on the
observation that the endo-oriented C(5)H in 8, 10, 13 or 15
invariably appeared downfield in comparison to that of the
exo-oriented C(5)H in 9, 11, 14 or 16, respectively (Table 3).
We have no rationale to offer for such a difference in the
chemical shifts; however, it is a diagnostic trend that would
enable the assignment of the stereochemistry of this important
class of cycloaddition reactions.
Using a similar procedure to that described above cis-1,4-di-t-
butyldimethylsilyloxybut-2-ene (12d) (colourless liquid) (27%) and
cis-4-t-butyldimethylsilyloxybut-2-en-1-ol (12c) (colourless liquid)
(36%) were obtained from cis-but-2-ene-1,4-diol (12b). cis-1,4-di-
t-Butyldimethylsilyloxybut-2-ene (12d): (Found: C, 60.5; H, 11.3.
C16H36O2Si2 requires C, 60.69; H, 11.46%.); nmax (neat) 3026, 2953,
2930, 2889, 2857,1467, 1405, 1362, 1255, 1085, 1005, 940, 840 and
777 cm-1; dH (CDCl3) 0.068 (12H, s), 0.90 (18H, s), 4.23 (4H, d,
J = 2.8 Hz), 5.55 (2H, t, J = 2.8 Hz); dC (CDCl3) –5.2, 18.3, 25.9, 59.6,
130.2. cis-4-t-Butyldimethylsilyloxybut-2-en-1-ol (12c): (Found: C,
59.1; H, 10.8. C10H22O2Si requires C, 59.35; H, 10.96%.); nmax (neat)
3351, 3024, 29.53, 2930, 2886, 2857, 1469, 1407, 1361, 1255, 1088,
1035, 939, 838 and 777 cm-1; dH (CDCl3) 0.088 (6H, s), 0.91 (9H, s),
2.50 (1H, br, OH), 4.19 (2H, d, J = 5.2 Hz), 4.25 (2H, d, J = 5.2 Hz),
5.65 (1H, td, J = 5.5, 11.3 Hz), 5.69 (1H, td, J = 5.5, 11.3 Hz);
dC (CDCl3) –5.2, 18.3, 25.9, 58.7, 59.6, 130.1, 131.2.
A systematic study of asymmetric reactions of the chiral
methylenenitrone 2 with several 1,2-di-substituted alkenes
has been carried out for the first time. The distereoselection
observed in our study reflects the scope and limitations inherent
in these important cycloaddition reactions. The remarkable
regio- and stereo-selectivity observed in the magnesium-
chelated cycloadditions paves the way for the synthesise of
isoxazolidines having a variety of functionalities.
Methyl g-hydroxycrotonate (7g) was prepared as described.37
MgBr2 wasfreshlypreparedbyreactionofMgwith1,2-dibromoethane
in THF. The chiral hydroxylamine (R)-3-hydroxyamino-2-
phenylethanol (6) was prepared in 80% yield according to the
literature procedures,38,39 m.p. 68–68.5°C (methanol–ether) (lit.39
m.p. 67–68°C); [a]23 –62 (c 2.00, methanol) (lit.39 [a]20 –38
Experimental
General
Elemental analysis was carried out on a EuroVector Elemental
Analyser Model EA3000. All melting points are uncorrected.
IR spectra were recorded on a Perkin Elmer 16F PC FTIR spectrometer.
1H and 13C NMR spectra were measured in CDCl3 at 20°C using TMS
as internal standard on a JEOL LA 500 MHz spectrometer. Silica gel
chromatographic separations were performed with Silica Gel 100
from Fluka Chemie AG (Buchs, Switzerland). Paraformaldehyde,
cis-but-2-ene-1,4-diol, dimethyl maleate, dimethyl fumarate, trans-
methyl crotonate, trans-methyl cinnamate, trans-crotonaldehyde,
m-chloroperbenzoic acid (70% purity), D(-)-a-phenylglycinol
(i.e. (R)-phenylglycinol), hydroxylamine hydrochloride from Fluka
were used as received.
trans-Crotyl alcohol (7f) was obtained by NaBH4 reduction
of trans-crotonaldehyde, while trans-but-2-ene-1,4-diol (7i) was
prepared by reduction of dimethyl fumarate with DIBAH using
the procedure as described.34 trans-t-butyl –crotonates35 and
–cinnamates36 were prepared as described.
D
D
(c 0.99, CHCl3). All solvents were of reagent grade. Dichloromethane
was passed through alumina before use.
General procedure for the cycloaddition reactions
In all the cycloadditions involving electron deficient conjugated
alkenes, a mixture of hydroxylamine 6 (2.0 mmol), paraformaldehyde
(3.0 mmol) and toluene (6 cm3) was stirred in a closed flask at 65°C
for 2 h to generate the nitrone 2. The nitrone solution was then treated
with anhydrous MgSO4 (0.5 g) and the alkene. The conjugated alkene
was not added prior to the formation of the nitrone to avoid any
Michael addition of the hydroxylamine. For the additions involving
normal alkenes, all the reactants and anhydrous MgSO4 were added
in the beginning, and the reaction mixture was directly heated at the
specified temperatures (Tables 1 and 2). For the reaction involving
trans- (7i) and cis-but-2-en-1,4-diol (12b), the alkenes were found
to be insoluble in the system; ethanol (1 cm3) was added so as to
make the system homogeneous. The alkenes used, with the amount
in mmol written in parentheses, were as follows: 7a (3), 7b (3), 7c
(15), 7d (4), 7e (10), 7f (10), 7g (4), 7h (2.5), 7i (5), 7j (4), 7k (4),
12a (3), 12b (5), 12c (4), 12d (4). 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
analysed.
Silyloxy alkenes (7j, 7k) and (12c, 12d) were prepared from
but-2-ene-1,4-diols 7i and 12b, respectively, using tBuMe2SiCl
in the presence of imidazole in DMF. Thus to a solution of trans-
but-2-ene-1,4-diol (7i) (2.02 g, 23.0 mmol) in anhydrous distilled
DMF (20 cm3) was added imidazole (5.18 g, 76 mmol) followed by
Table 3 1H NMR chemical shifts of C(5)H signals of some
isoxazolidines
Isoxazolidine
endo-C(5)H
d (ppm)
Isoxazolidine
exo-C(5)H
d (ppm)
8a
8b
8c
8d
8g
8h
8i
8j
8k
10c
13a
13b
13c
13d
5.50
5.45
4.54
4.48
4.59
4.99
4.10
4.07
4.03
4.12
4.90
4.42
4.43
4.41
9a
9b
5.29
5.20
4.28
4.20
4.37
4.89
3.98
3.95
3.90
4.09
4.75
4.22
4.24
4.17
Cycloaddition of nitrone 2 with methyl cinnamate (7a): The crude
mixture of cycloadducts was purified by chromatography over silica
using hexane/ether as eluant to give a non-separable mixture of
isomers 8a–11a (87%) as a colourless liquid. 1H NMR analysis of the
crude and purified samples gave similar composition of the isomers.
Mixture of isomers 8a–11a: (Found: C, 69.5; H, 6.5; N, 4.2.
C19H21NO4 requires C, 69.71; H, 6.47; N, 4.28%.) nmax (neat) 3440,
3063, 3030, 2951, 2881, 1735, 1597, 1494, 1453, 1436, 1348,
1207, 1178, 1053, 1022, 939, 908, 760, and 700 cm-1. The 1H NMR
signals of the major isomer 8a were as follows: dH (CDCl3) 2.50–
3.50 (4H, m), 3.73 (3H, s), 3.88 (1H, m), 4.10 (1H, m), 4.15 (1H,
9c
9d
9g
9h
9i
9j
9k
11c
14a
14b
14c
14d
1
m), 5.50 (1H, br), 7.32 (10H, m). The H NMR spectrum in CDCl3
revealed the presence of 8a–11a as indicated by the presence of
four methyl singlets at d 3.73, 3.71, 3.82, 3.80 ppm, respectively.
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44 JOURNAL OF CHEMICAL RESEARCH 2008
The phenyl group at C(5) in 8a and 9a was indicated by the presence
of signals at d 5.50 (broad, major) and 5.29 (d, J = 6.4 Hz, minor)
which were assigned to the C(5)Hs in similar cases.40 The C(5)H of
10a appeared at d 4.60 (d, J = 4.6 Hz). The spectrum in toluene-d8
revealed the presence of the corresponding methyl singlets of 8a–11a
free of any overlapping signals at d 3.24, 3.20, 3.32, 3.30 ppm in a
ratio of 73:8:13:6, respectively. The downfield methyl singlets were
attributed to the C(5)CO2Me signals of 10a and 11a, as a result of
their proximity to the ring oxygen.
of moisture. To the nitrone solution was then added BF3.OEt2
(1.0 mmol) and the reaction mixture was heated at 80°C for 12 h.
A similar experiment was carried out using ZnCl2 (1.0 mmol) instead
of BF3.OEt2. After removal of the solvent, the reaction mixture
was taken up in water (10 cm3), basified (K2CO3), and extracted
with CH2Cl2 (3 × 10 cm3). The combined organic layers was dried
(Na2SO4), concentrated and purified by silica gel chromatograpy
using 97:3 CH2Cl2/methanol as eluant to give a mixture of 8c–11c
as a colourless liquid in 60 and 65% yields in BF3.OEt2 and ZnCl2,
respectively, in a ratio of 59:13:15:13 and 58:14:17:11.
A mixture of cycloadducts 8c–11c in a ratio of 58:14:17:11
was reduced with LiAlH4. To a stirred solution of 8c–11c (107 mg,
0.40 mmol) in ether (15 cm3) was added lithium aluminium 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 solution
(0.1 g) and water (0.4 g). The mixture was stirred for 1 h, decanted
and the residue washed with CH2Cl2. The organic layer was dried
(Na2SO4), concentrated, and purified by silica gel chromatography
using a 95:5 CH2Cl2/methanol as the eluant to give a non-separable
mixture of alcohols 8f–11f as a colourless liquid (95%). The 1H NMR
spectrum revealed the presence of 8f–11f in an almost similar ratio of
~58:14:17:11.
Cycloaddition of nitrone 2 with t-butyl cinnamate (7b), and
conversion of cycloadducts 8b–11b into methyl cinnamate adducts
8a–11a: The crude mixture of cycloadducts was purified by
chromatography over silica using hexane/ether as eluant to give a
non-separable mixture of isomers 8b–11b (85%).
Mixture of isomers 8b–11b: 1H NMR analysis of the crude and
purified samples gave similar composition. (Found: C, 71.3; H, 7.2;
N, 3.7. C22H27NO4 requires C, 71.52; H, 7.37; N, 3.79%.) nmax (neat)
3443, 3060, 3031, 2976, 2933, 2882, 1727, 1600, 1493, 1454, 1368,
1
1251, 1154, 1052, 845, 759, and 700 cm-1. The H NMR signals of
the major isomer 8b were as follows: dH (CDCl3) 1.44 (9H, s), 2.50–
3.50 (4H, m), 3.80 (1H, m), 4.10 (1H, m), 4.15 (1H, m), 5.45 (1H,
br), 7.32 (10H, m). The t-butyl proton signals for 8b–1b appeared
in CDCl3 at d 1.44, 1.43, 1.52, 1.47 ppm, respectively in a ratio of
76:7:12:5. The t-butyl singlets were well separated and free of any
competing signals. The C(5) H of 8b and 9b appeared at d 5.45 ppm
(broad, major) and 5.20 (d, J = 6.4 Hz, minor), respectively. As a
result of nitrogen inversion most of the signals were very broad.
The mixture of t-butyl cinnamate adduct 8b–11b in a ratio of
76:7:12:5 (50.0 mg, 0.153 mmol) in 5:1 (w/w) methanol/HCl (1
cm3) was stirred at 20°C for 6 h. After removal of methanol, the
residual liquid was taken up in CH2Cl2 (15 cm3) and washed with
5% K2CO3 (5 cm3). The organic layer was dried (Na2SO4) and
concentrated to give methyl cinnamate adducts 8a–11a as a colourless
liquid (48 mg, 97%). The 1H NMR spectrum as analysed above
revealed isomers 8a–11a (hence 8b–11b) in a ratio of 78:7:10:5,
Cycloaddition of nitrone 2 with t-butyl crotonate (7d), and
conversion of cycloadducts 8d–11d into methyl crotonate adducts
8c–11c: The crude mixture of cycloadducts was purified by
chromatography over silica using hexane/ether as eluant to give
a non-separable mixture of four isomers 8d–11d as a colourless
liquid (252 mg, 82%). (Found: C, 66.3; H, 8.1; N, 4.5. C17H25NO4
requires C, 66.43; H, 8.20; N, 4.56%.) nmax (neat) 3465, 3029, 2975,
2928, 2871, 1727, 1454, 1368, 1247, 1219, 1156, 1089, 1061, 905,
1
845, 760, and 701 cm-1. H NMR analysis of the crude and purified
1
samples gave similar composition. The H NMR signals in CDCl3
were broadened due to nitrogen signals. However in toluene-d8, the
non-overlapping methyl signals of 8d–11d appeared as doublets
at d 1.17 (J = 6.1 Hz), 1.20 (J = 6.4 Hz), 0.86 (J = 6.7 Hz), 0.82
(J = 6.7 Hz) ppm, respectively in a ratio of 53:9:22:16, respectively.
The pair of downfield methyl doublets were attributed to the C(5)
Me of 8d and 9d as a result of their proximity to the ring oxygen in
compare to C(4)Me of 10d and 11d. The t-butyl singlets of 8d–11d
toluene-d8 appeared at d 1.26, 1.25, 1.37, and 1.35 ppm, respectively.
The C(5)H of 8d and 9d in CDCl3 appeared at d 4.48 (m) and 4.20
(m), respectively.
The mixture of t-butyl crotonate adducts 8d–11d (50.0 mg, 0.162
mmol) was converted into methyl crotonate adducts 8c–11c as a
colourless liquid (41 mg, 95%) using the ester exchange reaction.
The NMR spectrum revealed 8c–11c (hence 8d–11d) in a ratio of
55:10:21:17, respectively.
1
respectively. The H NMR spectrum revealed the absence of t-butyl
protons thereby implying complete ester exchange with methanol.
Cycloaddition of nitrone 2 with trans-methyl crotonate (7c) in the
absence and presence of Lewis acid catalysts, and lithium aluminium
hydride reduction of cycloadducts 8c–11c to 8f–11f: The crude
mixture of cycloadducts was purified by chromatography over silica
using CH2Cl2 as eluant to give a non-separable mixture of 8c–10c.
Continued elution gave a mixture of all four isomers followed by
a pure sample of 11c as a colourless liquid. The combined yield of
the cycloadducts was found to be 84%. Careful 1H NMR analysis of
the crude and the separated fraction revealed the ratio of the isomers
8c–11c as 57:9:18:16, respectively. The 1H NMR spectra at 20°C in
toluene-d8 were helpful in the determination of isomeric composition;
the C(5)-methyl protons of 8c and 9c, and C(4)-methyl of 10c and
11c appeared at d 1.13 (d, J = 6.1), 1.16 (d, J = 6.1), 0.83 (d, J = 7.0),
0.78 (d, J = 6.8), while the corresponding CO2Me appeared as singlets
at d3.25, 3.22, 3.30, 3.33 ppm, respectively.
Mixture of isomers 8c–10c: (Found: C, 63.2; H, 7.2; N, 5.2.
C14H19NO4 requires C, 63.38; H, 7.22; N, 5.28%.) nmax (neat) 3453,
3030, 2954, 1739, 1603, 1494, 1453, 1380, 1204, 1062, 912, 846,
761, and 703 cm-1. Careful analysis of the spectra of the mixture 8c–
10c identified the following signals belonging to the major isomer
8c: dH (CDCl3) 1.41 (3H, d, J = 6.2 Hz), 2.75–3.50 (4H, m), 3.71
(3H, s), 3.70–4.10 (3 H, m), 4.54 (1H, m) 7.30 (5H, m). The C(5)-
methyl of 9c and C(4)-methyl of 10c appeared at d 1.44 (d, J = 6.1
Hz) and 1.22 (d, J = 6.8 Hz), respectively, while the corresponding
CO2Me singlet appeared at d 3.69 and 3.80 ppm, respectively. Most
of the signals were broad due to nitrogen inversion. The broad signal
at d 4.54 ppm for C(5)H of 8c became a distinct quintet at –40°C
(J = 6.1 Hz), while the corresponding signal for the minor isomer
9c at d 4.28 also became a distinct quintet (quintet, J = 6.2 Hz). The
spectrum revealed the C(5)H of the isomer 10c as a doublet at d 4.12
ppm (J = 5.3 Hz).
Cycloaddition of nitrone 2 with trans-crotonaldehyde (7e) and
sodium borohydride reduction of cycloadducts 8e–11e to 8f–11f:
The crude mixture of cycloadducts 8e–11e in methanol (5 cm3)
was treated with NaBH4 (200 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 (10 cm3), and extracted
with CH2Cl2 (3 × 15 cm3). The combined organic layers were dried
(Na2SO4), concentrated and the residual liquid was purified by
silica gel chromatography using 95:5 CH2Cl2/methanol as eluant
gave a non-separable mixture of diols 8f–11f as a colourless liquid
1
(90%). The H NMR revealed the presence of 8f–11f in a ratio of
32:26:19:23, respectively.
Cycloaddition of nitrone
2 with trans-crotyl alcohol (7f):
The crude mixture of cycloadducts was purified by chromatography
over silica using 95:5 CH2Cl2/methanol as eluant to give a non-
separable mixture of diols 8f–11f as a colourless liquid (89%).
Mixture of isomers 8f–11f: (Found: C, 65.6; H, 7.9; N, 5.8.
C13H19NO3 requires C, 65.80; H, 8.07; N, 5.90%.) nmax (neat) 3386,
3030, 3060, 2963, 2928, 2873, 1494, 1454, 1411, 1380, 1314, 1212,
1061, 1028, 895, 760 and 702 cm-1; dH (CDCl3) 1.00–1.40 (3H, four
doublets), 1.60–3.40 (5H, m), 3.60–4.10 (6H, m), 7.32 (5H, m).
1H NMR spectrum revealed the presence of the C(5)Me of 8f and
9f, and C(4)Me of 10f and 11f at d 1.35 (d, overlapping), 1.36 (d,
J = 6.1), 1.09 (d, J = 6.8), 1.06 (d, J = 6.4) ppm, respectively,
in a ratio of 38:7:45:10. Adduct 10f and 11f are further characterised
below.
11c: (Found: C, 63.3; H, 7.1; N, 5.3. C14H19NO4 requires C, 63.38;
H, 7.22; N, 5.28%.) nmax (neat) 3500, 3027, 2956, 2875, 1741, 1493,
1453, 1440, 1366, 1277, 1209, 1086, 1057, 1031, 787, 759, and 702
cm-1; dH (CDCl3) 1.20 (3H, d, J = 6.6 Hz), 2.60 (1H, br), 2.83 (1H,
m), 3.06 (1H, m), 3.46 (1H, br, OH), 3.78 (1H, m), 3.82 (3H, s), 3.97
(1H, dd, J = 3.7, 7.5 Hz), 4.09 (1H, br), 4.18 (1H, dd, J = 7.5, 11.3
Hz), 7.32 (5H, m).
The above reaction was repeated in the absence of MgSO4 using
hydroxylamine 6 (1.0 mmol) in toluene (10 cm3). The resultant
nitrone solution was concentrated to a volume of 5 cm3 by blowing
a gentle stream of N2 at 60°C. This was done to ensure the removal
Cycloaddition of nitrone 2 with trans-methyl g-hydroxycrotonate
(7g), and lithium aluminium hydride reduction of cycloadducts 8g–
11g to 8i and 9i: The crude mixture of cycloadducts was purified by
chromatography over silica using 95:5 CH2Cl2/methanol as eluant
to give a non-separable mixture of adducts 8g–11g as a colourless
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JOURNAL OF CHEMICAL RESEARCH 2008 45
liquid (79%) in a ratio of 50:13:30:7, respectively, as determined
by 1H NMR integration or peak height of the CO2Me singlets which
appeared at d 3.70 (for 9g), 3.72 (for 8g), 3.82 (for 11g), and 3.88
(for 10g). The pair of downfield singlets were assigned to the
C(5)CO2Me of 10g and 11g as a result of their proximity to the
ring oxygen.
Mixture of isomers 8g–11g: (Found: C, 59.6; H, 6.6; N, 4.8.
C14H19NO5 requires C, 59.78; H, 6.81; N, 4.98%.) nmax (neat) 3391,
3060, 3025, 2952, 2877, 1734, 1729, 1494, 1453, 1431, 1355, 1209,
1058, 761 and 703 cm-1; dH (CDCl3) 1.70–2.30 (2H, broad), 2.50–
3.50 (5H, m), 3.60–4.60 (9H, m including the four CO2Me singlets),
7.32 (5H, m).
Using the procedure as described, the above mixture of isomers
8g–11g in a ratio of 50:13:30:7 was reduced with LiAlH4. Because
of the presence of three polar hydroxy groups, the lithium salts
were extensively washed with CH2Cl2/MeOH (90:10) to ensure
the extraction of the triols into the organic layer. The product was
purified by silica gel chromatography using 95:5 CH2Cl2/MeOH as
eluant to give a mixture of 8i and 9i as a colourless liquid(70%) in a
~78:22 ratio.
Cycloaddition of nitrone 2 to dimethyl fumarate (7h), and lithium
aluminium hydride reduction of cycloadducts 8h, 9h to 8i, 9i:
The crude mixture of cycloadducts was separated by chromatography
over silica using 98:2 dichloromethane/ether as eluant to give
8h followed by 9h as colourless liquid in a total yield of 91%.
Spectroscopic analysis of the crude as well as the isolated yields
revealed the presence of the 8h and 9h in a ratio of 70:30,
respectively.
8h: (Found: C, 58.0; H, 6.0; N, 4.5. C15H19NO6 requires C, 58.25;
H, 6.19; N, 4.53%.) nmax (neat) 3500, 3055, 3026, 3002, 2954, 2886,
2847, 1738, 1494, 1437, 1376, 1222, 1087, 1061, 1024, 937, 761,
733, and 703 cm-1; dH (CDCl3) 2.65 (1H, m), 3.20 (1H, m), 3.37 (1H,
t, J = 9.0 Hz), 3.73 (3H, s), 3.83 (3H, s), 3.65–4.05 (4H, m), 4.99
(1H, d, J = 4.0 Hz), 7.30 (5H, m); dC (CDCl3) 50.7, 52.6, 52.7, 56.6,
66.7, 71.8, 76.9, 128.1 (2C), 128.3, 128.6 (2C), 137.9, 171.5, 171.6.
9h: (Found: C, 58.3; H, 6.1; N, 4.4. C15H19NO6 requires C, 58.25;
H, 6.19; N, 4.53%.) nmax (neat) 3473, 3055, 3026, 2997, 2954, 2857,
1741, 1494, 1437, 1381, 1219, 1060, 932, 856, 761, 734, and 703 cm-1;
dH (CDCl3) 2.5–3.5 (3H, m), 3.71 (3H, s), 3.82 (3H, s), 3.65–4.0 (3H,
m), 4.15 (1H, m), 4.89 (1H, m), 7.33 (5H, m). dC (CDCl3) 50.6, 52.6,
52.7, 55.1, 65.8, 70.9, 76.7, 128.2, 128.5, 136.0, 171.0, 171.5.
Using the procedure as described above, 8h (421 mg, 1.36 mmol)
was reduced with LiAlH4. Because of the presence of three polar
hydroxy groups, the lithium salts were extensively washed with
CH2Cl2/MeOH (90:10) to ensure the extraction of the triols into the
organic layer. The product was purified by silica gel chromatography
using 95:5 CH2Cl2/MeOH as eluant to give 8i as a colourless liquid
(215 mg, 62%).
8i: (Found: C, 61.4; H, 7.5; N, 5.4. C13H19NO4 requires C, 61.64;
H, 7.56; N, 5.53%.) nmax (neat) 3355, 3031, 3007, 2927, 2876, 1452,
1420, 1386, 1218, 1061, 923, 875, 756, and 703 cm-1; dH(CDCl3)
2.10–3.45 (6H, m), 3.50–3.85 (m, 6H), 4.05 (1H, dd, J = 6.9, 11.5
Hz), 4.10 (1H, m), 7.31 (5H, m); dC (CDCl3) 46.7, 58.0, 63.2, 64.6,
67.9, 73.7, 81.3, 128.1, 128.3 (2C), 128.7 (2C), 137.7.
Using the procedure as described above, 9h (250 mg, 0.81 mmol)
was reduced with LiAlH4. Because of the presence of three polar
hydroxy groups, the lithium salts were extensively washed with
CH2Cl2/MeOH (90:10) to ensure the extraction of the triols into the
organic layer. The product was purified by silica gel chromatography
using 95:5 CH2Cl2/MeOH as eluant to give 9i as a colourless liquid
(125 mg, 61%).
adducts 8j–11j (89%) as a colourless liquid. Spectroscopic analysis
of the crude as well as the purified adducts revealed the presence of
the 8j–11j in a ratio of 56:24:13:7, respectively, as determined by
integration and peak heights of several proton signals (belonging to
SitBuMe2) of the crude as well as purified adducts.
Mixture of isomers 8j–11j: (Found: C, 61.8; H, 8.8; N, 3.6.
C19H33NO4Si requires C, 62.09; H, 9.05; N, 3.81%.) dH (CDCl3)
~0.035 (6H, singlets), ~0.9 (9H, singlets), 2.25–3.25 (4 H, m),
3.50–4.15 (9H, m), 7.31 (5 H, m). The Me2Si protons appeared at
d 0.032 (s) for 8j; d 0.017 (s) and 0.024 (s) for 9j; d 0.114 (s) for
10j; d 0.108 (s) for 11j. The C(5)H of 8j appeared around 4.07.
The t-buytl Si protons appeared at d 0.87 (s) for 8j; d 0.855 (s) for
9j; d 0.917 (s) for 10j and 11j. The downfield singlets of tBuSi and
Me2Si were assigned to 10j and 11j as a result of their proximity to
the ring oxygen. Compound 9j is further analysed below.
To a solution of the above mixture of isomers 8j–11j in a ratio
of 56:24:13:7 (70 mg), in methanol (2 cm3) was added 300 mg of
a 3:1 (w/w) MeOH/HCl mixture. The reaction mixture was stirred
at 20°C for 20 min. After removal of the solvent by a gentle stream
of N2, the residual liquid was taken up in a saturated K2CO3 solution
(1 cm3) and extracted with CH2Cl2 (3 × 5 cm3). The organic layer
was dried (Na2SO4), concentrated to give the triols 8i and 9i in an
almost quantitative yield in a ratio of 70:30, respectively, as analysed
above.
Cycloaddition of nitrone 2 to trans-1,4-di-tbutyldimethylsiloxybut-
2-ene (7k), and conversion of cycloadduct 8k to 8i: The crude
mixture of cycloadducts was purified by chromatography over silica
using 5:1 hexane/ether as eluant to give 8k followed by a mixture
of 8k/9k and finally 9k as colourless liquids in a total yield of 73%.
Spectroscopic analysis of the crude as well as separated fractions
revealed the presence of the 8k and 9k in a ratio of 75:25, as
determined by integration and peak heights of several proton signals
of the crude as well as separated fractions.
Major isomer 8k: (Found: C, 62.0; H, 9.6; N, 2.8. C25H47NO4Si2
requires C, 62.32; H, 9.83; N, 2.91%.) nmax (neat) 3543, 3063, 3031,
2953, 2887, 2857, 1469, 1389, 1361, 1254, 1098, 1006, 938, 840,
778, and 702 cm-1; dH (CDCl3) 0.022 (6H, s), 0.092 (6H, s), 0.87
(9H, s), 0.91 (9H, s), 1.67 (1H, br OH), 2.36 (2H, m), 3.03 (1H, m),
3.50–3.85 (7H, m), 4.03 (1H, m), 4.07 (1H, dd, J = 7.8, 11.5 Hz),
7.30 (5H, m).
Minor isomer 9k: (Found: C, 62.4; H, 9.9; N, 2.8. C25H47NO4Si2
requires C, 62.32; H, 9.83; N, 2.91%.) nmax (neat) 3500, 3064, 3031,
2929, 2857, 1468, 1388, 1362, 1255, 1097, 1007, 938, 838, 778, and
702 cm-1; dH (CDCl3) 0.00 (3H, s), 0.003 (3H, s), 0.084 (3H, s), 0.094
(3H, s), 0.86 (9H, s), 0.91 (9H, s), 2.49 (1 H, m), 2.60 (1 H, m), 2.76
(1 H, m), 3.61 (2 H, m), 3.71 (2 H, m), 3.79 (2 H, m), 3.90 (1 H, m),
4.06 (1H, dd, J = 7.3, 11.3 Hz), 7.30 (5H, m).
The cycloadduct 8k was hydrolysed in methanolic HCl as above to
obtain the alcohol 8i in an almost quantitative yield.
Cycloaddition of nitrone 2 with dimethyl maleate (12a), and
lithium aluminium hydride reduction of cycloadducts 13a and 14a
to 13b and 14b: The crude mixture of cycloadducts was purified by
chromatography over silica using 98:2 dichloromethane/ether as
eluant to give 13a followed by a mixture of 13a/14a and finally 14a
as colourless liquids in a total yield of 90%. Spectroscopic analysis
of the crude as well as the separated fractions revealed the presence
of the 13a and 14a in a ratio of 40:60 as determined by integration of
the C5(H) signals at d 4.90 (minor) and 4.75 (major) ppm as well as
by peak heights of the CO2Me singlets.
Minor isomer 13a: (Found: C, 58.1; H, 6.2; N, 4.4. C15H19NO6
requires C, 58.25; H, 6.19; N, 4.53%.) nmax (neat) 3474, 3031, 3002,
2953, 2881, 1743, 1494, 1437, 1349, 1290, 1214, 1065, 940, 822,
761, and 703 cm-1; dH (CDCl3) 2.98 (2H, m), 3.35 (1H, m), 3.68 (3H,
s), 3.77 (3H, s), 3.82 (2H, m), 3.96 (2H, m), 4.90 (1H, d, J = 9.5
Hz), 7.34 (5H, m); dC (CDCl3) 49.8, 52.3, 52.4, 55.4, 66.6, 71.7, 76.7,
128.1 (2C), 128.2, 128.7 (2C), 137.8, 169.6, 170.2.
Major isomer 14a: (Found: C, 58.3; H, 6.3; N, 4.5. C15H19NO6
requires C, 58.25; H, 6.19; N, 4.53%.) nmax (neat) 3474, 3031, 3002,
2953, 2886, 1743, 1494, 1438, 1353, 1290, 1214, 1059, 942, 763 and
704 cm-1; dH (CDCl3) 2.70–3.25 (3H, m), 3.63 (1H, m), 3.67 (3H, s),
3.77 (3H, s), 3.81 (1H, m), 4.02 (1H, dd, J = 4.2, 7.0 Hz), 4.11 (1H,
m), 4.75 (1H, d, J = 8.8 Hz), 7.33 (5H, m); dC (CDCl3) 50.0, 52.3,
52.4, 55.8, 66.2, 73.1, 76.9, 128.3 (2C), 128.7 (3C), 137.1, 169.6,
170.2.
13a (166 mg, 0.536 mmol) was reduced with LiAlH4. Because of
the presence of three polar hydroxy groups, the lithium salts were
extensively washed with CH2Cl2/MeOH (90:10) to ensure the
extraction of the triols into the organic layer. The product was purified
by silica gel chromatography using 95:5 CH2Cl2/MeOH as eluant to
9i: (Found: C, 61.5; H, 7.4; N, 5.4. C13H19NO4 requires C, 61.64;
H, 7.56; N, 5.53%.) nmax (neat) 3354, 3031, 3002, 2927, 2876, 1492,
1452, 1386, 1352, 1218, 1032, 889, 757 and 702 cm-1; dH (CDCl3)
2.50–3.30 (6H, m), 3.50–3.85 (m, 6H), 3.98 (1H, m), 4.07 (1H, m),
7.31 (5H, m); dC (CDCl3) 45.8, 57.3, 63.2, 63.6, 67.8, 73.7, 83.0,
128.0, 128.2 (2C), 128.8 (2C), 137.8.
Cycloaddition of nitrone
2 to trans-but-2-ene-1,4-diol (7i):
The crude mixture of cycloadducts was purified by chromatography
over silica using 95:5 CH2Cl2/MeOH as eluant to give a non-
separable mixture 8i and 9i as a colourless liquid (92%). Careful
analysis of the 1H and 13C spectra (Section 3.2.8) (signals at d 83.01
for 9i versus and 81.34 ppm for 8i, as well as 45.81 for 9i versus
and 46.70 ppm for 8i) revealed the presence of the 8i and 9i in an
approximate ratio of 80:20.
Cycloaddition of nitrone 2 to trans-4-t-butyldimethylsiloxy-2-
butene-1-ol (7j), and conversion of cycloadducts 8j–11j into 8i, 9i:
The crude mixture of cycloadducts was purified by chromatography
over silica using 98:2 CHCl3/MeOH as eluant to give a mixture
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46 JOURNAL OF CHEMICAL RESEARCH 2008
give 13b as a colourless liquid (95 mg, 70%). 13b: (Found: C, 61.4;
H, 7.3; N, 5.4. C13H19NO4 requires C, 61.64; H, 7.56; N, 5.53%.)
nmax (neat) 3330, 3031, 2934, 2881, 1603, 1492, 1453, 1415, 1386,
1218, 1046, 856, 758 and 703 cm-1; dH(CDCl3) 2.93 (3H, m), 3.10–
4.00 (9H, m), 4.04 (1H, dd, J = 6.4, 11.6 Hz), 4.42 (1H, br), 7.32 (5H,
m); dC(CDCl3) 45.1, 56.0, 60.3, 61.1, 67.3, 72.0, 78.9, 128.2 (2C),
128.3, 128.8 (2C), 137.7.
14a (233 mg, 0.75 mmol) was reduced with LiAlH4. The product
was purified by silica gel chromatography using 95:5 CH2Cl2/MeOH
as eluant to give 14b as a colourless liquid (145 mg, 76%).
14b: (Found: C, 61.5; H, 7.4; N, 5.3. C13H19NO4 requires C, 61.64;
H, 7.56; N, 5.53%.) nmax (neat) 3355, 3026, 3002, 2934, 2876, 1602,
1497, 1453, 1420, 1391, 1218, 1045, 893, 851, 756, and 702 cm-1;
dH (CDCl3) 2.10–3.5 (6H, m), 3.60–3.95 (6H, m), 4.08 (1H, dd,
J = 8.0, 12.5 Hz), 4.22 (1H, br), 7.32 (5H. m); dc (CDCl3) 45.7, 57.3,
60.31 (2C), 67.6, 74.1, 79.3, 128.3 (2C), 128.7 (3C), 137.6.
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 evaporation along with CH2Cl2. Then MgBr2 (184 mg,
1.0 mmol) was added to the solution. After stirring the resulting
suspension under N2 was stirred at 20°C for 15 min, crotyl alcohol
7f (1.1 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. After the elapsed time,
the reaction mixture was cooled to room temperature and was taken
up in 10% K2CO3 (10 cm3) and extracted with CH2Cl2 (3 × 20 cm3).
The combined organic layers was dried (Na2SO4), concentrated, and
purified by silica gel chromatography using CH2Cl2/MeOH (95:5)
as eluent to give a non-separable mixture of alcohols 10f and 11f as a
colourless liquid (222 mg, 96%). The 1H NMR spectrum revealed the
presence of 10f and 11f in a ratio of 9:91, respectively, as determined
by integration of the C(5)Me doublets.
Mixture of 9:91 10f/11f: (Found: C, 65.6; H, 7.8; N, 5.8. C13H19NO3
requires C, 65.80; H, 8.07; N, 5.90%.) nmax (neat) 3387, 3030, 3060,
2963, 2928, 2873, 1494, 1453, 1381, 1222, 1060, 1028, 898, 844,
761, and 702 cm-1; dH(CDCl3) 1.06 (3H, d, J 6.4), 2.30–3.30 (5H, m),
3.55–3.98 (5H, m), 4.10 (1H, m), 7.32 (5H, m). The minor C(5)Me
doublets of the minor isomer 10f appeared at d 1.09.
Cycloaddition of nitrone 2 to trans-methyl g-hydroxycrotonate
(7g) in the presence of MgBr2, and lithium aluminium hydride
reduction of cycloadducts 8g and 9g to 8i and 9i: As described
above, the addition reaction was carried out using trans-methyl
g-hydroxycrotonate (7g) instead of 7f at 65°C for 48 h. After usual
work up, the residual liquid was purified by chromatography over silica
using 95:5 CH2Cl2/MeOH as eluant to give a non-separable mixture
of alcohols 8g and 9g as a colourless liquid (76%). The 1H NMR
spectrum revealed the presence of 8g and 9g in a ratio of 19:81,
respectively, as determined by integration of the C(5)CO2Me singlets.
The NMR spectra of the crude as well as purified mixture failed to
detect the presence of regioisomers 10g and 11g. The C(5)H of the
isomers 8g and 9g appeared at d4.59 and 4.37, respectively, as broad
signals due to nitrogen inversion.
Mixture of 19:81 8g/9g: (Found: C, 59.9; H, 6.9; N, 4.8. C14H19NO5
requires C, 59.78; H, 6.81; N, 4.98%.) nmax (neat) 3379, 3081, 3060,
3025, 2952, 2877, 1736, 1731, 1494, 1453, 1431, 1355, 1207, 1176,
1055, 962, 890, 849, 788, 761 and 702 cm-1. Signals attributed to the
major isomer 9g: dH (CDCl3) 2.50–3.50 (5H, m), 3.60–4.10 (5H, m),
3.70 (3H, s), 4.37 (1H, m), 7.32 (5H, m).
The mixture of isomers 8g and 9g in a ratio of 19:81 upon LAH
reduction gave triols 8i and 9i as a colourless liquid(73%) in a
~20:80 ratio.
Cycloaddition of nitrone 2 to trans-2-butene-1,4-diol (7i) in the
presence of MgBr2: The addition reaction was carried out using trans-
but-2-ene-1,4-diol (7i) instead of 7f at 65°C for 36 h. After usual
work up (using saturated K2CO3) the residual liquid was purified by
chromatography to give adducts 8i and 9i (74%). Careful analysis of
the 1H and 13C spectra revealed the presence of the 8i and 9i in a ratio
of 6:94, respectively.
Cycloaddition of nitrone 2 with trans-4-t-butyldimethylsiloxybut-
2-ene-1-ol (7j) in the presence of MgBr2, and conversion of
9j to 9i: The addition reaction was carried out using trans-4-
t-butyldimethylsiloxybut-2-ene-1-ol (7j) instead of 7f at 65°C
for 36 h. After usual work up the residual liquid was purified by
chromatography to give adducts 8j and 9j (88%) as a colourless
liquid. Spectroscopic analysis of adducts revealed the presence of the
8j and 9j in an approximate ratio of 4:96, respectively.
Cycloaddition of nitrone 7 with cis-but-2-ene-1,4-diol (12b):
The crude mixture of cycloadducts was purified by chromatography
over silica using 95:5 CH2Cl2/MeOH as eluant to give a non-separable
mixture 13b and 14b as a colourless liquid (93%). Careful 1H (several
proton signals) and 13C (signals at d 78.89 for 13b versus 79.31 ppm
for 14b) spectroscopic analysis of adducts revealed the presence of
the 13b and 14b in an approximate ratio of 48:52, respectively. The
C(5)H of 13b and 14b appeared at d4.42 and 4.22 ppm, respectively.
Cycloaddition of nitrone 2 with cis-4-t-butyldimethylsiloxybut-2-
ene-1-ol (12c), conversion of cycloadducts 13c–16c to 13b and 14b:
The crude mixture of cycloadducts was purified by chromatography
over silica using 98:2 CHCl3/MeOH as eluant to give a non-separable
mixture adducts 13c–16c (92%) as a colourless liquid. Spectroscopic
analysis of the crude as well as the separated fractions revealed
the presence of 13c–16c in a ratio of 55:23:15:7, respectively, as
determined by integration and peak heights of several proton signals
(belonging to SitBuMe2) of the crude as well as separated fractions.
Mixture of isomers 13c–16c: (Found: C, 61.8; H, 8.8; N, 3.6.
C19H33NO4Si requires C, 62.09; H, 9.05; N, 3.81%); dH (CDCl3)
~0.04 (6H, singlets), ~0.85 (9H, singlets), 2.60–3.30 (4 H, m), 3.50–
4.50 (9H, m), 7.31 (5 H, m). The Me2Si protons appeared at d0.035
(s) and 0.043 (s) for 13c; d0.047 (s) and 0.051 (s) for 14c; d0.13 (s)
t
for 15c; d0.14 (s) for 16c. The BuSi protons appeared at d0.86 (s)
for 13c; d0.87 (s) for 14c; d0.915 (s) for 15c; d0.923 (s) for 16c.
The downfield singlets were assigned to the tBuSi and Me2Si of 15c
and 16c as a result of their proximity to the ring oxygen.
The above mixture of isomers 13c–16c in a ratio of 55:23:15:7
was hydrolysed as described above to give triols 13b and 14b in
an almost quantitative yield in a ratio of ~70:30, respectively, as
analysed above.
Cycloaddition of nitrone 2 with cis-1,4-di-t-butyldimethylsiloxybut-
2-ene (12d), and conversion of cycloadduct 13d to 13b: The crude
mixture of cycloadducts was purified by chromatography over silica
using 4:1 hexane/ether as eluant to give 13d followed by a mixture
of 13d/14d and finally 14d as colourless liquids in a total yield of
89%. Spectroscopic analysis of the crude as well as the separated
fractions revealed the presence of the 13d and 14d in a ratio of 72:28,
respectively, as determined by integration and peak heights of several
proton signals of the crude as well as separated fractions.
Major isomer 13d: (Found: C, 61.9; H, 9.6; N, 2.7. C25H47NO4Si2
requires C, 62.32; H, 9.83; N, 2.91%.) nmax (neat) 3533, 3063, 3031,
2932, 2859, 1465, 1393, 1361, 1254, 1095, 939, 840, 777, and 701
cm-1; dH (CDCl3) 0.0079 (6H, s), 0.085 (6H, s), 0.85 (9H, s), 0.91
(9H, s), 2.78 (1H, m), 2.87 (2H, m), 3.52 (1H, m), 3.66 (1H, m), 3.73
(1H, m), 3.76 (1H, m), 3.87 (1H, m), 3.92 (1H, d, J = 5.5 Hz), 4.12
(1H, dd, J = 7.9, 11.6 Hz), 4.41 (1H, m), 7.30 (5H, m).
Minor isomer 14d: (Found: C, 62.0; H, 9.6; N, 2.8. C25H47NO4Si2
requires C, 62.32; H, 9.83; N, 2.91%.) nmax (neat) 3545, 3063, 3031,
2930, 2886, 2857, 1468, 1391, 1361, 1255, 1093, 1007, 938, 908, 838,
777, and 701 cm-1; dH (CDCl3) 0.00 (6H, s), 0.084 (3H, s), 0.095 (3H,
s), 0.85 (9H, s), 0.91 (9H, s), 2.75(1H, m), 3.07 (1H, t, J = 8.2 Hz),
3.25 (1H, m), 3.60 (1H, dd, J = 6.9, 10.2 Hz), 3.65–3.90 (5H, m),
4.10 (1H, dd, J = 7.7, 11.3 Hz), 4.17 (1H, m), 7.30 (5H, m).
As described above, adduct 13d was hydrolysed by MeOH/HCl
to give the triol 13b in almost quantitative yield. The spectroscopic
analysis revealed that the alcohol 13b obtained from 13d matches
with the stereochemistry of the alcohol 13b obtained from LiAlH4
reduction of 13a.
9j: (Found: C, 61.7; H, 8.8; N, 3.7. C19H33NO4Si requires C,
62.09; H, 9.05; N, 3.81%.) nmax (neat) 3376, 3063, 3031, 2954, 2857,
1493, 1469, 1389, 1361, 1255, 1092, 938, 838, 777, and 702 cm-1;
dH (CDCl3) 0.018 (3H, s), 0.026 (3H, s), 0.86 (9H, s), 2.5–3.1 (5H,
m), 3.5–3.85 (6H, m), 3.95 (1H, m), 4.04 (1H, dd, J = 7.6, 10.7 Hz),
7.30 (5H, m). The singlet at d0.87 indicated the presence of the minor
adduct 8j.
The cycloadduct 9j (containing about 4% of the minor isomer 8j)
was hydrolysed in methanolic HCl to obtain alcohol 9i (containing
minor amount of 8i) in an almost quantitative yield.
Cycloaddition of nitrone 2 to dimethyl maleate (12a) in the presence
of MgBr2: The addition reaction was carried out using dimethyl
maleate (12a) instead of 7f at 65°C for 36 h. After usual work up the
residual liquid was purified by chromatography to give adducts 13a
and 14a as a colourless liquid (150 mg, 45%). Spectroscopic analysis
of the crude as well as the purified adducts revealed the presence of
the 13a and 14a in a ratio of 53:47.
Cycloaddition of nitrone 2 in the presence of MgBr2
Cycloaddition of nitrone 2 to trans-crotyl alcohol (7f) in the presence
of MgBr2: To a solution of hydroxylamine 6 (153 mg, 1.0 mmol) in
dichloromethane (20 cm3), was added paraformaldehyde (34 mg,
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JOURNAL OF CHEMICAL RESEARCH 2008 47
3
4
5
S. Kanemasa, Synlett, 2002, 1371.
Cycloaddition of nitrone 2 with cis-but-2-ene-1,4-diol (12b)
in the presence of MgBr2: The addition reaction was carried out
using cis-but-2-ene-1,4-diol (12b) instead of 7f at 65°C for 36 h.
After usual work up (using K2CO3) the residual liquid was purified by
chromatography to give adducts 13b and 14b (182 mg, 72%). Careful
X. Ding, K. Taniguchi, Y. Ukaji and K. Inomata, Chem. Lett., 2001, 468.
W.S. Jen, J.J.M. Wiener and D.W.C. MacMillan, J. Am. Chem. Soc., 2000,
122, 9874.
K.V. Gothelf and K.A. Jorgensen, Chem. Commun., 2000, 1449.
G. Zecchi and G. Broggini, Synthesis, 1999, 905.
H. Pellissier, Tetrahedron, 2007, 63, 3235.
6
7
8
9
1
analysis of H (several proton signals) and 13C spectra revealed the
presence of 13b and 14b in an approximate ratio of 20:80.
S. Karlsson and H. –E. Högberg, Org. Prep. Proc. Int., 2001, 33, 103.
Cycloaddition of nitrone 2 to cis-4-t-butyldimethylsiloxybut-2-ene-
1-ol (12c) in the presence of MgBr2 and conversion of cycloadducts
13c and 14c to 13b and 14b: The addition reaction was carried out
using cis-4-tbutyldimethylsiloxybut-2-ene-1-ol (12c) instead of 7f at
65°C for 48 h. After usual work up the residual liquid was purified by
chromatography to give adducts 13c and 14c (84%) as a colourless
liquid. Spectroscopic analysis of adducts revealed the presence of the
13c and 14c in an approximate ratio of 20:80, respectively.
Mixture of 20:80 13c/14c: (Found: C, 61.8; H, 9.0; N, 3.6.
C19H33NO4Si requires C, 62.09; H, 9.05; N, 3.81%.) nmax (neat) 3391,
3061, 3031, 2930, 2858, 1492, 1468, 1392, 1361, 1255, 1092, 939,
839, 777, 737, and 702 cm-1; dH(CDCl3) 0.038 (0.20 × 3H, s, minor),
0.045(0.20 × 3H, s, minor), 0.051 (0.80 × 3H, s, major), 0.054 (0.80 ×
3H, s, major), 0.86 (0.20 × 9H, s, minor), 0.88(0.80 × 9H, s, major),
1.70 (1H, m), 2.55-3.15 (3H, m), 3.50-3.80 (7H, m), 4.07 (1H, m), 4.24
(0.80 × 1H, m, major), 4.43 (0.20 × 1H, m, minor), 7.32 (5H, m).
A portion of the above mixture of cycloadducts 13c and 14c in a
ratio of 20:80, respectively, was hydrolysed in methanolic HCl to
obtain a mixture of alcohols 13b and 14b in a ratio of ~20:80 in an
almost quantitative yield.
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Cycloaddition of nitrone 2 to cis-1,4-di-t-butyldimethylsiloxybut-
2-ene (12d) in the presence of MgBr2: The addition reaction was
carried out using cis-1,4-di-tbutyldimethylsiloxybut-2-ene (12d)
instead of 7f at 65°C for 48 h. After usual work up the residual liquid
was purified to give adducts 13d and 14d (40 mg, 8.3%) in a ratio of
9:1. As determined by careful analysis of the 1H NMR spectra.
The facilities provided by the King Fahd University of
Petroleum and Minerals, Dhahran, are gratefully acknowledged.
We thank Mr. M. Arab for recording NMR spectra.
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Received 13 November 2007; accepted 26 Janaury 2008
Paper 07/4939
doi: 10.3184/030823408X287087
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2
PAPER: 07/4939