A torquoselective extrusion of isoxazoline N-oxides. Application to the synthesis of aryl vinyl and divinyl ketones for Nazarov cyclization

Article abstract of DOI:10.1016/j.tet.2008.10.003

A mild, convenient reaction sequence for the synthesis of Nazarov cyclization substrates is described. The [3+2] dipolar cycloaddition of a nitrone and an electron-deficient alkyne gives an isolable isoxazoline intermediate, which upon oxidation undergoes stereoselective extrusion of nitrosomethane to give aryl vinyl or divinyl ketones.

Full text of DOI:10.1016/j.tet.2008.10.003

Tetrahedron 65 (2009) 3165–3179
Contents lists available at ScienceDirect
Tetrahedron
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A torquoselective extrusion of isoxazoline N-oxides. Application to the
synthesis of aryl vinyl and divinyl ketones for Nazarov cyclization
,
Daniel P. Canterbury a, Ildiko R. Herrick a, Joann Um b, K.N. Houk b, Alison J. Frontier a
*
a Department of Chemistry, University of Rochester, Rochester, NY 14627, United States
b Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 August 2008
Received in revised form 1 October 2008
Accepted 2 October 2008
Available online 10 October 2008
A mild, convenient reaction sequence for the synthesis of Nazarov cyclization substrates is described. The
[3þ2] dipolar cycloaddition of a nitrone and an electron-deficient alkyne gives an isolable isoxazoline
intermediate, which upon oxidation undergoes stereoselective extrusion of nitrosomethane to give aryl
vinyl or divinyl ketones.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Upon treatment with m-CPBA, the ring nitrogen of isoxazoline 1
is thought to undergo oxidation to give intermediate 2, which
One of the most important factors determining synthetic utility
of Nazarov cyclization is the efficiency of divinyl ketone prepara-
tion. A number of specific methods have been developed for their
synthesis, depending on the vinyl substitution pattern desired.1–5
For the preparation of substrates with electron-withdrawing
groups such as those employed in Lewis acid-catalyzed Nazarov
cyclizations of polarized substrates,6 Knoevenagel condensation
has been the only option.7 Disadvantages of the procedure include:
cannot be isolated or even observed by NMR spectroscopy. Instead,
immediate extrusion of nitrosomethane from putative N-oxide 2
occurs at low temperature to give 3 with surprisingly high ster-
eoselectivity. The yields were good in the reported cases, although
the scope was limited. This sequence provided us with a useful
starting point to solve the problems associated with the prepara-
tion of Nazarov substrates.
This paper describes a mild and versatile [3þ2] cycloaddition/
nitrosomethane extrusion process for the synthesis of divinyl ke-
tones for Nazarov cyclization. The reaction sequence is shown in
Scheme 2: cycloaddition of a nitrone and an electron-deficient al-
kyne gives a stable isoxazoline 5 (see Scheme 1). Oxidation leads to
extrusion of nitrosomethane at low temperature to give a Nazarov
precursor of type 6.
the requirement for a b-ketoester precursor, which can be quite
difficult to prepare efficiently; reaction conditions involving high
temperatures; long reaction times; and either acidic or basic pH, all
of which can destroy sensitive functionality. Because the conden-
sation is thermodynamically controlled, mixtures of diastereomers
are obtained. Finally, it can be difficult to prevent the divinyl ketone
from undergoing premature Nazarov cyclization during acid-cata-
lyzed Knoevenagel condensation.
H3C
O
H
CH3
N
An unusual reaction was reported by Padwa in 1987, in which
N
4-isoxazolines
1
underwent oxidative extrusion of nitroso-
R2
D
EWG
+
Δ
O
methane to give a-b
-unsaturated ketones 3 (Scheme 1).8
R1
EWG
5
R1
R2
CH3
N
O-
N+
H3C
O
4
R3
m-CPBA
R2
R3
[O]
-H3CN=O
R1=aryl, alkenyl
R3
R2
O
O
R1
O
O
R1
R2
CH3
N
R1
EWG
R2
EWG
and/or
1
2
3
O
R2
6a "in"
Scheme 1. Padwa’s oxidation of
D
4-isoxazolines.
6b "out"
Scheme 2. [3þ2]/[O] sequence for synthesis of Nazarov substrates.
The reaction sequence has not only proven to be an efficient and
stereoselective method for the synthesis of Nazarov cyclization
* Corresponding author. Tel.: þ1 585 275 2568; fax: þ1 585 276 0205.
E-mail address: frontier@chem.rochester.edu (A.J. Frontier).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.003

3166
D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
Table 2
precursors, but the unexpected stereoselectivities observed have
also raised interesting questions about the factors controlling the
‘cheletropic’ fragmentation of oxidized isoxazolines like 2. Chele-
tropic extrusions are a class of retro-cycloaddition reactions in
which two sigma bonds flanking a single atom of a ring system are
broken during a concerted bond reorganization.9 Two examples of
cheletropic extrusions of (4nþ2) systems that give stereochemistry
consistent with Woodward–Hoffmann theory are shown in Eqs. 1
and 2.
Synthesis of alkynes bearing different electron-withdrawing groups
O
EWG
TIPSO
TIPSO
TIPSO
A or B
CH3
a
9a-f
8
OTIPS
OTIPS
OTIPS
Entry
1
Electrophile
Conditions
Product
Yield (%)
98
O
Na2N2O3
O
A
CH3
H3C
H3C
(1)
dil. HCl, Δ
N
H
H3C
OCH3
9a
Cl
OCH3
N(CH3)2
OEt
+ N2
O
O
2
3
4
5
A
77
95
74
83
Na2N2O3
N(CH3)2
Cl
9b
CH3
H3C
CH3
H3C
dil. HCl, Δ
(2)
N
H
+ N2
O
O
Extrusion can occur in either an inward or an outward di-
rection,10 and for unsymmetric substrates two diastereomeric
products can be obtained. If one of these senses of rotation is fa-
vored over the other, the reaction is termed ‘torquoselective,’ as
defined by Houk. Typically, the sense of rotation is controlled by
stereoelectronic effects rather than steric effects, and the stereo-
chemical outcome of many torquoselective reactions, including
OEt
A
A
B
P
P
Cl
OEt
OEt
9c
N
N
N
9d
CN
Nazarov cyclizations, sigmatropic shifts, electrocyclic ring openings
11,12
and closures, and the Cope rearrangement,
can be predicted
using Houk’s theoretical model.11 An alternative theory, proposing
a role for geminal bonds in the torquoselectivity of retro-electro-
cyclizations, has also been proposed.11f,13 As will be discussed, the
stereochemistry observed in the oxidation/extrusion sequences
could not be rationalized using conventional methods, but
CH3
CH3
O
NaO
S
O
S
O
9e
O
Table 1
Preparation of alkynoates
6
A
–Cl 9f
61
N
Cl
Entry
1
Substrate
Conditions
A
Product
Yield (%)
O
O
Reaction conditions: (a) i. LDA, THF, ꢀ78 ꢁC; ii. ClP(O)(OEt)2, ꢀ78 to 23 ꢁC; iii. LDA,
O
THF, ꢀ78 to 23 ꢁC. (A) n-BuLi, electrophile, THF, ꢀ78 ꢁC. (B) i. CAN, NaI, p-tolSO2Na,
7a
4a 89
OEt
O
CH3CN; ii. K2CO3, acetone, D.
H
O
O
computational studies led to new mechanistic proposals to explain
the torquoselective extrusion.
O
O
O
O
H
O
OEt
2
3
4
7b
7c
7d
A
A
B
4b 63
4c 78
4d 58
O
2. Results
A majority of the acetylenic esters were prepared from the
corresponding aldehydes via Corey–Fuchs14 protocol, followed by
acylation of the resulting alkyne (Table 1). Ester 4a15 was made
from commercially available piperonal 7a, in 89% overall yield
(entry 1). Pyranyl ester 4b was readily prepared from pyranyl al-
dehyde 7b16 in 63% overall yield (entry 2). Known methyl
substituted cyclohexenyl aldehyde 7c17 gave methylcyclohexenyl
ester 4c in 78% yield over two steps (entry 3). Cyclopentenyl ester
4d was prepared by the addition of lithiated ethyl propiolate to
commercially available cyclopentanone 7d, followed by de-
hydration with POCl3 in pyridine, to give 58% yield over two steps
(entry 4). Cyclohexenyl ester 4e was obtained by acylation of enyne
7e18 with ethyl chloroformate in 95% yield (entry 5).
O
OEt
H
CH3
CH3
O
O
OEt
O
A series of substrates were prepared from the terminal alkyne 8,
which was obtained from the methyl ketone by a three-step one-
pot reaction sequence (Table 2).19 Deprotonation of alkyne 8 fol-
lowed by addition of a range of electrophiles provided 9a–f in good
overall yields. N-Cyanobenzotriazole was selected as a cyanating
reagent to prepare 9d. Sulfone 9e was synthesized by reacting
OEt
5
7e
C
4e 95
Reaction conditions: (A) 1. CBr4, PPh3, CH2Cl2; 2. n-BuLi, ClC(O)OEt, THF, ꢀ78 ꢁC. (B)
LiCC–C(O)OEt, THF, ꢀ78 ꢁC; 2. POCl3, pyridine, 90 ꢁC. (C) n-BuLi, ClC(O)OEt, THF,
ꢀ78 ꢁC.

D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
3167
Table 3
Preparation of nitrones
isomer by 1:3 (entry 4). Interestingly, when 2,4,6-trimethoxy-
phenyl substituent was changed to 3,4,5-trimethoxyphenyl, the
product mixture again favored the ‘in’ isomer >15:1 (entry 5).
Other less sterically bulky substituents such as cyclohexyl, trans-
cinnamyl, and n-butyl all favored the ‘in’ stereoisomeric product
in a ratio of 12:1 or higher (entries 6–8). C-Aliphatic nitrones,
ketonitrones and C-unsubstituted nitrones are difficult to pre-
pare due to rapid dimerization behavior of aliphatic/unsub-
stituted nitrones, and facile hydrolysis of ketonitrones. We
therefore devised a one-pot method to trap these unstable
nitrones by preparing them in situ with ynoate dipolarophiles,
.
R2NHOH HCl
R2
H
O
O
H
N
NaHCO3, MgSO4
R1
CH2Cl2, 45 °C
R1
Entry
R1
R2
Yield (%)
1
2
3
4
5
6
7
8
9
10
Phenyl
Cyclohexyl
Me
Me
Me
Me
Me
Me
Me
t-Bu
t-Bu
t-Bu
10a (84)
10b (89)
10c (82)
10d (89)
10e (83)
10f (89)
10g (25)
10h (69)
10i (73)
10j (75)
trans-Cinnamyl
trans- -Methylcinnamyl
2,4,6-Trimethoxyphenyl
3,4,5-Trimethoxyphenyl
Triethylphenyl
Phenyl
a
which successfully gave the corresponding
high yields (entries 8–10).
b-ketoalkylidenes in
Alkynes bearing electron-withdrawing groups other than ester
were also examined in the [3þ2] cyclization/oxidative extrusion
reaction sequence (Table 6).
Cyclohexyl
trans-Cinnamyl
This reaction sequence worked well, giving b-ketoalkylidenes in
alkyne 8 with sodium p-toluenesulfinate in the presence of ceric
ammonium nitrate and sodium iodide, followed by base-induced
elimination of H–I to recover the alkyne 9e.20 Haloalkyne 9f was
easily synthesized by deprotonation of terminal alkyne 8 followed
by addition of N-chlorosuccinimide. These alkynyl substrates could
be prepared on multigram scale with no complications.
Nitrones can be prepared in a variety of ways, most commonly
by condensation of carbonyl compounds with N-alkyl hydroxyl-
amines.21 The condensations are typically run in the presence of
either an acid scavenger or a water scavenger. We obtained the best
results when both an acid scavenger and MgSO4 in refluxing
methylene chloride were used (Table 3). In this way it was possible
to prepare aryl, alkyl, and conjugated nitrones 10a–g (entries 1–7).
Additional nitrones bearing a different substituent on the nitrogen
were prepared using tert-butyl hydroxyl amine giving nitrones
10h–j (entries 8–10).
With an array of alkynes and nitrones in hand, we applied
the cyclization/oxidation reaction sequence to obtain dienones
(Table 4). The [3þ2] cycloaddition of alkynoates and nitrones
proceeded without complication to provide isoxazolines, which
were either isolated in good yield, or carried directly to the next
step without purification. Oxidation was carried out using m-
CPBA, generating trisubstituted olefins via extrusion of nitroso-
methane at low temperature and in high yield. The resulting
olefin geometry is denoted as ‘in’ or ‘out’ depending on the
stereochemistry of the olefin substituent relative to the alkyl or
aryl substituent that is installed from the alkyne starting ma-
terial. Identification of stereoisomers was assigned by analysis of
3JC,H coupling constants.22 It was found that for most substrates,
the extrusion was highly stereoselective, favoring one olefin di-
astereoisomer. In most cases, the substituent R2 emerged cis to
the ketone to give ‘in’ stereoisomers in >15:1 selectivity (entries
1, 7, and 8). However, in a few cases the ‘out’ stereoisomeric
product, in which R2 is cis to the ester, was dominant (entries 2
and 4). When the ester substitution was changed from ethyl
(entry 5) to tert-butyl (entry 6), the product mixture showed
decreased selectivity for the ‘in’ isomer.
moderate yield over two steps. Alkynyl ester 9a was reacted with
two different nitrones (entries 1–2), and the relative stereochem-
istry of the products reflected the substitution pattern of the
nitrone utilized: when the nitrone contained a methyl substitution
in the alpha position (entry 1), the product favored the ‘out’ ste-
reoisomer 29b, however, when the nitrone replaced the methyl
group with a hydrogen (entry 2), the product distribution com-
pletely reversed to favor the ‘in’ isomer 30a. Alkyne 9e was slow to
undergo [3þ2] cyclization (entry 6); however, when the tempera-
ture was raised above 80 ꢁC, the isoxazoline continued to react to
give the b-ketoaziridine, which is a known transformation in the
literature.23 Performing the [3þ2] reaction at or below 80 ꢁC cir-
cumvented this problem, though cycloaddition of alkynyl sulfone
9e took 5–8 days to go to completion. Haloalkyne 9f did not un-
dergo [3þ2] reaction and slowly dehalogenated to the terminal
alkyne over extended reaction times. In an effort to bolster the
reactivity of chloroalkyne 9f, Lewis acid promoters were added, as
these have been used in [3þ2] nitrone–alkene cycloadditions to
improve regioselectivity.24 Unfortunately, catalytic and stoichio-
metric amounts of either Mg(OTf)2 or Zn(OTf)2 were unable to
polarize the alkynyl chloride 9f toward reaction. A survey of the
literature revealed surprisingly few examples of [3þ2] cyclizations
with either alkenyl or alkynyl halides, though the examples found
were reported to cyclize in moderate yields.25
We also attempted the cycloaddition/oxidation sequence to
prepare b-diketones (Table 7). Preliminary experiments were run
with the N-methyl substituted isoxazolines (entries 1 and 2). The
results obtained were unexpectedly poor, giving only trace amounts
of desired product and a large number of unidentified side products.
A Hoffman-type26 elimination of the isoxazolino-N-oxide was
considered as a decomposition pathway that could be responsible
for the poor results (Scheme 3).
It was reasoned that an isoxazoline intermediate without
a
-hydrogens on the N-alkyl substituent would be unable to
decompose via Hoffman elimination, so N-tert-butyl substituted
nitrones were tested in the sequence (Table 7, entries 3–5). We
were pleased to observe smooth extrusion of the N-tert-butyl
We next investigated this reaction sequence using piperonal
derived alkyne 4a and nitrones that contained aryl groups with
varying steric bulk and electronics (Table 5). Using an unsub-
stituted phenyl ring on the nitrone, the major product after
oxidative extrusion was the ‘in’ stereoisomer in a ratio of >15:1
(entry 1). When the alkynyl ester 4a was replaced with an
analogous tert-butyl ester, the same stereoisomer was favored,
and the ratio dropped to 8:1 (entry 2) as we had observed in
Table 1 (entries 5 and 6). By replacing the phenyl substituent
with 2,4,6-triethylphenyl, the product mixture flipped to favor
the ‘out’ stereoisomer by <1:15 (entry 3), and changing to 2,4,6-
trimethoxyphenyl lowered the ratio while still favoring the ‘out’
isoxazolines, which gave b-diketones in good yields. Phenyl
substitution on the nitrone gave the ‘out’ isomer in a <1:15
ratio (entry 3), and cyclohexyl completely reversed this selec-
tivity to the ‘in’ isomer by >15:1 (entry 4). A trans-cinnamyl
substituent on the nitrone gave a 7:1 ratio favoring the ‘in’
isomer (entry 5).
In addition to using the [3þ2]/[O] sequence to the prepa-
ration of b-ketoesters and b-diketones, we attempted to apply
these reactions to the synthesis of Baylis–Hillman-type ad-
ducts (Scheme 4). The Baylis–Hillman reaction27 is a popular
method of preparing
a-alkylidene-b-hydroxyketones, which
are valuable building blocks for organic synthesis, especially

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D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
Table 4
[3þ2]/[O] sequence for the synthesis of divinyl ketones
O
O
CO2Et
H3C
O
H
CO2Me
R2
CO2Me
+
R1
+
N
R1
R2
4
R1
R2
a "in"
b "out"
10
Entry
1
R1
R2
Yield (%) [3þ2]
Major product
from extrusion
Yield (%) (aþb)
Ratio (a:b)
O
O
Ph
94
94
>15:1
OEt
Ph
H
11a
O
H
O
OMe
OEt
OCH3
2
3
4
67
74
67
96
83
93
1:2.6
MeO
OMe
H3CO
OCH3
12a
O
O
H
OEt
6:1
Ph
O
13a
O
OMe
OEt
OCH3
1:12
H
MeO
OMe
H3CO
OCH3
14b
O
O
H
OEt
5
6
7
Ph
Ph
Ph
61
85
90
64
8:1
6:1
Ph
O
15a
O
a
O-t-Bu
Ph
H
16a
O
O
OEt
64
53
>15:1
Ph
O
H
17a
O
O
O
OEt
8
Ph
35
>15:1
Ph
H
18a
Reaction conditions: i. 1 equiv alkyne, 2 equiv nitrone, 0.2 M toluene, 65 ꢁC, 16 h; ii. 1.5 equiv m-CPBA, 0.9 M DCM, 0 ꢁC, 1 h.
a
Ester¼t-Bu instead of Et, isoxazoline was not isolated.
in enantiopure form. However, while the Baylis–Hillman re-
adduct 43. Coupled with an enantioselective reduction of
ketone 41,28 the strategy could provide chiral products with
high enantiomeric excess.
To test this strategy, two complementary isoxazolines 44 and
47 were prepared via [3þ2] cyclization. Isoxazoline 44 was re-
duced under Luche29 conditions to yield the product alcohol 45
in 70% yield, with a diastereomeric ratio of 1.3:1. Treatment of
hydroxyisoxazoline 45 with m-CPBA under the standard oxida-
action is very effective for preparation of
a-methylene-b-
hydroxyketones (e.g., 43, R3¼H), reactivity often becomes
a problem for more highly substituted analogs. Since an R3
substituent is easily introduced via a [3þ2] cyclization, we
sought to provide an alternative method for synthesis of
a
-alkylidene-b-hydroxyketones of type 43. It was envisioned
that an isoxazoline of type 41 could be reduced to give the
corresponding hydroxyisoxazoline 42, and subsequent oxida-
tion/extrusion would provide the desired Baylis–Hillman
tion conditions led to 73% yield of the desired
b-hydroxyketone
isomers 46a and 46b in a ratio of 1:2 ‘in’:’out’ relative to the

D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
3169
Table 5
Scope of nitrone substitution in the [3þ2]/[O] sequence
O
O
CO2Et
H3C
O
R2
R1
CO2Me
+
R2
CO2Me
R1
O
O
O
O
N
O
O
+
4
R1
R2
10
a "in"
b "out"
Entry
1
R1, R2
Ph, H
Yield (%) [3þ2]
Major product
from extrusion
Yield (%) (aþb)
Ratio (a:b)
O
O
93
85
>15:1
O
O
OEt
Ph
O
H
O
19a
O
b
2a
Ph, H
71
8:1
O-t-Bu
O
Ph
H
20a
O
O
Et
O
O
OEt
Et
b
3
89
94
<1:15
H
Et
Et
, H
Et
Et
21b
O
H
O
OMe
O
OEt
OCH3
b
4
1:3
O
MeO
OMe
, H
H3CO
O
OCH3
22b
O
OEt
O
O
OMe
OMe
H
b
5
6
85
93
>15:1
>15:1
H3CO
H3CO
OMe
, H
OCH3
O
23a
O
OEt
O
O
86
H
, H
24a
O
O
O
O
OEt
OEt
7
8
95
81
92
95
12:1
12:1
H
O
H
, H
Ph
25a
O
O
O
Bu, Hc
Bu
26a
O
O
O
OEt
OEt
9
H, Hc
85
79
91
96
n/a
n/a
O
H
O
H
O
27
O
O
10
Me, Mec
Me
Me
28
Reaction conditions: i. 1 equiv alkyne, 2 equiv nitrone, 0.2 M toluene, 65 ꢁC, 16 h; ii. 1.5 equiv m-CPBA, 0.9 M DCM, 0 ꢁC, 1 h.
a
Ester¼t-Bu instead of Et.
b
Isoxazoline was not isolated, but subjected immediately to the oxidation procedure.
c
Nitrone prepared in situ from corresponding aldehyde.

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D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
Table 6
[3þ2]/[O] sequence applied to alkynes bearing varied electron-withdrawing groups
O
O
R1
TIPSO
+
R1
R2
TIPSO
R1
H
TIPSO
H3C
O
H
+
N
9
H
R2
R2
TIPSO
TIPSO
10
OTIPS
b "out"
a "in"
Entry
1
R1
R2
Major product
from extrusion
Yield aþb (%)
Ratio (a:b)
O
O
O
O
O
TIPSO
9a
65
<1:19
OCH3
CH3
OCH3
OCH3
CH3
TIPSO
Ph
29b
TIPSO
O
OCH3
2a
9a
9b
9c
9d
67
63
57
57
>19:1
<1:19
<1:19
<1:19
TIPSO
Ph
30a
O
O
TIPSO
O
N(CH3)2
CH3
3
N(CH3)2
OEt
CH3
CH3
CH3
TIPSO
Ph
31b
O
O
OEt
OEt
CH3
TIPSO
P
O
4
P
OEt
TIPSO
Ph
N
32b
O
TIPSO
N
5
CH3
Ph
TIPSO
33b
CH3
O
O
O
CH3
TIPSO
S
O
O
6b
9e
9f
43
<1:19
CH3
S
O
CH3
CH3
TIPSO
TIPSO
Ph
Cl
34b
7c
–Cl
d
d
CH3
Ph
TIPSO
35b
Reaction conditions: i. 1 equiv alkyne, 2 equiv nitrone, 0.2 M toluene, 80 ꢁC, 16 h; ii. 2 equiv m-CPBA, 0.2 M CH2Cl2, 0 ꢁC, 1 h.
a
N-Methylnitrone prepared from trans-cinnamaldehyde was used.
b
Reaction time¼5 days.
c
Starting material was recovered unreacted, even with 1 equiv Mg(OTf)2 or Zn(OTf)2.
ketone (Eq. 3). Reduction of isomeric isoxazoline 47 with
DIBAL30 successfully gave alcohol 48 in 79% yield as a 3.6:1
mixture of diastereomers. Treatment of hydroxyl isoxazoline 48
isomers 49a and 49b in a ratio of 1:1 (Eq. 4).31 So, it was
possible to prepare the desired Baylis–Hillman adducts using
this method, but mixtures of products were obtained. The re-
duction of isoxazoline ketones 44 and 47 using simple hydride
with m-CPBA gave 73% yield of the desired
b-hydroxyketone
O
Bu
N
O
CH3
Bu
CH3
R3
O
H
OH
*
O
N
O
N
H- reduction
oxidation/
extrusion
OH
O
complex
mixture
O
N
R2
R1
R1
R3
R1
Ph
O
Ph
R3
43
41
42
H3C
O
R2
H2C
*
R2
HO
Scheme 3. Potential competing Hoffman elimination pathway.
Scheme 4. Strategy for the preparation of Baylis–Hillman adducts.

D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
3171
Table 7
[3þ2]/[O] sequence used to prepare
b
-diketone systems
O
H
O
O
O
H
O
H3C
O
H
Bu
Bu
+
+
N
R1
R1
R1
Bu
10
b "out"
a "in"
Entry
1
R1
R2
Yield [3þ2] (%)
Major product
from extrusion
Yield aþb (%)
Ratio (a:b)
O
O
Me
Ph
92
d
d
Bu
Ph
O
36
O
Bu
2
3
Me
96
50
12
61
d
37
O
O
Bu
Bu
t-Bu
Ph
<1:15
H
O
Ph
O
36b
4
t-Bu
83
66
>15:1
H
37a
O
O
H
Bu
5
t-Bu
64
63
7:1
Ph
Reaction conditions: i. 1 equiv alkyne, 1.5 equiv nitrone, 0.5 M toluene, 65 ꢁC; ii. 1.5 equiv m-CPBA, 0.9 M CH2Cl2, 0 ꢁC.
38a
reducing agents was not selective, which complicated analysis of
selectivity in the oxidation/extrusion.
Reaction conditions: (a) NaBH4, CeCl3$7H2O, MeOH; (b) m-CPBA,
CH2Cl2, 0 ꢁC; (c) DIBAL-H, toluene/hexane.
Fortunately, it was possible to separate the two dia-
stereomers of hydroxyisoxazoline 45 by column chromato-
graphy and oxidize each diastereomer separately. Oxidation of
the minor diastereomer gave a 7.8:1 mixture of products, and
oxidation of the major diastereomer gave a 1:1 mixture of
products. The complexity of the results obtained with iso-
xazolines 44 and 47 was discouraging, but our studies have
shown that extrusion selectivity is highly substrate-dependent
(vide supra), so other isoxazolines may be better candidates for
this strategy.
Ph
Ph
O
OH
Bu
O
H
OH
Bu
O
OH
Bu
a
b
O
N
O
Ph
Ph
+
(3)
Bu 70%
73%
N
t-Bu
Ph
H
t-Bu
Ph
46b
Ph
Ph
44
45: 1.3:1 dr
1:2
46a
Bu
Bu
O
OH
Ph
O
H
OH
Ph
O
OH
c
b
O
N
O
Bu
Bu
+
(4)
Ph 79%
73%
Ph
N
t-Bu
Ph
H
t-Bu
Ph
49b
Ph
Ph
48: 3.6:1 dr
47
1:1
49a

3172
D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
Table 8
3. Discussion
Extrusion results using different oxidants
Me
While the sequence represents a useful method for the syn-
thesis of Nazarov cyclization precursors, we did not understand
why the reaction was so stereoselective. For the intermediate
N-oxides 2, the ring substituent R2 could rotate either inward (to
give diastereomer 6a) or outward (to give diastereomer 6b) during
the extrusion (Scheme 5). In the Padwa study, the reaction se-
quence always gave a single olefin isomer as product.8 Our exper-
iments confirm the high selectivity of the sequence, and indicate
that the olefin geometry of the product can change depending on
the substitution pattern of the isoxazoline intermediate. The high
torquoselectivities observed in both studies were rather surprising,
especially since extrusion was selective for one olefin isomer (6a) in
some cases and for the isomer with opposite olefin geometry (6b) in
others.
O
N
oxidant
O
O
R2
6a (in) + 6b (out)
OEt
O
R2
Oxidanta
Ratio 6a/6b
2,4,6-Trimethoxyphenyl
2,4,6-Trimethoxyphenyl
Cinnamyl
m-CPBA
50
m-CPBA
50
1:2
1:10
12:1
7:1
Cinnamyl
O
N
O
O
S
a
oxidant 50¼
.
Cl
Cl
The selectivities observed were not consistent with stereo-
electronic predictions,11a and there were no obvious nonbonding
interactions in the N-oxide intermediate that accounted for the
product distribution. The ‘in’/‘out’ratios obtainedfromextrusion did
not match ratios obtained from the analogous Knoevenagel con-
densation, indicating that the extrusion is not thermodynamically
controlled.32 Another possibility was that selectivity might arise
from opposite directions of extrusion for the two diastereomeric
N-oxide intermediates 2a and 2b, i.e., that one isomer undergoes
selective inward extrusion, and the other selective outward extru-
sion to give the two product isomers 6a and 6b (Scheme 5).
Few literature cases of extrusions of this type could be found.
One study on a system related to 2 has been reported, describing
torquoselective extrusion of dimethylamine from N,N-dimethyl
isoxazolinium salts, via an intermediate without a stereocenter at
nitrogen.33 Like our results, the stereoselectivity in these cases
could not be rationalized easily. Since it was not possible to char-
acterize the behavior of the N-oxides 2 directly, attempts were
made to alter the ratio of N-oxides 2 generated in the oxidation
step. Different oxidation reagents might have different selectivity
for the two faces of the isoxazoline; in which case, we would expect
to observe a different ratio of extrusion products 6a and 6b with
different oxidants. Indeed, extrusion selectivity was slightly dif-
ferent when m-CPBA vs oxaziridine 50 was employed in oxidation
experiments with two different isoxazolines (Table 8).
Calculations on the oxidation/extrusion sequence were also
performed in collaboration with the Houk group.34 Oxidation by
m-CPBA and oxaziridine models was calculated to favor a cis re-
lationship between R2 and the N-methyl group (see 2b) in order to
minimize repulsion between the oxidant and R2. These results are
not consistent with the hypothesis that oxidation stereoselectivity
dictates product stereochemistry. The change in the 6a/6b ratio
may be explained by the fact that the activation barrier for oxida-
tion by 50 was calculated to be significantly higher (by approxi-
mately 14 kcal/mol) than oxidation by m-CPBA. A closer interaction
between 50 and the isoxazoline exists in this ‘later’ transition state,
which may alter the mode of decomposition of the resulting
N-oxide. Thus, although experimental data suggests that the
N-oxide stereochemistry affects torquoselectivity, because a single
diastereomer may rotate ‘in’ or ‘out,’ depending on the oxidant and
the isoxazoline substituents (see Scheme 5), a direct correlation
between N-oxide stereochemistry and product stereochemistry
cannot be made.
It was found that a diradical species was the most accessible re-
action intermediate, consistent with a stepwise rather than a con-
certed extrusion process. Finally, the calculations predicted
torquoselectivity favoring the ‘in’ products for most substrates,
consistent with the experimentalfindings. Theselectivityarosefrom
an extrusion pathway that maintained optimal charge separation in
the diradical intermediate. Calculations were also performed on
selected cases with ‘out’ torquoselectivity, which appear to result
from subtle nonbonded interactions in the diradical intermediate
that can reverse the direction of rotation during extrusion.
4. Summary and conclusions
In summary, a [3þ2] cycloaddition/oxidation/extrusion se-
quence has been developed to synthesize aryl vinyl and divinyl
ketones for Nazarov cyclization. The procedure is easy to conduct,
and does not require either acidic or basic reaction conditions.
Alkynyl esters, sulfones, phosphonates, and amides all participate
readily in the reaction. A range of substituents on the electron-
deficient alkyne (i.e., R1) are tolerated, with best results obtained
with R1¼aryl. Depending on the substitution pattern, the reaction
gave moderate to high selectivities of olefin isomers. The sequence
was usually selective for the ‘in’ extrusion product, although in
some cases the ‘out’ product dominated. It is important to note that
both ‘in’ and ‘out’ isomers undergo efficient Nazarov cyclization to
give the same cyclopentenone product,32 so this method will be
valuable for the synthesis of any Nazarov cyclization substrates,
even in the few cases when torquoselectivity is poor. Experimental
and computational results show that the extrusion sequence is
complicated and that torquoselectivity is not controlled by a single
factor. There is strong computational evidence that the sequence
proceeds through a stepwise pathway, and that stereoelectronic
effects in the diradical intermediate have a strong influence on the
R1
O
R2
EtO2C
H
"in" isomer 6a
H
R1
H
R1
R1
O
O
m-CPBA
H
O
extrusion
EtO2C
out
EtO2C
O
Me
and/or
EtO2C
N
in
N
N
R2
R2
out
R2
in
R1
O
H
"out " isomer 6b
Me
Me
O
EtO2C
2a
and/or
2b
1
R2
Scheme 5. N-Oxide Intermediates in the oxidation/extrusion sequence.

D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
3173
direction of rotation during extrusion.34 Investigations to further
elucidate the mechanism are underway.
(neat) cmꢀ1: 2935, 2202, 1704, 1446, 1365, 1265, 1207, 1141. HRMS
(m/z): calcd for C10H13O2 [MꢀHþ], 165.0910; found, 165.19189.
5. Experimental section
5.1. General
5.3. Preparation of nitrones
Nitrones 10a–10d and 10h–j are known compounds and were
prepared using the general procedure described below. Typically,
the nitrones were not purified, but isolated in crude form and used
directly in the [3þ2] dipolar cycloaddition.
Reagents were used as obtained from commercial supplier
without further purification. Reaction solvents were purchased
from Fisher and dispensed using the Glass Contour solvent purifi-
cation system. ACS grade hexanes and ethyl acetate (EtOAc) are
used for column chromatography. Thin layer chromatography (TLC)
analysis was determined using precoated silica gel 60 F254 glass-
supported plate (EMD product). Spots were visualized by UV light
(254 nm), or by staining with potassium permanganate or p-ani-
saldehyde solutions followed by heating. Column chromatography
separations were carried out on silica gel 60 (230–400 mesh) (EMD
product).
5.3.1. Representative procedure for preparation of nitrones
In a 250 mL round-bottom flask, MgSO4 (10.5 g), NaHCO3
(14.7 g, 0.2 mol), and N-methylhydroxylamine$HCl (7.6 g, 0.1 mol)
were combined, and CH2Cl2 (75 mL) was added with the appro-
priate aldehyde (36.0 mmol). The solution was stirred for 6 h, then
concentrated. The crude mixture was purified by column chroma-
tography (2:1 hexanes/ethyl acetate) to give the nitrone.
1H NMR spectra were recorded on either a 400 MHz or
a 500 MHz Avance spectrometer. 13C NMR spectra were recorded
on either a 100 MHz or 125 MHz Avance spectrometer. Product
E/Z stereochemistry was assigned based on carbon–hydrogen
coupling constants obtained for the ester and(or) the ketone of
the divinyl ketone, according to Kingsbury et al.22 Infrared spectra
were recorded on a 8400s Shimadzu FTIR spectrometer using
NaCl plates. High resolution mass spectra were done on a Ther-
moFinnigan MAT 95XL (ESI) at the Chemistry Instrumentation
Center of the University of Buffalo.
5.3.2. Methanamine, N-((2,4,6-trimethoxyphenyl)methylene)-N-
oxide (10e)
Prepared as above. 1H NMR (400 MHz, CDCl3):
d
7.32 (s, 1H), 6.13
163.0, 159.8,
(s, 2H), 2.88 (m, 12H). 13C NMR (100 MHz, CDCl3):
d
130.2, 101.4, 90.7, 55.8, 55.4, 53.4. IR (neat) cmꢀ1: 3048, 3014, 2934,
2838, 1606, 1575, 1499, 1456, 1407, 1398. HRMS: calcd for
C12H15ON2Na [MꢀNaþ], 226.1077; found, 226.1077.
5.3.3. Methanamine, N-((3,4,5-trimethoxyphenyl)methylene)-N-
oxide (10f)
Prepared as above. 1H NMR (500 MHz, CDCl3):
d
7.53 (s, 2H), 3.81
5.2. Preparation of electron-deficient alkynes
(m, 12H). 13C NMR (100 MHz, CDCl3):
d 152.7, 139.7, 134.8, 125.9,
105.7, 60.7, 56.0, 54.1. IR (neat) cmꢀ1: 3116, 3015, 2964, 2935, 2831,
1583,1568,1497,1471,1454,1435,1412,1400,1338,1306,1232,1167.
HRMS: calcd for C11H16O4N [MꢀHþ], 226.1074; found, 226.1072.
Alkynyl esters 4a–4d were prepared from commercially avail-
able aldehydes using the Corey–Fuchs protocol,14 followed by car-
boalkoxylation of the resulting terminal alkyne with the
appropriate chloroformate. A full description of the preparation of
alkynes 9a–9f can be found in the supplementary data accompa-
nying Ref. 32.
5.3.4. Methanamine, N-((2,4,6-trimethylphenyl)methylene)-N-
oxide (10g)
Prepared as above. 1H NMR (400 MHz, CDCl3):
d
7.56 (s,1H), 6.93
(s, 2H), 3.83 (s, 3H), 2.5 (m, 6H), 1.19 (m, 9H). 13C NMR (100 MHz,
5.2.1. 2-(Benzo[1,3]dioxole)-propynoic acid ethyl ester (4a)
CDCl3): d 145.8, 143.4, 135.4, 125.4, 124.8, 87.4, 53.0, 44.1, 28.8, 26.7,
1H NMR (500 MHz, CDCl3):
d
7.10 (d, J¼8.0 Hz, 1H), 6.95 (s, 1H),
15.4, 15.1. HRMS: calcd for C14H22ON [MꢀHþ], 220.1694; found,
6.75 (d, J¼8.0 Hz, 1H), 5.97 (s, 2H), 1.5 (s, 9H). 13C NMR (100 MHz,
220.1678.
CDCl3): d 153.1,149.7,147.5,128.5,112.8,112.3,108.6,101.6, 84.1, 83.2,
80.9, 65.8, 28.0, 27.3, 15.2. IR (neat) cmꢀ1: 2213, 1706, 1105. HRMS
(m/z): calcd for C14H14O4Na [MꢀNaþ], 269.0771; found, 269.0777.
5.4. General procedures for the [3D2] cycloaddition/
cheletropic extrusion sequence
5.2.2. (5,6-Dihydro-4H-pyran-2-yl)-propynoic acid ethyl ester (4b)
1H NMR (500 MHz, CDCl3):
d
5.48 (m, 1H), 4.18 (q, J¼7.0 Hz, 2H),
5.4.1. General procedure A for the preparation of isoxazolines
([3þ2] cycloaddition)
3.99 (m, 2H), 2.09 (m, 2H), 1.80 (m, 2H), 1.24 (t, J¼7.0 Hz, 3H). 13C
NMR (100 MHz, CDCl3):
d
153.3, 135.6, 114.9, 81.3, 78.5, 66.4, 61.8,
Alkyne (0.56 mmol) and nitrone (1.23 mmol) were covered with
toluene (0.5 mL) at rt under argon. The resulting suspension was
heated to 65 ꢁC and stirred until completion as indicated by TLC
(about 18 h). The reaction mixture was loaded directly onto a silica
gel column and eluted with ethyl acetate/hexane to give the iso-
xazoline product.
21.2, 20.9, 13.8. IR (neat) cmꢀ1: 2976, 2936, 1712, 1463, 1444, 1244.
HRMS (m/z): calcd for C10H12O3 [Mþ], 180.0781; found, 180.0786.
5.2.3. (2-Methyl-cyclohex-1-enyl)-propynoic acid ethyl ester (4c)
1H NMR (400 MHz, CDCl3):
d
4.11 (q, 2H J¼7.2 Hz), 2.05 (s, 2H),
1.98 (s, 2H), 1.82 (s, 3H), 1.5 (m, 4H), 1.19 (t, 3H J¼7.2 Hz). 13C NMR
(400 MHz, CDCl3):
d
154.1, 149.5, 111.9, 87.0, 82.9, 61.2, 31.3, 28.5,
5.4.2. General procedure B for the preparation of isoxazolines
([3þ2] cycloaddition)
22.4, 22.1, 21.8, 13.7. IR (neat) cmꢀ1: 2981, 2933, 2862, 2825, 2208,
2192, 1745, 1704, 1629, 1442, 1423, 1365, 1336, 1282, 1259, 1215,
1178, 1143, 1095, 1024, 748. HRMS (m/z): calcd for C12H17O2
[MꢀHþ], 193.1223; found, 193.1215.
Alkyne (0.48 mmol), aldehyde (0.72 mmol), N-methylhydroxyl-
amine hydrochloride (0.64 mmol), and diisopropylethyl amine
(0.64 mmol) were all combined at rt, covered with ethanol (0.30 mL)
and heated to 50 ꢁC for 12 h. The resulting solution was then heated
to 80 ꢁC for another 12 h. The solution was cooled to rt, diluted with
Et2O (2 mL), washed with satd NH4Cl (2ꢂ1 mL), brine (1 mL), dried
over MgSO4 and concentrated. Purification by column chromato-
graphy (ethyl acetate/hexane) gave the desired isoxazoline.
5.2.4. (1-Hydroxy-cyclopentyl)-propynoic acid ethyl ester (4d)
1H NMR (400 MHz, CDCl3):
d
6.33 (m, 1H), 4.12 (q, J¼7.0 Hz, 2H),
2.45 (m, 4H), 1.88 (m, 2H), 1.24 (t, J¼7.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): d 153.8, 149.6, 121.8, 83.5, 81.7, 61.6, 35.4, 33.5, 23.0, 13.8. IR

3174
D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
5.4.3. General procedure C (oxidation of isoxazoline intermediate)
m-CPBA (0.20 mmol) was added to a solution of isoxazoline
(0.14 mmol) in DCM (0.16 mL) at 0 ꢁC. The reaction was stirred at
0 ꢁC until complete by TLC (about 5 min). The reaction was diluted
with Et2O (1 mL), washed with 1 M NaOH (1 mL), and the organic
layer was dried over MgSO4 and concentrated. Column chroma-
tography (ethyl acetate/hexane) gave the desired product.
1607, 1584, 1508. HRMS (m/z): C21H27O6 [MꢀHþ], 375.1738; found,
375.1711. JC–H: 9.3 Hz.
5.5.3. 2-(Cyclohex-1-enecarbonyl)-5-phenyl-penta-2,4-dienoic
acid ethyl ester ((E)-13a)
The intermediate isoxazoline (5-cyclohex-1-enyl-2-methyl-3-
styryl-2,3-dihydro-isoxazole-4-carboxylic acid ethyl ester) was pre-
pared according to general procedure A (74% yield). 1H NMR
5.4.4. General procedure D (one-pot [3þ2] cycloaddition/oxidation)
In a dry 100 mL round-bottom flask was weighed the nitrone
(8.0 mmol), alkyne (7.1 mmol), and toluene (35 mL), and the solu-
tion was heated at 80 ꢁC for 16 h. The solution was concentrated,
and CH2Cl2 (35 mL) was added, cooled to ꢀ20 ꢁC, and m-CPBA
(11.6 mmol) was added and stirred for 30 min. The reaction was
quenched with saturated Na2SO3 (50 mL), the layers were sepa-
rated and the aqueous phase was extracted with CH2Cl2 (2ꢂ50 mL),
the organic phases were combined and washed with brine (50 mL).
The organic phase was dried over Na2SO4, filtered, and concen-
trated. The crude material was purified by column chromatography
(ethyl acetate/hexane).
(400 MHz, CDCl3):
d
7.40–7.20 (m, 5H), 6.66 (d, J¼16 Hz, 1H), 6.48
(m, 1H), 6.28 (dd, Jab¼16 Hz, Jac¼7 Hz, 1H), 4.60 (d, J¼7 Hz, 1H),
4.19–4.11 (m, 2H), 2.85 (s, 3H), 2.42 (m, 1H), 2.21 (m, 3H), 1.72–1.65
(m, 4H), 1.26 (t, J¼7 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d 164.1,
136.8, 135.9, 130.6, 128.3, 127.6, 127.4, 126.4, 126.3, 100.6, 74.0, 59.6,
45.9, 26.0, 25.5, 22.1, 21.4, 14.1. IR (neat) cmꢀ1: 2913, 2842, 1784,
1614. HRMS (m/z): calcd for C21H25NO3Na [MꢀNaþ], 362.1727;
found, 362.1722.
General procedure C provided (E)-13a as a 6:1 ratio of isomers
with (Z)-13b. The isomers could be separated by column chroma-
tography on silica, eluting with ethyl acetate/hexanes: 1H NMR
(500 MHz, CDCl3):
d
7.53–7.31 (m, 6H), 6.99 (d, J¼15.0 Hz, 1H),
6.77–6.69 (m, 2H), 4.24 (q, J¼7.0 Hz, 2H), 2.39 (m, 2H), 2.24 (m, 2H),
5.5. Preparation of aryl vinyl and divinyl ketones
1.73–1.63 (m, 4H), 1.27 (q, J¼7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d
195.0, 165.1, 144.8, 142.5, 142.0, 140.2, 135.6, 132.0, 129.3, 128.6,
5.5.1. 2-(Cyclohex-1-enecarbonyl)-3-phenyl-acrylic acid
ethyl ester (11a)
The intermediate isoxazoline (5-cyclohex-1-enyl-2-methyl-3-
phenyl-2,3-dihydro-isoxazole-4-carboxylic acid ethyl ester) was pre-
pared according to general procedure A (88% yield): 1H NMR
127.6, 127.4, 123.2, 109.5, 60.8, 26.2, 22.6, 21.7, 21.4, 14.0. IR (neat)
cmꢀ1: 3050, 3020, 2974, 2924, 2860, 2842, 2753, 1684, 1674, 1603,
1542, 1505, 1448, 1250, 1190. HRMS: calcd for C21H25O3 [MꢀHþ],
325.1785; found, 325.1787. (Z)-13b d 7.82 (m, 1H), 1.53 (m, 2H), 7.35
(m, 4H), 6.98–6.94 (m, 2H), 6.69 (m, 1H), 4.28 (q, J¼7.0 Hz, 2H), 2.33
(400 MHz, CDCl3):
d
7.28–7.37 (m, 5H), 6.5 (m, 1H), 4.93 (s, 1H), 2.92
(m, 2H), 2.24 (m, 2H), 1.67 (m, 4H), 1.30 (t, J¼7.0 Hz, 3H). JC–H
:
(s, 3H), 2.22–2.5 (m, 4H),1.66–1.73 (m, 4H), 1.14 (t, J¼7.2 Hz, 3H). 13C
7.8 Hz.
NMR (100 MHz, CDCl3):
d 164.0, 141.6, 135.8, 128.2, 127.5, 127.0,
126.2, 109.3,102.3, 76.3, 59.5, 46.8, 31.4, 26.0, 25.5, 22.1, 21.4,13.9. IR
(neat) cmꢀ1: 2817, 2269, 1703, 1618, 1501, 1475, 1392, 1315, 1225,
1068, 911. HRMS (m/z): calcd for C19H23NO3 [Mþ], 313.1672; found,
313.1668.
5.5.4. 2-(2-Methyl-cyclohex-1-enecarbonyl)-3-(2,4,6-trimethoxy-
phenyl)-acrylic acid ethyl ester (14b)
The intermediate isoxazoline (2-methyl-5-(2-methyl-cyclohex-
1-enyl)-3-(2,4,6-trimethoxy-phenyl)-2,3-dihydro-isoxazole-4-carboxy-
lic acid ethyl ester) was prepared according to general procedure
General procedure C provided the title compound (11a) from the
intermediate isoxazoline (94% yield). 1H NMR (400 MHz, CDCl3):
A (49% yield): 1H NMR (400 MHz, CDCl3):
d 6.10 (s, 2H), 5.70 (s,
d
7.79 (s, 1H), 7.32 (m, 5H), 6.82 (m, 1H), 4.27 (q, J¼7.2 Hz, 2H), 2.35
1H), 3.78–4.00 (m, 2H), 3.78 (s, 9H), 2.94 (s, 3H), 2.30–2.68 (m,
(m, 2H), 2.13 (m, 2H), 1.68–1.55 (m, 4H), 1.28 (t, J¼7.2 Hz, 3H). 13C
2H), 2.05 (m, 2H), 1.73 (s, 3H), 1.66 (m, 4H), 1.06 (t, J¼7 Hz, 3H). 13C
NMR (125 MHz, CDCl3):
d
196.5, 165.1, 144.6, 141.3, 139.2, 133.2,
NMR (100 MHz, CDCl3): d 164.5, 164.1, 160.5, 159.6, 137.2, 120.3,
131.7, 129.9, 129.8, 128.5, 61.2, 26.1, 22.6, 21.6, 21.3, 14.0. IR (neat)
cmꢀ1: 3050, 3020, 2974, 2924, 2860, 1662, 1654, 1633, 1570, 1497,
1448, 1250, 1190. HRMS (m/z): calcd for C18H20O3 [Mþ], 284.1407;
found, 284.1411. JC–H: 7.8 Hz.
109.3, 90.9, 66.9, 58.8, 55.6, 55.1, 31.2, 27.8, 22.4, 22.3, 20.5, 14.0. IR
(neat) cmꢀ1: 2998, 2971, 2940, 2926, 2852, 2840, 1672, 1606, 1588.
HRMS (m/z): calcd for C23H32NO6 [MꢀHþ], 418.2224; found,
418.2236.
General procedure C provided the title compound (14b) from
5.5.2. 2-(Cyclohex-1-enecarbonyl)-3-(2,4,6-trimethoxy-phenyl)-
acrylic acid ethyl ester (12b)
the intermediate isoxazoline (96% combined yield with 14a). 1H
NMR (500 MHz, CDCl3):
d
7.70 (s, 1H), 6.07 (s, 2H), 4.18 (q, J¼7.5 Hz,
The intermediate isoxazoline (2-methyl-5-(2-methyl-cyclohex-1-
enyl)-3-(2,4,6-trimethoxy-phenyl)-2,3-dihydro-isoxazole-4-carboxyl-
ic acid ethyl ester) was prepared according to general procedure A
2H), 3.84 (s, 3H), 3.78 (s, 6H), 2.24 (m, 2H), 2.03 (m, 2H), 1.70 (s, 3H),
1.65 (m, 4H), 1.23 (t, J¼7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d
199.4, 167.4, 163.6, 159.9, 136.9, 134.7, 133.4, 132.9, 105.7, 90.3,
(67% yield): 1H NMR (400 MHz, CDCl3):
d
6.31 (s, 1H), 6.08 (s, 2H),
60.3, 55.45, 55.43, 31.3, 27.4, 22.6, 22.3, 21.1, 14.1. IR (neat) cmꢀ1
:
5.65 (s, 1H), 3.93 (m, 2H), 3.76 (m, 9H), 2.87 (s, 3H), 2.36–2.17 (m,
2926, 2852, 2841, 2830, 1707, 1646, 1629, 1607, 1584, 1508. HRMS
4H), 1.67 (m, 4H), 1.03 (t, J¼7 Hz, 3H). 13C NMR (100 MHz, CDCl3):
(m/z): calcd for C22H29O6 [MꢀHþ], 389.1935; found, 389.1944. JC–H
:
d
164.44, 164.42, 160.5, 159.6, 133.6, 127.0, 110.5, 99.8, 90.8, 67.1,
12.4 Hz.
58.9, 55.7, 55.0, 47.9, 26.1, 25.3, 22.2, 21.5, 13.8. IR (neat) cmꢀ1
:
2996, 2971, 2942, 2928, 2852, 2840, 1672, 1649, 1625, 1606, 1588.
HRMS (m/z): calcd for C22H30NO6 [MꢀHþ], 404.2068; found,
404.2074.
5.5.5. 2-(2-Methyl-cyclohex-1-enecarbonyl)-3-phenyl-acrylic acid
ethyl ester (15a)
The intermediate isoxazoline (2-methyl-5-(2-methyl-cyclohex-1-
enyl)-3-phenyl-2,3-dihydro-isoxazole-4-carboxylic acid ethyl ester)
was prepared according to general procedure A (61% yield): 1H
General procedure C provided the title compound (12b) from
the intermediate isoxazoline (96% combined yield with 12a). 1H
NMR (500 MHz, CDCl3):
d
7.79 (s, 1H), 7.53 (dd, Jab¼8.0 Hz,
NMR (400 MHz, CDCl3):
d
7.39 (d, J¼7.2 Hz, 2H), 7.33 (t, J¼6.8 Hz,
Jac¼1.5 Hz, 1H), 6.80 (d, J¼8.0 Hz, 1H), 6.59 (s, 2H), 6.03 (s, 2H), 4.25
1H), 7.27 (m, 1H), 4.09–3.98 (m, 2H), 2.96 (s, 3H), 2.23 (m, 2H), 2.06
(q, J¼7.0 Hz, 2H), 3.79 (s, 3H), 3.66 (s, 6H), 1.21 (t, J¼7.0 Hz, 3H). 13C
(m, 2H), 1.72 (s, 3H), 1.68 (m, 4H), 1.14 (t, J¼7.2 Hz, 3H). 13C NMR
NMR (125 MHz, CDCl3):
d
195.1, 167.0, 163.2, 159.4, 141.1, 138.5,
(100 MHz, CDCl3): d 164.7, 163.7, 142.2, 138.1, 182.2, 127.5, 127.0,
134.8, 129.3, 105.5, 90.2, 90.1, 65.8, 35.4, 35.3, 35.0, 26.0, 23.0, 22.1,
21.8, 14.2. IR (neat) cmꢀ1: 2928, 2850, 2841, 2832, 1706, 1646, 1629,
119.6,103.9, 75.8, 59.4, 47.2, 31.2, 27.7, 22.3, 22.2, 20.6,13.9. IR (neat)
cmꢀ1: 2977, 2927, 2858, 2360, 2337, 1693, 1627, 1442, 1373, 1330,

D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
3175
1276, 1234, 1172, 1076. HRMS (m/z): calcd for C20H26NO3 [MꢀHþ],
(125 MHz, CDCl3):
d
164.1, 161.1, 150.0, 147.2, 141.6, 128.4, 127.8,
328.1907; found, 328.1915.
127.2, 125.1, 120.7, 110.2, 107.8, 102.6, 101.5, 76.8, 60.0, 53.4, 14.0. IR
(neat) cmꢀ1: 3101, 3015, 2981, 2897, 1701, 1692, 1633, 1604, 1488,
1446, 1326, 1255, 1232, 1074, 1039, 813. HRMS (m/z): calcd for
C20H20NO5 [MꢀHþ], 354.1336; found, 354.1341.
General procedure C provided the title compound (15a) from the
intermediate isoxazoline (85% combined yield with 15b) and char-
acterized as a 2:1 mixture. 1H NMR (500 MHz, CDCl3):
d 7.68 (s, 1H),
7.47 (m, 2.5H), 7.33 (m, 5H), 4.35 (m, 2.82H), 2.23 (m, 0.9H), 2.18 (m,
2H), 2.10 (m, 3H), 2.02 (s, 3H),1.70 (m, 2.5H), 1.48 (m, 4.5H),1.26 (m,
General procedure C provided the title compound (19a) from
the intermediate isoxazoline (94% yield). 1H NMR (400 MHz,
4.6H). 13C NMR (100 MHz, CDCl3):
d
197.3, 194.6, 165.3, 149.5, 142.7,
CDCl3):
d
7.91 (s, 1H), 7.51 (d, J¼8.0 Hz, 1H), 7.48 (s, 1H), 7.37–7.22
140.4, 135.6, 134.7, 133.5, 133.2, 131.87, 131.83, 131.5, 130.6, 129.9,
129.7,129.6,128.8,128.5, 61.5, 61.3, 34.5, 31.1, 27.3, 26.3, 22.48, 22.46,
22.3, 22.1, 22.0, 21.1, 14.2, 13.9. IR (neat): 3051, 3022, 2974, 2924,
2862, 1662, 1654, 1636, 1570, 1497, 1448, 1253, 1192. HRMS (m/z):
calcd for C19H22O3 [Mþ], 298.1563; found, 298.1567.
(m, 5H), 6.78 (d, J¼8.0 Hz, 1H), 6.02 (s, 1H), 4.25 (q, J¼7.2 Hz, 2H),
1.21 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d 193.6, 165.0,
152.6, 148.4, 142.1, 132.8, 131.3, 130.3, 130.1,128.7, 126.4, 108.1, 102.0,
61.5, 14.1. IR (neat) cmꢀ1: 2980, 2903, 1712, 1658, 1600, 1502, 1486,
1438, 1244. HRMS (m/z): calcd for C19H16O5 [MꢀHþ], 325.1071;
found, 325.1076. JC–H: 7.8 Hz.
5.5.6. 2-(Cyclopent-1-enecarbonyl)-3-phenyl-acrylic acid ethyl
ester (17a)
The intermediate isoxazoline (2-methyl-5-(2-methyl-cyclohex-1-
enyl)-3-phenyl-2,3-dihydro-isoxazole-4-carboxylic acid ethyl ester)
was prepared according to general procedure A (89% yield): 1H
5.5.9. 2-(Benzo[1,3]dioxole-5-carbonyl)-3-(2,4,6-triethyl-phenyl)-
acrylic acid ethyl ester (21b)
The intermediate isoxazoline (5-benzo[1,3]dioxol-5-yl-2-methyl-
3-(2,4,6-triethyl-phenyl)-2,3-dihydro-isoxazole-4-carboxylic acid et-
hyl ester) was prepared according to general procedure A (38%
NMR (400 MHz, CDCl3):
d 7.26–7.38 (m, 5H), 6.92 (m, 1H), 4.98 (s,
1H), 4.04 (m, 2H), 2.92 (s, 3H), 2.52–2.81 (m, 4H), 1.98 (m, 2H), 1.13
yield). 1H NMR (500 MHz, CDCl3):
1H), 6.88 (m, 2H), 6.02 (s, 2H), 5.75 (s,1H), 3.95 (m, 2H), 3.05 (s, 3H),
d
7.39 (d, J¼8.5 Hz, 1H), 7.33 (s,
(t, J¼7 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d
163.9, 158.7, 141.7,
141.5, 130.8, 128.2, 127.5, 127.1, 103.3, 59.6, 46.8, 33.5, 23.1, 13.9. IR
(neat) cmꢀ1: 3093, 3035, 2958, 2939, 2906, 2873, 2852, 1703, 1681,
1610,1581,1456,1392, 1371, 1323,1298,1276,1261, 1232, 1195,1172,
1130, 1074, 950. HRMS (m/z): calcd for C18H21NO3 [Mþ], 299.1516;
found, 299.1510.
2.98–2.84 (m, 4H), 2.60 (q, J¼7.5 Hz, 2H), 1.23 (m, 9H), 0.95 (t,
J¼7 Hz, 3H). 13C NMR (125 MHz, CDCl3):
d 163.9, 160.7, 149.6, 147.1,
143.5, 131.7, 126.7, 124.3, 121.1, 109.8, 107.8, 103.2, 101.4, 73.4, 59.6,
47.8, 28.4, 16.3, 15.3, 13.7. IR (neat) cmꢀ1: HRMS (m/z): calcd for
C26H32NO5 [MꢀHþ], 438.2275; found, 438.2268.
General procedure C provided the title compound (17a) from
General procedure C provided the title compound (21b) from
the intermediate isoxazoline (89% yield). 1H NMR (400 MHz,
the intermediate isoxazoline (64% yield). 1H NMR (500 MHz,
CDCl3):
2H), 2.65 (m, 2H), 2.43 (m, 2H), 1.99 (m, 2H), 1.33 (t, J¼7.2 Hz,
3H). 13C NMR (125 MHz, CDCl3):
193.5, 165.1, 148.3, 145.4, 141.2,
d
7.77 (s, 1H), 7.35 (m, 5H), 6.60 (s, 1H), 4.26 (q, J¼7.2 Hz,
CDCl3):
d
7.52 (s, 1H), 7.5 (d, J¼8.0 Hz, 1H), 7.41 (s, 1H), 6.9 (s, 2H),
6.88 (d, J¼8.0 Hz, 1H), 6.06 (s, 2H), 3.98 (q, J¼7.0 Hz, 2H), 2.60 (m,
d
6H), 1.26–1.17 (m, 9H), 0.89 (t, J¼7.0 Hz, 3H). 13C NMR (100 MHz,
133.2, 132.3, 130.1, 129.9, 128.7, 61.4, 34.0, 30.2, 22.9, 14.1.
CDCl3): d 191.0, 164.9, 151.9, 148.2, 144.8, 140.7, 137.5, 131.6, 130.2,
IR (neat) cmꢀ1: 2974, 2955, 1714, 1703, 1650, 1609, 1448. HRMS
125.6, 125.0, 108.8, 107.8, 101.9, 60.8, 28.6, 26.9, 15.5, 14.8, 13.4. IR
(m/z): calcd for C17H18O3 [Mþ], 269.1172; found, 269.1175. JC–H
:
(neat) cmꢀ1: 2963, 2930, 2871, 1728, 1603, 1483, 1439, 1371. HRMS
7.8 Hz.
(m/z): calcd for C25H29O5 [MꢀHþ], 409.2010; found, 409.2013. JC–H
:
12.4 Hz.
5.5.7. 2-(5,6-Dihydro-4H-pyran-2-carbonyl)-3-phenyl-acrylic acid
ethyl ester ((E)-18a)
5.5.10. 2-(Benzo[1,3]dioxole-5-carbonyl)-3-(2,4,6-trimethoxy-
The intermediate isoxazoline (5-(5,6-dihydro-4H-pyran-2-yl)-2-
methyl-3-phenyl-2,3-dihydro-isoxazole-4-carboxylic acid ethyl ester)
was prepared according to general procedure A (53% yield). 1H NMR
phenyl)-acrylic acid ethyl ester (22b)
The intermediate isoxazoline (5-benzo[1,3]dioxol-5-yl-2-methyl-
3-(2,4,6-trimethoxy-phenyl)-2,3-dihydro-isoxazole-4-carboxylic acid
ethyl ester) was prepared according to general procedure A (72%
(400 MHz, CDCl3):
d
7.38–7.26 (m, 5H), 5.71 (t, J¼4 Hz, 1H), 4.97 (s,
1H), 4.14–4.03 (m, 4H), 2.93 (s, 3H), 2.22 (m, 2H), 1.92 (m, 2H), 1.14
yield). 1H NMR (400 MHz, CDCl3):
d
7.41 (d, J¼8.4 Hz, 1H), 7.39 (s,
(t, J¼7 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d
163.4, 156.5, 142.2,
1H), 6.83 (d, J¼8 Hz, 1H), 6.10 (s, 2H), 5.97 (s, 2H), 5.75 (s, 1H), 3.96
140.8, 128.2, 127.7, 127.2, 109.0, 104.5, 76.6, 66.4, 59.8, 46.6, 21.7,
20.4, 13.9. IR (neat) cmꢀ1: 3028, 2927, 2874, 2840, 1700, 1685, 1666,
1607, 1453, 1391, 1387, 1371. HRMS: calcd for C18H21O4N [Mþ],
315.1465; found, 315.1466.
(m, 2H), 3.76 (m, 9H), 2.96 (s, 3H), 1.02 (t, J¼7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3):
d 164.3, 161.2, 160.7, 159.6, 149.3, 146.9, 124.2,
121.6, 109.8, 107.6, 101.2, 100.2, 90.9, 67.6, 60.2, 59.1, 55.8, 55.1, 13.8.
IR (neat) cmꢀ1: 2999, 2976, 2949, 2932, 2874, 1690, 1636, 1591,
1505, 1487. HRMS (m/z): calcd for C23H26NO8 [MꢀHþ], 444.1653;
found, 444.1655.
General procedure C provided the title compound (18a) from
the intermediate isoxazoline. 1H NMR (500 MHz, CDCl3):
d 7.81 (s,
1H), 7.39–7.33 (m, 5H), 6.00 (t, J¼4.5 Hz, 1H), 4.28 (t, J¼7.0 Hz, 2H),
General procedure C provided the title compound (22b) from
4.07 (m, 2H), 2.14 (m, 2H), 1.82 (m, 2H), 1.29 (t, J¼7.0 Hz, 3H). 13C
the intermediate isoxazoline (94% combined yield with 22a). 1H
NMR (100 MHz, CDCl3):
d
190.5, 164.9, 151.2, 142.9, 133.0, 130.3,
NMR (500 MHz, CDCl3):
d
8.09 (s, 1H), 7.47 (d, J¼8.0 Hz, 1H), 7.42 (s,
130.2, 128.7, 116.0, 66.5, 61.5, 21.3, 21.0, 14.1. IR (neat) cmꢀ1: 3070,
3000, 2945, 2892, 2860, 1675, 1614, 1601, 1570, 1497, 1448, 1250,
1190. JC–H: 7.3 Hz.
1H), 6.78 (d, J¼8.0 Hz, 1H), 6.01 (s, 2H), 5.96 (s, 2H), 4.19 (q,
J¼7.2 Hz, 2H), 3.77 (s, 3H), 3.51 (s, 6H), 1.56 (t, J¼7.2 Hz, 3H). 13C
NMR (125 MHz, CDCl3):
d 192.0, 176.6, 166.7, 163.4, 159.6, 150.9,
147.7, 135.5, 132.8, 128.7, 125.1, 108.3, 107.5, 105.1, 101.6, 90.2, 60.8,
55.3, 54.7, 14.1. IR (neat) cmꢀ1: 2975, 2938, 2901, 2839, 1703, 1661,
1598, 1573, 1436. HRMS (m/z): calcd for C22H22O8Na [MꢀNaþ],
415.1387; found, 415.1393. JC–H: 8.5 Hz.
5.5.8. 2-(Benzo[1,3]dioxole-5-carbonyl)-3-phenyl-acrylic acid ethyl
ester (19a)
The intermediate isoxazoline (5-benzo[1,3]dioxol-5-yl-2-methyl-
3-phenyl-2,3-dihydro-isoxazole-4-carboxylic acid ethyl ester) was
prepared according to general procedure A (85% yield). 1H NMR
5.5.11. 2-(Benzo[1,3]dioxole-5-carbonyl)-3-(3,4,5-trimethoxy-
phenyl)-acrylic acid ethyl ester (23a)
The intermediate isoxazoline (5-benzo[1,3]dioxol-5-yl-2-methyl-
3-(3,4,5-trimethoxy-phenyl)-2,3-dihydro-isoxazole-4-carboxylic acid
(500 MHz, CDCl3):
d
7.50 (d, J¼8 Hz, 1H), 7.43 (m, 3H), 7.37 (t,
J¼7 Hz, 2H), 7.31 (m, 1H), 6.84 (d, J¼8 Hz, 1H), 6.05 (s, 2H), 5.07 (s,
1H), 4.11 (q, J¼7 Hz, 2H), 3.01 (s, 3H), 1.14 (t, J¼7 Hz, 3H). 13C NMR

3176
D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
ethyl ester) was prepared according to general procedure A (70%
yield). 1H NMR 400 MHz (CDCl3):
5.5.14. 2-(Benzo[1,3]dioxole-5-carbonyl)-hept-2-enoic acid ethyl
ester (26a)
The intermediate isoxazoline (5-benzo[1,3]dioxol-5-yl-3-butyl-2-
methyl-2,3-dihydro-isoxazole-4-carboxylic acid ethyl ester) was pre-
pared according to general procedure B (72% yield). 1H NMR (400
d
7.46 (d, J¼8 Hz, 1H), 7.44 (s, 1H),
6.83 (d, J¼8 Hz, 1H), 6.64 (s, 2H), 5.98 (s, 2H), 4.99 (s, 1H), 4.09 (q,
J¼7.2 Hz, 2H), 3.86 (s, 6H), 3.84 (s, 3H), 2.98 (s, 3H), 1.14 (t, J¼7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3):
d 163.9, 161.0, 153.2, 150.0, 147.2,
137.5, 137.1, 125.0, 120.6, 110.1, 107.8, 104.0, 102.4, 101.5, 60.6, 59.9,
56.0, 46.8, 20.9, 14.1. IR (neat) cmꢀ1: 2968, 2942, 2926, 2901, 2829,
1765, 1688, 1635, 1592, 1504, 1486, 1442, 1421. HRMS (m/z): calcd
for C23H26NO8 [MꢀHþ], 444.1653; found, 444.1654.
MHz CDCl3):
d
7.42 (d, J¼8 Hz, 1H), 7.36 (s, 1H), 6.84 (d, J¼8.4 Hz,
1H), 6.01 (s, 2H), 4.18 (m, 2H), 3.98 (m, 1H), 2.84 (s, 3H), 1.32–1.77
(m, 6H), 1.27 (t, J¼7.2 Hz, 3H), 0.82 (t, J¼7 Hz, 3H). 13C NMR
(100 MHz, CDCl3):
d 164.4, 160.9, 149.7, 147.0, 124.8, 121.1, 110.0,
General procedure C provided the title compound (23a) from the
intermediate isoxazoline (85% yield). 1H NMR (500 MHz, CDCl3):
107.7, 101.9, 101.4, 73.2, 59.8, 46.9, 34.4, 27.6, 22.5, 14.1, 13.9. IR
(neat) cmꢀ1: 2979, 2902, 1697, 1627, 1600, 1504, 1488, 1448, 1332,
1251, 1226, 1130, 1108, 1039, 968, 933, 813, 761. HRMS (m/z): calcd
for C18H24NO5 [MꢀHþ], 334.1653; found, 334.1655.
d
7.79 (s,1H), 7.53 (d, J¼8.0 Hz,1H), 7.45 (s,1H), 6.80 (d, J¼8.0 Hz,1H),
6.59 (s, 2H), 6.04 (s, 2H), 4.24 (q, J¼7.2 Hz 2H), 3.80 (s, 3H), 3.68 (s,
6H),1.22 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d
193.8, 165.0,
General procedure C provided the title compound (26a) from
the intermediate isoxazoline (95% combined yield with 26b). 1H
152.9,152.6,148.4,142.0,139.9,131.2,130.3,128.1,126.2,108.2,108.0,
107.6, 102.0, 61.4, 60.8, 55.8, 14.0. IR (neat) cmꢀ1: 2937, 2903, 2838,
1712, 1657, 1601, 1579, 1503, 1486, 1439, 1244. HRMS (m/z): calcd for
C22H23O8 [MꢀHþ], 415.1387; found, 415.1387. JC–H: 8.3 Hz.
NMR (500 MHz, CDCl3):
d
7.44–7.41 (m, 2H), 7.11 (t, J¼8.0 Hz, 1H),
6.82 (d, J¼8.0 Hz, 1H), 6.05 (s, 2H), 4.17 (q, J¼7.2 Hz, 2H), 2.10 (q,
J¼7.5, 2H), 1.43–1.20 (m, 4H), 1.18 (t, J¼7.5 Hz, 3H), 0.82 (t, J¼7.2 Hz,
3H). 13C NMR (125 MHz, CDCl3):
d 192.6, 164.5, 152.3, 148.3, 147.9,
5.5.12. 2-(Benzo[1,3]dioxole-5-carbonyl)-3-cyclohexyl-acrylic acid
ethyl ester (24a)
The intermediate isoxazoline (5-benzo[1,3]dioxol-5-yl-3-cyclo-
hexyl-2-methyl-2,3-dihydro-isoxazole-4-carboxylic acid ethyl ester)
was prepared according to general procedure A (86% yield). 1H NMR
133.6,131.8,126.3,108.2,108.0,101.9, 61.0, 30.4, 29.3, 22.3,14.0,13.7.
IR (neat) cmꢀ1: 2957, 2930, 2905, 2861, 1711, 1663, 1602, 1503, 1487,
1439, 1366. HRMS (m/z): calcd for C17H21O5 [MꢀHþ], 305. 1384;
found, 305.1388. JC–H: 7.3 Hz.
(400 MHz, CDCl3):
1H), 6.00 (s, 2H), 4.17 (q, J¼7 Hz, 2H), 3.87 (d, J¼6.6 Hz, 1H), 2.81 (s,
3H), 1.17–1.34 (m, 13H). 13C NMR (125 MHz, CDCl3):
164.6, 161.2,
125.0, 121.2, 110.2, 107.7, 101.4, 77.8, 59.8, 47.6, 42.0, 29.7, 26.7, 26.5,
26.4, 26.2, 14.2. IR (neat) cmꢀ1: 2970, 2956, 2849, 1769, 1693,
1606,1589,1503,1490,1448,1357,1344,1241,1067,1082, 947. HRMS
(m/z): calcd for C20H26NO5 [MꢀHþ], 360.1805; found, 360.1811.
General procedure C provided the title compound (24a) from
the intermediate isoxazoline (93% yield). 1H NMR (400 MHz,
d
7.39 (d, J¼8 Hz,1H), 7.33 (s,1H), 6.83 (d, J¼8 Hz,
5.5.15. 2-(Benzo[1,3]dioxole-5-carbonyl)-acrylic acid
ethyl ester (27)
The intermediate N-methyl isoxazoline (5-benzo[1,3]dioxol-5-yl-
2-methyl-2,3-dihydro-isoxazole-4-carboxylic acid ethyl ester) was
prepared according to general procedure B (85% yield). 1H NMR
d
(500 MHz, CDCl3):
d
7.45 (d, J¼8 Hz, 1H), 7.38 (s, 1H), 6.84 (d,
J¼8 Hz, 1H), 6.00 (s, 2H), 4.58 (m, 1H), 4.21 (q, J¼7 Hz, 2H), 3.96 (m,
1H), 2.87 (s, 3H), 1.28 (t, J¼7 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d
164.0, 161.1, 149.7, 147.1, 124.6, 120.7, 109.8, 107.7, 101.4, 98.0, 62.5,
CDCl3):
6.06 (s, 2H), 4.16 (q, J¼7.2 Hz, 2H), 2.17 (m,1H), 1.64 (m, 5H),1.14 (m,
9H). 13C NMR (100 MHz, CDCl3):
192.5, 164.8, 152.3, 152.1, 148.2,
d
7.43 (m, 2H), 6.94 (d, J¼10.8 Hz,1H), 6.85 (d, J¼8.0 Hz,1H),
59.9, 47.5, 14.2. IR (neat) cmꢀ1: 3085, 2979, 2960, 2902, 2875, 2781.
HRMS: calcd for C14H16NO5 [MꢀHþ], 278.1023; found, 278.1031.
Alternatively, the intermediate N-tert-butyl isoxazoline
d
131.9, 131.7, 126.2, 108.1, 107.9, 101.9, 61.0, 38.5, 31.5, 25.4, 24.9, 13.9.
IR (neat) cmꢀ1: 2924, 2850, 1715, 1663, 1602, 1503, 1486, 1439.
HRMS (m/z): calcd for C19H22O5Na [MꢀNaþ], 353.1359; found,
353.1359. JC–H: 8.6 Hz.
(5-benzo[1,3]
carboxylic acid ethyl ester) was prepared according to general
procedure B (79% yield). 1H NMR (500 MHz, CDCl3):
7.20 (dd,
dioxol-5-yl-2,3,3-trimethyl-2,3-dihydro-isoxazole-4-
d
Jab¼8 Hz, Jab¼1 Hz, 1H), 7.12 (d, J¼1 Hz, 1H), 5.99 (s, 2H), 4.16 (q,
J¼7 Hz, 2H), 2.77 (s, 3H), 1.42 (s, 6H), 1.20 (t, J¼7 Hz, 3H). 13C NMR
5.5.13. 2-(Benzo[1,3]dioxole-5-carbonyl)-5-phenyl-penta-2,4-
dienoic acid ethyl ester (25a)
The intermediate isoxazoline (5-benzo[1,3]dioxol-5-yl-2-methyl-
3-styryl-2,3-dihydro-isoxazole-4-carboxylic acid ethyl ester) was
prepared according to general procedure A (96% yield). 1H NMR
(125 MHz, CDCl3): d 164.5, 161.7, 149.5, 147.0, 124.3, 121.9, 109.8,
107.7, 107.4, 101.4, 69.9, 59.6, 53.4, 38.4, 14.05. IR (neat) cmꢀ1: 2975,
2929, 2902, 1689, 1604, 1504, 1488, 1446, 1371. HRMS: calcd for
C16H20NO5 [MꢀHþ], 306.1336; found, 306.1344.
General procedure C provided the title compound (27) from ei-
ther the N-methyl or N-tert-butyl intermediate isoxazoline. 1H NMR
(500 MHz, CDCl3):
d
7.49 (d, J¼8 Hz, 1H), 7.42 (m, 3H), 7.30 (m, 2H),
7.23 (m, 1H), 6.86 (d, J¼8.5 Hz, 1H), 6.72 (d, J¼16 Hz, 1H), 6.36 (dd,
Jab¼16 Hz, Jac¼6.5 Hz, 1H), 5.99 (s, 2H), 4.75 (d, J¼6.5 Hz, 1H), 4.20
(m, 2H), 2.95 (s, 3H), 1.27 (t, J¼7.2 Hz, 3H). 13C NMR (125 MHz,
(400 MHz, CDCl3):
d
7.45 (m, 2H), 6.87 (d, J¼8.0 Hz, 1H), 6.66 (s, 1H),
6.08 (s, 2H), 6.00 (s, 1H), 4.28 (q, J¼7.0 Hz, 2H), 1.25 (t, J¼7.0 Hz, 3H).
13C NMR (100 MHz, CDCl3):
d
191.3, 164.3, 152.3, 148.2, 141.3, 131.0,
CDCl3):
d
164.1, 161.2, 150.0, 147.2, 136.8, 131.0, 128.5, 127.6, 127.4,
130.4,126.6,108.6,107.8,101.9, 61.4,13.9. IR (neat) cmꢀ1: 2981, 2897,
1718,1661,1603,1502,1487,1439,1392,1367,1354,1316,1248,1219,
1092. HRMS: calcd for C13H13O5 [MꢀHþ], 249.0758; found,
249.0753.
126.6, 125.0, 120.8, 110.1, 107.8, 101.5, 101.0, 74.5, 60.1, 46.1, 14.2. IR
(neat) cmꢀ1: 3031, 2981, 2964, 2904, 1764, 1701, 1632, 1613, 1600,
1503. HRMS (m/z): calcd for C22H22NO5 [MꢀHþ], 308.1492; found,
380.1499.
General procedure C provided the title compound (25a) from
5.5.16. 2-(Benzo[1,3]dioxole-5-carbonyl)-3-methyl-but-2-enoic
acid ethyl ester (28)
the intermediate isoxazoline (92% combined yield with 25b). 1H
NMR (400 MHz, CDCl3):
d
7.68 (d, J¼11.6 Hz, 1H), 7.49–7.30 (m,
The intermediate isoxazoline (5-benzo[1,3] dioxol-5-yl-2,3,3-tri-
methyl-2,3-dihydro-isoxazole-4-carbxylic acid ethyl ester) was pre-
7H), 7.05 (d, J¼15.4 Hz, 1H), 6.86 (d, J¼8.5 Hz, 1H), 6.78 (dd,
Jab¼15.4 Hz, Jac¼8.5 Hz, 1H), 6.08 (s, 2H), 4.23 (q, J¼7.2 Hz, 2H),
pared by method B (0.248 g, 79%). 1H NMR (500 MHz, CDCl3):
d 7.20
1.21 (t, J¼7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3):
d
192.5, 165.1,
(dd, Jab¼8 Hz, Jab¼1 Hz,1H), 7.12 (d, J¼1 Hz,1H), 5.99 (s, 2H), 4.16 (q,
152.4, 148.3, 143.5, 143.2, 135.5, 131.9, 131.3, 129.6, 128.7, 127.6,
126.6, 122.9, 108.3, 108.1, 102.0, 61.2, 14.1. IR (neat) cmꢀ1: 2979,
2909, 1715, 1648, 1612, 1600, 1590, 1502, 1487, 1439, 1248. HRMS
J¼7 Hz, 2H), 2.77 (s, 3H), 1.42 (s, 6H), 1.20 (t, J¼7 Hz, 3H). 13C NMR
(125 MHz, CDCl3):
d 164.5, 161.7, 149.5, 147.0, 124.3, 121.9, 109.8,
107.7, 107.4, 101.4, 69.9, 59.6, 53.4, 38.4, 14.05. IR (neat) cmꢀ1: 2975,
2929, 2902, 1689, 1604, 1504, 1488, 1446, 1371. HRMS: calcd for
C16H20NO5 [MꢀHþ], 306.1336; found, 306.1344.
(m/z): calcd for C21H19O5 [MꢀHþ], 351.1227; found, 351.1236. JC–H
:
8.1 Hz.

D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
3177
3
General procedure C provided the title compound (28) from the
intermediate isoxazoline. 1H NMR (400 MHz, CDCl3):
7.47 (dd,
C
40H65O6PSi2Na 751.3950; found, 751.3964. JC–H¼7.8 Hz for
d
Cketone–H.
Jab¼8.0 Hz, Jac¼1.2 Hz, 1H), 7.42 (d, J¼1.2 Hz, 1H), 6.84 (d, J¼8.0 Hz,
2H), 6.06 (s, 2H), 4.11 (d, J¼7.0 Hz, 2H), 2.30 (s, 3H), 1.79 (s, 3H), 1.09
5.5.21.
a
-[(2E)-2-Methyl-3-phenyl-2-propen-1-ylidene]-
b-oxo-3,5-
(t, J¼8.0 Hz, 3H). 13C NMR (125 MHz, CDCl3):
d
193.7, 164.7, 153.9,
bis[[tris(1-methylethyl)silyl]oxy]-, (a
Alkynyl nitrile 9d (2.4 g, 5.1 mmol) was subjected to general
procedure D using the nitrone 10d to obtain 1.8 g (57%) of 33b. 1H
E) benzenepropanenitrile (33b)
152.1, 148.3, 132.0, 129.3, 125.9, 108.2, 108.0, 101.9, 60.4, 24.1, 22.1,
13.9. IR (neat) cmꢀ1: 2979, 2899, 1714, 1661, 1601, 1503, 1485, 1436,
1366, 1354, 1281, 1223. HRMS: calcd for C15H17O5 [MꢀHþ],
277.1071; found, 277.1070.
NMR (CDCl3, 400 MHz):
d 7.68 (s, 1H), 7.41 (m, 5H), 7.09 (s, 1H),
6.90 (d, J¼2.0 Hz, 2H), 6.65 (t, J¼2.0 Hz, 1H), 2.50 (s, 3H), 1.24 (m,
6H), 1.10 (d, J¼9.0 Hz, 36H). 13C NMR (CDCl3, 100 MHz):
d 189.6,
5.5.17.
a
-[(2E)-2-Methyl-3-phenyl-2-propen-1-ylidene]-
b
-oxo-3,5-
160.3, 157.2, 147.5, 137.7, 135.4, 133.8, 130.0, 129.3, 128.6, 116.5,
113.7, 109.5, 17.9, 15.6, 12.6. IR (neat, cmꢀ1): 2943, 2866, 2210, 1555,
1581, 1435, 1172, 1030. HRMS (EI) calculated for C37H55NO3Si2
bis[[tris(1-methylethyl)silyl]oxy]-, (
aZ) benzenepropanoic acid
methyl ester (29b)
3
3
Alkynyl ester 9a was subjected to general procedure D using the
617.3715; found, 617.3743. JC–H¼6.0 Hz for Cketone–H, JC–H¼
nitrone 10d to yield 3.0 g (65%) of 29b. 1H NMR (CDCl3, 400 MHz):
13.4 Hz for Cester–H.
d
7.66 (d, J¼0.8 Hz, 1H), 7.34 (m, 5H), 7.07 (d, J¼2.4 Hz, 2H), 6.98 (s,
1H), 6.65 (t, J¼2.0 Hz, 1H), 3.69 (s, 3H), 1.79 (s, 3H), 1.24 (m, 6H), 1.12
5.5.22. 1-[3,5-Bis[[tris(1-methylethyl)silyl]oxy]phenyl]-4-methyl-2-
[(4-methylphenyl)sulfonyl]-5-phenyl-, (2Z,4E) 2,4-pentadien-
1-one (34b)
Alkynyl sulfone 9e (739 mg, 1.2 mmol) was subjected to general
procedure D using the nitrone 10d to obtain 191 mg (43%) of 34b.
(d, J¼9.0 Hz, 36H). 13C NMR (CDCl3, 100 MHz):
d 195.0, 165.8, 157.3,
147.8, 141.9, 138.9, 136.2, 133.3, 129.7, 129.2, 128.3, 128.0, 117.3, 113.7,
52.3, 17.8, 12.5. IR (neat, cmꢀ1): 3024, 2945, 2892, 1724, 1714, 1679,
1672, 1588, 1443, 1334, 1249, 1198. HRMS (EI) calculated for
C38H58O5Si2 650.3817; found, 650.3817. 3JC–H¼4.2 Hz for Cketone–H,
3JC–H¼7.5 Hz for Cester–H.
1H NMR (CDCl3, 400 MHz):
d
7.74 (d, J¼8.0 Hz, 2H), 7.69 (d,
J¼0.5 Hz, 1H), 7.30 (m, 5H), 7.17 (d, J¼8.0 Hz, 2H), 7.03 (d, J¼2.0 Hz,
2H), 6.92 (s, 1H), 6.64 (t, J¼2.0 Hz, 1H), 2.42 (s, 3H), 1.68 (s, J¼1.0 Hz,
3H),1.24 (m, 6H),1.10 (d, J¼9.0 Hz, 36H). 13C NMR (CDCl3,100 MHz):
5.5.18.
b-Oxo-a-[(2E)-3-phenyl-2-propen-1-ylidene]-3,5-
bis[[tris(1-methylethyl)silyl]oxy]-, (
a
E) benzenepropanoic acid
d 191.6, 176.5, 157.3, 145.8, 144.4, 142.5, 139.0, 138.2, 137.3, 135.7,
methyl ester (30a)
131.9, 130.2, 129.6, 129.0, 128.3, 128.1, 117.8, 114.2, 21.6, 17.4, 16.2,
12.5. IR (neat, cmꢀ1): 2948, 2729, 1746, 1666, 1453, 1244, 1087.
HRMS (EI) calculated for C43H62O5SSi2Na 769.3749; found,
769.3740. JC–H¼8.8 Hz for Cketone–H.
Alkynyl ester 9a (0.8 g, 1.5 mmol) was subjected to general
procedure D using the nitrone 10c to yield 320 mg (67%) of 30a. 1H
3
NMR (500 MHz, CDCl3):
d
7.69 (d, J¼12.0 Hz, 1H), 7.34 (m, 5H), 7.05
(d, J¼2.5 Hz, 2H), 7.02 (d, J¼16.0 Hz, 1H), 6.70 (dd, J¼2.5 Hz, 3.0 Hz,
1H), 6.66 (t, J¼2.4 Hz, 1H), 3.71 (s, 3H), 1.26 (m, 6H), 1.10 (d,
5.5.23. 2-Benzylidene-1-phenyl-heptane-1,3-dione (36b)
J¼8.5 Hz, 18H). 13C NMR (100 MHz, CDCl3):
d
194.0, 176.6, 165.4,
The intermediate N-methyl isoxazoline (5-butyl-2-methyl-3-
phenyl-2,3-dihydro-isoxazol-4-yl)-phenyl-mathanone) was prepared
157.4, 143.6, 143.4, 138.7, 135.5, 131.0, 129.6, 128.7, 127.6, 123.0, 117.5,
113.9, 52.2, 17.8, 12.6. IR (neat, cmꢀ1): 2944, 2866, 1719, 1672, 1584,
according to general procedure A. 1H NMR (400 MHz, CDCl3):
d 7.55
1462, 1438, 1279, 1171. HRMS (EI) calculated for C37H56O53Si2Na:
(m, 2H), 7.53–7.23 (m, 8H), 5.27 (s, 1H), 2.96 (s, 3H), 2.22 (t, J¼7 Hz,
3
659.3558; found, 659.3542. JC–H¼9.0 Hz for Cketone–H, JC–H
¼
2H), 1.55 (m, 2H), 1.22 (m, 2H), 0.80 (t, J¼7 Hz, 3H). 13C NMR
6.6 Hz for Cester–H.
(100 MHz, CDCl3): d 191.9, 166.0, 141.0, 140.5, 140.2, 131.4, 128.4,
128.2, 127.7, 127.4, 127.2, 114.1, 77.1, 47.1, 28.9, 26.5, 22.2, 13.5. IR
(neat) cmꢀ1: 2958, 2931, 1612, 1577, 1450, 1361, 1230, 1157. HRMS:
calcd for C21H23O2N [Mþ], 321.1723; found, 321.1717.
The intermediate N-tert-butyl isoxazoline (5-butyl-2-tert-butyl-
3-phenyl-2,3-dihydro-isoxazol-4-yl)-phenyl-mathanone) was pre-
pared according to general procedure A. 1H NMR (500 MHz, CDCl3):
5.5.19. N,N-Dimethyl-
ylidene]- -oxo-3,5-bis[[tris(1-methylethyl)silyl]oxy]-, (
benzenepropanamide (31b)
a
-[(2E)-2-methyl-3-phenyl-2-propen-1-
b
aZ)
Alkynyl amide 9b (1.6 g, 2.8 mmol) was subjected to general
procedure D using the nitrone 10d to obtain 1.2 g (63%) of 31b. 1H
d
7.44–7.39 (m, 5H), 7.35 (m, 2H), 2.26 (m, 2H), 7.20 (m, 1H), 5.64 (s,
NMR (CDCl3, 400 MHz):
d 7.34 (m, 5H), 7.02 (s, 1H), 6.88 (d,
1H), 5.29 (s, 1H), 2.15 (t, J¼8 Hz, 2H), 1.53 (m, 2H), 1.27 (m, 3H), 1.18
J¼2.4 Hz, 2H), 6.79 (s, 1H), 6.62 (t, J¼2.0 Hz,1H), 3.08 (s, 3H), 3.01 (s,
(s, 9H), 1.88 (t, J¼8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d 191.7,
3H), 2.08 (s, 3H), 1.24 (m, 6H), 1.10 (d, J¼9.0 Hz, 36H). 13C NMR
166.0, 143.5, 140.4, 131.2, 128.28, 128.21, 127.6, 127.5, 127.1, 115.5,
68.9, 61.2, 29.1, 26.5, 24.9, 22.4, 13.5. IR (neat) cmꢀ1: 2974, 2958,
2928, 2873, 2857, 1633, 1595, 1574, 1494, 1457, 1447, 1371, 1363.
HRMS: calcd for C24H30O2N [MꢀHþ], 364.2271; found, 364.2260.
General procedure C provided the title compound (36b) from
the N-tert-butyl intermediate isoxazoline (61% yield). 1H NMR
(CDCl3, 100 MHz):
d 194.2, 168.0, 156.9, 147.9, 141.5, 139.4, 136.3,
134.4, 133.7, 129.5, 128.3, 128.1, 115.5, 113.9, 38.2, 34.6, 17.8, 14.6,
12.6. IR (neat, cmꢀ1): 2945, 2867, 1643, 1585, 1437, 1393, 1336,1239,
1072. HRMS (EI) calculated for C39H61NO4Si2Na 686.4031; found,
3
686.4056. JC–H¼2.5 Hz for Cketone–H, 3JC–H¼10.5 Hz for Cester–H.
(500 MHz, CDCl3):
2.66 (t, J¼7.0 Hz, 2H), 2.60 (t, J¼7.0 Hz, 0.7H),1.64 (m, 4.2H),1.34 (m,
4.5H), 0.90 (m, 5H). 13C NMR (100 MHz, CDCl3):
198.2, 198.0, 141.8,
140.2, 139.4, 136.1, 134.5, 134.0, 133.0, 132.6, 130.4, 130.3, 130.2,
129.8, 129.5, 129.1, 128.95, 128.91, 128.7, 128.5, 127.9, 43.9, 39.3, 26.1,
25.3, 22.2, 22.0, 13.85, 13.81. IR (neat) cmꢀ1: 3060, 3029, 2919, 1706,
1700, 1640, 1609, 1598, 1449, 1320. HRMS: calcd for C20H21O2
[MꢀHþ]; 293.1562; found, 293.1569.
d 7.92 (m, 2H), 7.80 (m, 1.6H), 7.61–7.21 (m, 15H),
5.5.20. P-[(1Z,3E)-1-[3,5-Bis[[tris(1-methylethyl)silyl]oxy]benzoyl]-
3-methyl-4-phenyl-1,3-butadien-1-yl]-, phosphonic acid diethyl
ester (32b)
d
Alkynyl phosphate 9c (2.7 g, 4.5 mmol) was subjected to
general procedure D using the nitrone 10d to obtain 1.9 g (57%) of
32b. 1H NMR (CDCl3, 400 MHz):
d
7.47 (d, J¼26.0 Hz, 1H), 7.27 (m,
5H), 7.11 (d, J¼2.0 Hz, 2H), 6.87 (s, 1H), 6.64 (t, J¼2.0 Hz, 1H), 4.13
(quint., J¼7.2 Hz, 4H), 1.75 (s, 3H), 1.24 (m, 12H), 1.12 (d, J¼9.0 Hz,
36H). 13C NMR (CDCl3, 100 MHz):
d 195.0, 157.2, 155.9, 151.2,
5.5.24. 2-Cyclohexylmethylene-1-phenyl-heptane-1,3-dione (37a)
The intermediate N-methyl isoxazoline ((5-butyl-3-cyclohex-
enyl-2-methyl-2,3-dihydro-isoxazol-4-yl)-phenyl-mathanone) was
prepared according to general procedure A (96% yield). 1H NMR
140.4, 139.0, 136.2, 133.8, 133.6, 129.3, 128.2, 127.9, 117.3, 114.3,
114.0, 62.6, 17.8, 16.1, 12.5. IR (neat, cmꢀ1): 2868, 2728, 2359,
1666, 1587, 1445, 1334, 1173, 1027. HRMS (EI) calculated for

3178
D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
(400 MHz, CDCl3):
d
7.62 (m, 2H), 7.51 (m, 1H), 7.43 (m, 2H),
7 Hz (I). J13C–H ester (cis) couplings are on the order of w8–9 Hz and
J13C–H ketone (cis) couplings are on the order of w10–11 Hz. Because
these coupling constants can be easily distinguished, either the
4.06 (d, J¼4 Hz, 1H), 2.79 (s, 3H), 2.07 (m, 2H), 1.71–1.61 (m,
8H), 1.40 (m, 2H), 1.23–1.10 (m, 7H), 0.74 (t, J¼7 Hz, 3H). 13C
NMR (100 MHz, CDCl3):
d
192.5, 166.1, 140.4, 131.2, 128.1, 127.7,
J13
or the J13
can be measured to assign olefin ge-
C–H ketone
C–H ester
110.8, 77.7, 48.3, 41.5, 29.4, 28.8, 27.1, 26.2, 26.1, 25.9, 22.0, 13.3.
IR (neat) cmꢀ1: 2923, 2850, 1608, 1573, 1446, 1357, 1242. HRMS:
calcd for C21H30O2N [MꢀHþ]; 328.2271; found, 328.2278.
The intermediate N-tert-butyl isoxazoline ((5-butyl-2-tert-bu-
tyl-3-cyclohexyl-2,3-dihydro-isoxazol-4-yl)-phenyl-mathanone) was
prepared according to general procedure A (83% yield). 1H NMR
ometry, and in ambiguous cases both J13C–H ketone and J13C–H ester can
be measured to clarify the hydrogen–carbonyl relationship.
Literature reports of 13C-H coupling constants.
10.2 Hz
12.6 Hz
O
O
Ph
H
Ph
Ph
H
(500 MHz, CDCl3):
d
7.57 (m, 2H), 7.48 (m, 1H), 7.41 (m, 2H), 4.45
OMe
Me
(d, J¼3.5 Hz, 1H), 2.03 (m, 2H), 1.72–1.38 (m, 9H), 1.25–1.12 (m,
OEt
18H), 0.72 (t, J¼7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3):
d 192.0,
O
O
167.9, 140.8, 131.1, 128.2, 113.1, 68.4, 60.6, 43.4, 29.8, 29.0, 27.8,
26.53, 26.51, 26.4, 25.1, 22.5, 13.4. IR (neat) cmꢀ1: 2983, 2959,
2917, 2849, 1630, 1595, 1577, 1460, 1444, 1376, 1364, 1298, 1234,
1204, 1172. HRMS: calcd for C24H36NO2 [MꢀHþ], 370.2741; found,
370.2756.
8.3 Hz
II
6.6 Hz
I
The above data (along with data previously tabulated within our
group)6b assignments of product olefin geometry can be done with
General procedure C provided the title compound (37a) from
a high degree of confidence. All J13C–H were obtained using J13
C–H ester
the N-tert-butyl intermediate isoxazoline (66% yield). 1H NMR
with the exception of 15a. In that particular case J13
C–H ketone
(400 MHz, CDCl3):
d
7.76 (dd, Jab¼7.0 Hz, Jac¼5.0 Hz, 2H), 7.58 (m,
was used.
1H), 7.46 (m, 2H), 6.25 (d, J¼10.0 Hz, 1H), 2.61 (t, J¼7.0 Hz, 1H),
1.80–1.56 (m, 8H), 1.34–1.11 (m, 7H), 0.88 (t, J¼7.0 Hz, 3H). 13C
5.7. Preparation of Baylis–Hillman adducts
NMR (100 MHz, CDCl3):
d 202.9, 195.4, 154.5, 140.6, 137.4, 132.7,
129.5, 128.5, 43.4, 38.6, 32.1, 25.7, 25.6, 25.1, 22.1, 13.8. IR (neat)
cmꢀ1: 3060, 3029, 2932, 2856, 1709, 1700, 1657, 1652, 1613,
1450. HRMS: calcd for C20H26O2 [MꢀHþ]; 298.1927; found,
298.1939.
5.7.1. 1-(2-tert-Butyl-3,5-diphenyl-2,3-dihydro-isoxazole-4-yl)-
pentan-1-one (44)
Prepared by general procedure A. 1H NMR (400 MHz, CDCl3):
d
7.66–7.26 (m, 10H), 5.61 (s, 1H), 2.11 (t, J¼7.2 Hz, 2H), 1.35 (m, 2H),
1.28 (s, 9H), 0.99 (m, 2H), 0.67 (t, J¼7.6 Hz, 3H). 13C NMR (100 MHz,
5.5.25. 1-Phenyl-2-(3-phenyl-allylidene)-heptane-1,3-dione (38)
The intermediate isoxazoline (5-butyl-2-tert-butyl-3-styryl-
CDCl3): d 195.7, 162.8, 143.4, 131.0, 129.3, 128.5, 128.48, 128.42,
127.5, 127.3, 116.6, 68.8, 61.5, 40.2, 26.6, 25.0, 22.0, 13.6. IR (neat)
cmꢀ1: 3060, 3029, 2956, 2930, 2871, 1671, 1622, 1593, 1490, 1452,
1445, 1363, 1234, 1205, 1137. HRMS: calcd for C24H30NO2 [MꢀHþ],
364.2271; found, 364.2265.
2,3-dihydro-isoxazol-4-yl)-phenyl-mathanone)
according to general procedure
(64% yield). 1H NMR
(500 MHz, CDCl3): 7.57 (m, 2H), 7.49 (m, 1H), 7.42 (m, 2H),
was
prepared
A
d
7.36 (M, 2H), 7.26 (m, 2H), 7.20 (m, 1H), 6.56 (d, J¼16 Hz, 1H),
6.34 (dd, Jab¼16 Hz, Jac¼6.5 Hz, 1H), 5.36 (d, J¼6.5 Hz, 1H), 2.14
(m, 2H), 1.52–1.44 (m, 2H), 1.22 (m, 11H), 0.79 (t, J¼6.5 Hz, 3H).
5.7.2. 1-(2-tert-Butyl-3,5-diphenyl-2,3-dihydro-isoxazole-4-yl)-
pentan-1-ol (45)
13C NMR (125 MHz, CDCl3):
d
191.8, 166.9, 140.6, 136.9, 131.3,
NaBH4 (0.010 g, 0.28 mmol) was added slowly to a stirred so-
lution of isoxazoline 44 (0.100 g, 0.28 mmol) in MeOH (1 mL) at
0 ꢁC. This was stirred for about 1 h, when it was quenched with H2O
(2 mL). This was extracted with Et2O (3ꢂ5 mL), dried over MgSO4
and concentrated to give pure products as a 2:1 mixture of di-
130.5, 129.6, 129.5, 128.8, 128.5, 128.39, 128.32, 128.0, 127.7,
127.3, 126.6, 113.2, 67.0, 60.9, 29.0, 26.6, 25.0, 22.4, 13.5. IR
(neat) cmꢀ1: 3024, 2959, 2931, 2870, 1597, 1574, 1446, 1359,
1228, 1209, 1191. HRMS: calcd for C26H32NO2 [MꢀHþ], 390.2428;
found, 390.2424.
astereomers. 1H NMR (500 MHz, CDCl3):
d 7.68 (m, 1.4H), 7.55 (m,
General procedure C provided the title compounds (38a and
38b) as a mixture of isomers (7:1) from the intermediate iso-
1H), 7.47–7.26 (m, 11.4H), 5.37 (s, 0.3H), 5.23 (0.7H), 4.56 (t,
J¼6.5 Hz, 0.3H), 4.41 (t, J¼6.5 Hz, 0.7H), 1.67–1.60 (m, 2.1H), 1.35–
1.18 (m, 9H), 0.89 (t, J¼6.5 Hz, 3H), 0.78 (t, J¼6.5 Hz, 1.1H). 13C NMR
xazoline (63% yield). 1H NMR (500 MHz, CDCl3):
d 7.81 (d,
J¼7.0 Hz, 0.49H), 7.62 (d, J¼7.0 Hz, 2H), 7.59–7.26 (m, 15H), 7.01
(m, 2.43H), 6.69 (m, 0.22H), 2.64 (m, 2.63H), 1.63 (m, 3.18H),
1.32 (m, 4.02H), 0.89 (m, 4.37H). 13C NMR (125 MHz, CDCl3):
(100 MHz, CDCl3): d 151.0, 150.1, 145.0, 144.7, 131.0, 129.6, 129.4,
129.3, 129.2, 129.1, 128.8, 128.58, 128.53, 128.4, 128.1, 128.0, 127.8,
127.6, 127.5, 127.4, 127.2, 127.0, 126.8, 126.7, 112.8, 111.6, 68.9 (2),
67.9 (2), 61.2, 61.0, 35.9, 30.3, 28.3, 26.1, 25.1, 22.6, 22.3, 22.2, 14.0. IR
(neat) cmꢀ1: 3513, 3052, 3025, 2945, 2928, 2853, 1666, 1629, 1593,
1494, 1447, 1445, 1370, 1234, 1210, 1137. HRMS: calcd for C18H28NO2
[MꢀHþ], 290.2115; found, 290.2120.
d
203.3, 198.1, 196.9, 195.5, 145.7, 145.5, 144.0, 141.2, 139.5, 139.0,
137.7, 137.1, 135.7, 135.5, 134.5, 133.9, 1328, 129.9, 129.7, 129.4,
129.3, 128.9, 128.8, 127.9, 127.6, 123.8, 123.3, 77.2, 43.1, 39.4, 30.3,
26.2, 26.1, 22.3, 22.2, 13.8. IR (neat) cmꢀ1: 3060, 3029, 2932,
2856, 1709, 1700, 1657, 1652, 1613, 1575, 1449. HRMS: calcd for
C22H22O2 [Mþ], 318.1614; found, 318.1612.
5.7.3. 2-Benzylidene-3-hydroxy-1-phenyl-heptan-1-one (46)35
Oxidized according to general procedure C. 1H NMR (400 MHz,
5.6. Assignment of olefin geometry for
compounds
b
-ketoalkylidene
CDCl3):
d 7.83–7.02 (m,11H), 4.80 (m,1H), 3.89 (m,1H),1.94 (m, 1H),
1.72 (m, 1H), 1.48 (m, 1H), 1.34 (m, 3H), 0.877 (m, 3H). 13C NMR
(100 MHz, CDCl3):
d 201.1, 142.7, 141.3, 137.9, 134.4, 132.7, 129.8,
Product geometries were assigned based on carbon–hydrogen
coupling constants obtained for the ester and/or the ketone of the
divinyl ketone. A detailed study by Kingsbury gives tabulated
splitting constants for a wide variety of differentially substituted
olefins.22
129.2, 128.9, 128.6, 128.3, 70.0, 36.1, 28.4, 22.5, 14.0. IR (neat) cmꢀ1
3413, 2956, 1650, 1595, 1447, 1377, 1229, 1070, 1001, 950.
:
5.7.4. (5-Butyl-2-tert-butyl-3-phenyl-2,3-dihydro-isoxazol-4-yl)-
phenyl-mathanone (47)
As shown, J13C–H ester (trans) couplings are on the order of w12–
Prepared according to general procedure A. 1H NMR (500 MHz,
13 Hz (I) and J13
(cis) couplings are on the order of w6–
CDCl3): d 7.44–7.39 (m, 5H), 7.35 (m, 2H), 2.26 (m, 2H), 7.20 (m, 1H),
C–H ketone

D.P. Canterbury et al. / Tetrahedron 65 (2009) 3165–3179
3179
the geometry drawn for the product would have arisen from ‘outward’ dis-
rotation. The method used to assign the olefin geometry was not described.
9. (a) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry;
Chemie: Weinheim, 1970; (b) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int.
Ed. Engl. 1969, 8, 781.
5.64 (s, 1H), 5.29 (s, 1H), 2.15 (t, J¼8.0 Hz, 2H), 1.53 (m, 2H), 1.27 (m,
3H), 1.18 (s, 9H), 1.88 (t, J¼8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d
191.7, 166.0, 143.5, 140.4, 131.2, 128.28, 128.21, 127.6, 127.5, 127.1,
115.5, 68.9, 61.2, 29.1, 26.5, 24.9, 22.4, 13.5. IR (neat) cmꢀ1: 2974,
2958, 2928, 2873, 2857, 1633, 1595, 1574, 1494, 1457, 1447, 1371,
1363. HRMS: calcd for C24H30O2N [MꢀHþ], 364.2271; found,
364.2260.
10. (a) Mock, W. L. J. Am. Chem. Soc. 1966, 88, 2857; (b) McGregor, S. D.; Lemal, D. M.
J. Am. Chem. Soc. 1966, 88, 2858; (c) Lemal, D. M.; McGregor, S. D. J. Am. Chem.
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11. (a) Rondan, N. G.; Houk, K. N. J. Am. Chem. Soc. 1985, 107, 2099; (b) Doulbier, W.
R., Jr.; Koroniak, H.; Houk, K. N.; Sheu, C. Acc. Chem. Res. 1996, 29, 471; (c) Lee,
P. S.; Zhang, X. Y.; Houk, K. N. J. Am. Chem. Soc. 2003, 125, 5072 and references
therein; (d) Evanseck, J. D.; Thomas, B. E.; Spellmeyer, D. C.; Houk, K. N. J. Org.
Chem. 1995, 60, 7134; (e) For another study proposing a role for geminal bonds
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Inagaki, S. J. Org. Chem. 2004, 69, 7246 and references therein.
12. For recent theoretical investigations of torquoselective Nazarov-type cycliza-
tions, see: (a) Dieker, J.; Froehlich, R.; Wuerthwein, E.-U. Eur. J. Org. Chem. 2006,
23, 5339; (b) Cavalli, A.; Masetti, M.; Recanatini, M.; Prandi, C.; Guarna, A.;
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(e) Murakami, M.; Hasegawa, M.; Igawa, H. J. Org. Chem. 2004, 69, 587; (f)
Walker, M. J.; Hietbrink, B. N.; Thomas, B. E., IV; Nakamura, K.; Kallel, E. A.;
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5.7.5. (5-Butyl-2-tert-butyl-3-phenyl-2,3-dihydro-isoxazol-4-yl)-
phenyl-methanol (48)
DIBAL (1.0 M/toluene, 0.21 mL) was added slowly to a stirred
solution of isoxazoline 10f (0.050 g, 0.14 mmol) in dichloromethane
(0.28 mL) at 0 ꢁC. This was stirred for about 10 min, quenched with
MeOH (0.30 mL) and warmed to rt. The solid was filtered off, and
the filtrate was concentrated. Column chromatography provided
alcohol 47 (0.035 g, 73%) as a 3:1 mixture of diastereomers: 1H NMR
(500 MHz, CDCl3):
4.62 (s, 0.3H), 2.39 (m, 3H),1.64–1.37 (m, 9.2H),1.07 (s, 9H), 0.96 (m,
9.2H). 13C NMR (100 MHz, CDCl3):
153.1, 151.9, 143.8, 142.1, 142.0,
d 7.36–7.14 (m, 13H), 5.16 (m, 0.3H), 4.86 (m, 1H),
d
128.8, 128.3, 128.1, 128.0, 127.65, 127.60, 127.2, 127.08, 127.01, 126.0,
125.5, 110.1, 109.6, 70.0, 69.9, 69.2, 68.1, 60.59, 60.53, 29.7, 29.6,
24.9, 24.7, 24.3, 22.79, 22.73, 13.8. IR (neat) cmꢀ1: 3346, 2962, 2957,
2928, 2877, 2863, 1587, 1571, 1488, 1457, 1444, 1378, 1362. HRMS:
calcd for C24H32NO2 [MꢀHþ], 366.2479; found, 366.2473.
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Acknowledgements
We are grateful to the National Institutes of Health (GM-
079364) and the University of Rochester for generous financial
support. We thank Dr. Alice Bergmann (University of Buffalo) for
carrying out high-resolution mass spectroscopy, and Dr. Sandip Sur
(University of Rochester) for valuable assistance with NMR
spectroscopy.
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Supplementary data
1H and 13C spectra for all compounds can be found in the Sup-
plementary data. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2008.10.003.
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