A new access to pyrrolizidine derivatives: Ring contraction of methyl (E)-[1,2-oxazin-3-yl]propenoates

Article abstract of DOI:10.1055/s-2007-990946

Nitrosoalkene 2 generated in situ from oxime 3 underwent smooth hetero Diels-Alder reaction with enol ethers 1 to afford 1,2-oxazine derivatives 4 bearing an exocyclic C=C bond. Methoxyallene 8 and 2 provided 6H-1,2-oxazine 10 in good overall yield. The exocyclic double bond of this type of 1,2-oxazines can be employed for addition reactions as demonstrated by dihydroxylation of 4a with potassium permanganate, smoothly delivering 1,2-diol 11. A reductive cascade reaction involving ring cleavage at the N-O bond followed by cyclization steps furnished pyrrolizidinone derivatives 12 in good yields. In the case of 12b this transformation proceeded with excellent stereoselectivity. Finally, the lactam moiety of 12 could be reduced with borane to provide the corresponding pyrrolizidine derivatives 19 in good yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990946

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237
A New Access to Pyrrolizidine Derivatives: Ring Contraction of Methyl
(E)-[1,2-Oxazin-3-yl]propenoates
A
N
ewAccess to
e
P
yrrolizid
i
D
er
n
ivative
s
hold Zimmer,*a Markus Collas,b,1 Regina Czerwonka,b Ute Hain,b Hans-Ulrich Reissig*a
a
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
b
Institut für Organische Chemie, Technische Universität Dresden, Bergstraße 66, 01016 Dresden, Germany
Received 21 August 2007; revised 15 October 2007
Dedicated to Professor Volker Jäger on the occasion of his 65th birthday
erated in situ from the corresponding a-bromooxime 3 by
treatment with a base such as sodium carbonate
(Scheme 1).15 Cycloadducts 4 were generally obtained in
moderate to excellent yields. Dienophile 1c was used as
Abstract: Nitrosoalkene 2 generated in situ from oxime 3 under-
went smooth hetero Diels–Alder reaction with enol ethers 1 to af-
ford 1,2-oxazine derivatives 4 bearing an exocyclic C=C bond.
Methoxyallene 8 and 2 provided 6H-1,2-oxazine 10 in good overall
yield. The exocyclic double bond of this type of 1,2-oxazines can be an E/Z mixture of isomers (60:40), however, only the
employed for addition reactions as demonstrated by dihydroxyla-
tion of 4a with potassium permanganate, smoothly delivering 1,2-
diol 11. A reductive cascade reaction involving ring cleavage at the
methylsiloxy groups. The high kinetic preference for E-
N–O bond followed by cyclization steps furnished pyrrolizidinone
derivatives 12 in good yields. In the case of 12b this transformation
more reactive E-isomer underwent cycloaddition with 2
providing 4c in good yield and with trans-orientated tri-
configured dienophiles is a common feature of nitrosoalk-
ene cycloadditions.16
proceeded with excellent stereoselectivity. Finally, the lactam moi-
ety of 12 could be reduced with borane to provide the corresponding
pyrrolizidine derivatives 19 in good yield.
R3
R3
R2
CO2Me
CO2Me
r.t., 5–7 d
Key words: 1,2-oxazines, pyrrolizidines, hydrogenation, lactams,
pyrroles, hetero Diels–Alder reaction
+
R2
R1O
N
N
O
R1O
O
1
2
4
R1
Et
R2
H
R3
H
Yield
93%
25%
A common strategy for the construction of functionalized
heterocyclic compounds involves ring contraction of eas-
ily available precursor heterocycles. For this purpose, a
moiety allowing smooth ring opening is required, a prop-
erty which is given with the relatively weak N–O bond.2
The compound class of 1,2-oxazines fulfils this prerequi-
site and hence it is frequently employed in organic synthe-
sis.3 Ring cleavages and ring transformations could be
exploited for the synthesis of a variety of nitrogen-con-
taining heterocycles such as pyrroles,4 proline deriva-
Na2CO3, MeOt-Bu
CO2Me
a
b
c
d
SiMe3
SiMe3
SiMe3
H
H
Br
H
OSiMe3 83%
42%
NOH
-(CH2)4-
3
Scheme 1 Hetero Diels–Alder reactions of enol ethers 1 with nitro-
soalkene 2
Allyltrimethylsilane (5) is also a suitable dienophile for
hetero Diels–Alder reactions with nitrosoalkenes, al-
though the reactivity of 5 is lower in comparison with ole-
fins 1.16 The cycloaddition of 2 and 5 under standard
conditions (see Scheme 1) gave the 1,2-oxazine 6 only in
tives,4f,5
pyrrolidines,6
cyclic
five-membered
nitrones,4i,5a,7 aziridines,8 g-lactams,4i,9 pyridines,10 and in-
dolizidines.11 To date, not much is known about the prep-
aration of pyrrolidizines starting from 1,2-oxazine
derivatives.12 The pyrrolizidine core is found in many al-
kaloids including examples with interesting pharmacolog-
ical activity.13 Polyhydroxylated pyrrolidizine alkaloids
are of particular importance as inhibitors of glycosidases
and glycosyltransferases.14 The present report deals with
the preparation of methyl (E)-3-[1,2-oxazin-3-yl]prope-
noates and their simple transformation into pyrrolizidi-
none and pyrrolizidine derivatives.
Na2CO3,
CH2Cl2,
CO2Me
CO2Me
60 °C, 20 h
+
N
O
48%
Me3Si
N
O
SiMe3
5
2
6
CO2Me
_
1,2-Oxazines 4 with an exocyclic C=C bond at position 3
can easily be prepared by hetero Diels–Alder reaction of
electron-rich olefins 1 and nitrosoalkene 2, which are gen-
O
+
N
Me3Si
N
CO2Me
O
7 (14%, dr = 56:44)
SYNTHESIS 2008, No. 2, pp 0237–0244
x
x
.
x
x
.2
0
0
7
Advanced online publication: 07.12.2007
DOI: 10.1055/s-2007-990946; Art ID: T13407SS
© Georg Thieme Verlag Stuttgart · New York
Equation 1 Hetero Diels–Alder reaction of allyltrimethylsilane
with nitrosoalkene 2

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238
R. Zimmer et al.
PAPER
CO2Me
CO2Me
a
b
N
N
73%
93%
MeO
O
MeO
O
MeO
8
9
10
Scheme 2 Preparation of 6H-1,2-oxazine 10; Reagents and conditions: a) 2, Na2CO3, t-BuOMe, r.t., 6 d; b) DBU, CH2Cl2, r.t., 6 h.
low yield (4–30%).17 However, the yield of 6 could be im-
CO2Me
H2, Pd/C, MeOH
proved when the reaction was performed at 60 °C in an
N
N
N
70%
EtO
O
ACE pressure tube (Equation 1). The reaction time was
dramatically decreased under these conditions, but the ex-
pected product 6 was accompanied by bicyclic nitrone 7,
which was obtained as a mixture of two diastereomers (ca.
1:1). The formation of nitrone 7 can be explained by a
subsequent [3+2] cycloaddition of the primary adduct 6
with nitrosoalkene 2.7a It cannot be ruled out that 2 and 6
first undergo a [4+2] cycloaddition and the primary 2:1
adduct then rearranges to nitrone 7. This type of transfor-
mation of 1,2-oxazines into nitrones was reported earli-
er.4f,7b
O
4a
12a
H
CO2Me
H2, Pd/C, MeOH
51%
N
MeO
O
O
10
12b (dr = 96:4)
OH
H
OH
CO2Me
H2, Pd/C, MeOH
79%
OH
N
N
OH
EtO
O
Donor-substituted allenes, in particular alkoxyallenes, are
synthetically very useful dienophiles in [4+2] cycloaddi-
tions with nitrosoalkenes.18 Gratifyingly, the hetero Diels–
Alder reaction of nitrosoalkene 2 with methoxyallene (8)19
led to 5-methylene-5,6-dihydro-4H-1,2-oxazine 9 in ex-
cellent yield. Primary adduct 9 was smoothly converted
into the 6H-1,2-oxazine 10 containing two C=C bonds on
treatment with DBU at room temperature (Scheme 2).
O
11 (dr = 82:18)
12c (dr = 60:40)
Scheme 3 Reductive ring contraction and lactamization of 1,2-
oxazines leading to pyrrolizidinones 12
none 12b is excellent, whereas the reduction and
lactamization of 11 afforded the dihydroxylated pyrroliz-
idinone 12c as a 60:40 mixture of isomers. This strongly
differing stereoselectivity can be explained by the se-
quence of steps during this reductive ring contraction cas-
cade (see below).
The C=C bonds of 1,2-oxazines such as 4 or 10 can be
used to add new substituents or functional groups to the
heterocycle.17 This option is demonstrated in the dihy-
droxylation of 1,2-oxazine 4a with potassium permanga-
nate as the oxidizing reagent in the presence of
magnesium sulfate.20 The expected 1,2-diol 11 was ob-
tained in good yield and with surprisingly high diastereo-
selectivity (Equation 2). Although we could not
determine the relative configuration of the obtained dia-
stereomers, the high stereoselection exhibited by the axial
6-ethoxy group21 is quite remarkable. The asymmetric in-
duction operates in a 1,5/1,6 fashion with respect to the di-
hydroxylated C=C bond.22
A plausible mechanism for the formation of pyrrolizidi-
none 12b from 1,2-oxazine 10 is illustrated in Scheme 4.
The first step probably involves reduction of both C=C
bonds. Intermediate 13 is very likely generated with the
relative configuration as depicted, since the axial 6-meth-
oxy group of 10 should lead to a high induction for the re-
duction of the 4,5-double bond. The subsequent reduction
of the C=N bond of 13 is strongly influenced by the two
existing stereogenic centers to preferentially form inter-
mediate 14 with all-cis configuration as shown. This step
determines the high diastereoselectivity of the overall pro-
cess. Reductive cleavage of the N–O bond, ring closure,
and water elimination to give cyclic imine 16 followed by
a reduction of the C=N bond and finally lactamization of
intermediate 17 furnishes pyrrolizidinone 12b. This se-
quence of reduction steps explains the observed relative
configuration, whereas the mechanism as proposed in ear-
lier examples4i should lead to lower diastereoselectivity.
Since 1,2-oxazine 11 bears no substituent at C-5, but only
the more flexible stereogenic centers at the side chain, no
comparable stereoselectivity of the C=N reduction occurs
and 12c is generated as a 60:40 mixture of diastereomers.
KMnO4,
MgSO4,
EtOH,
OH
CO2Me
CO2Me
45 min,
–45 °C
N
N
OH
EtO
O
EtO
O
75%
4a
11 (dr = 82:18)
Equation 2 Dihydroxylation of 4H-1,2-oxazine 4a
Having attained a good access to heterocyclic precursors
4a, 10, and 11, we turned our attention to their conversion
into pyrrolizidinones. The hydrogenolysis of these 1,2-
oxazines furnished pyrrolizidinones 12a–c in good yields
(Scheme 3). We applied palladium on charcoal as catalyst
for this multi-step reaction.4i Interestingly, the diastereo-
selectivity in the case of 7-methyl-substituted pyrrolizidi-
We also attempted to prepare pyrrolizidinones by micro-
wave-assisted transfer hydrogenolysis, but failed. Treat-
ment of 1,2-oxazine 4a with ammonium formate in the
presence of palladium on charcoal furnished pyrrole de-
Synthesis 2008, No. 2, 237–244 © Thieme Stuttgart · New York

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PAPER
A New Access to Pyrrolizidine Derivatives
239
CO2Me
CO2Me
BH3⋅SMe2, THF
H2
N
N
N
N
77%
MeO
O
MeO
O
O
10
13
19a
12a
H
H
H2
BH3⋅SMe2, THF
N
N
CO2Me
77%
CO2Me
H2
O
N
NH2
19b (dr = 94:6)
12b (dr = 96:4)
O
MeO
O
H
– MeOH
OH
H
15
14
OH
H
– H2O
BH3⋅SMe2, THF
OH
OH
N
N
93%
O
H
19c (dr = 68:32)
12c (dr = 60:40)
H2
N
– MeOH
CO2Me
Scheme 5 Reduction of the pyrrolizidinones 12 to pyrrolizidines 19
N
N
H
CO2Me
O
16
17
12b
All reactions were performed under argon in flame-dried flasks, and
the components were added by means of syringes. All solvents were
dried by standard methods. IR spectra were measured with a Perkin-
Elmer IR-325 or Nicolet 205 spectrometer. 1H and 13C NMR spectra
were recorded on Bruker instruments (AC 200 or AC 300) in CDCl3
solution. The chemical shifts are given relative to the TMS or
CDCl3 signals (dH = 7.27, dC = 77.0). Missing signals of the minor
isomer are either hidden by signals of the major isomer or they
could not be unambiguously identified due to low intensity. Neutral
alumina (activity III, Merck) was used for column chromatography.
Boiling points of compounds obtained in small-scale experiments
refer to the temperature in a Büchi Kugelrohr oven. Melting points
(uncorrected) were measured with an apparatus from Rapido (Boë-
tius). Na2CO3 was freshly pulverized (electric coffee mill, Braun
KSM 1G) before use. All solvents were dried by standard methods.
Scheme 4 Proposed mechanism for the stereoselective formation of
pyrrolizidinone 12b
CO2Me HCO2NH4, Pd/C,
MW; 8 min, 130 °C
CO2Me
N
EtO
O
N
74%
H
4a
18
Equation 3 Transfer hydrogenation of 1,2-oxazine 4a under micro-
wave condition
rivative 1823 as a single product in good yield instead of
the expected pyrrolizidinone 12a (Equation 3). Apparent-
ly, only the C=C bond of 4a was saturated, the N–O bond
was reductively cleaved, and subsequent condensation led
to the pyrrole.
Syntheses of starting materials were done according to literature: si-
lyl enol ethers 1b,d27 and 1c,28 oxime 3,15 and methoxyallene (8).29
4H-1,2-Oxazines; General Procedure 1
Freshly ground Na2CO3 (6 equiv) was added to a solution of the cor-
responding olefin (10 equiv) and a-bromoketoxime 3 (1 equiv) in t-
BuOMe (12–16 mL/mmol of oxime 3). After stirring at r.t. for the
time indicated in the individual reaction, the suspension was filtered
through a pad of Celite to remove inorganic salts. The resulting fil-
trate was concentrated in vacuo and the excess of olefin was dis-
tilled off by Kugelrohr distillation. The residue was purified by
chromatography (alumina, elution with hexane–EtOAc, 4:1 or 9:1)
to furnish the 4H-1,2-oxazine.
Finally, pyrrolizidinones 12a–c were smoothly converted
into the corresponding pyrrolizidines 19a–c in high yields
by treatment of 12a–c with borane-dimethyl sulfide com-
plex in tetrahydrofuran at room temperature (Scheme 5).24
As to be expected, the ratios of diastereomers of the prod-
ucts are comparable to those of the starting bicyclic lac-
tams 12. The relative configuration of 19b was
established by comparison of the NMR data of the minor
diastereomer of 19b with those reported in the literature.25
Similar transformations leading to pyrrolizidinones and
pyrrolizidines should also be possible with the other 1,2-
oxazine derivatives as shown in Scheme 1.
Methyl (E)-3-(6¢-Ethoxy-5¢,6¢-dihydro-4¢H-1¢,2¢-oxazin-3¢-
yl)propenoate (4a)
According to general procedure 1, a mixture of 1a (26.0 g, 360
mmol), oxime 3 (7.99 g, 36.0 mmol), and Na2CO3 (22.9 g, 216
mmol) in t-BuOMe (400 mL) was stirred for 5 d at r.t. The resulting
crude product was purified by column chromatography (hexane–
EtOAc, 4:1) to give 1,2-oxazine 4a (7.16 g, 93%) as colorless crys-
tals; mp 52–53 °C.
In conclusion, we have established a simple, efficient and
selective route for the synthesis of pyrrolizidine deriva-
tives starting from enol ethers 1 and oxime 3 with the cor-
responding 1,2-oxazines 4 as crucial intermediates.26 The
overall yields for pyrrolizidinones are generally good:
65% 12a (2 steps), 35% 12b (3 steps), and 55% 12c (3
steps). This convenient, reliable, and potentially very flex-
ible procedure will enable rapid access to a variety of
pharmacologically significant pyrrolizidine derivatives.
IR (KBr): 3040–2800 (=C–H, C–H), 1715 (C=O), 1640 (C=C),
1570 cm–1 (C=N).
1H NMR (CDCl3, 200 MHz): d = 7.34, 6.17 (2 d, J = 16 Hz, 1 H
each, 3-H, 2-H), 5.16 (t, J = 2.5 Hz, 1 H, 6¢-H), 3.85, 3.62 (2 qd,
J = 7, 10 Hz, 1 H each, OCH2CH3), 3.79 (s, 3 H, CO2CH3), 2.45
(ddd, J = 7.5, 12.5, 17.5 Hz, 1 H, 4¢-Ha), 2.26 (ddd, J = 2.5, 6.5, 17.5
Synthesis 2008, No. 2, 237–244 © Thieme Stuttgart · New York

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PAPER
Hz, 1 H, 4¢-He), 2.06 (tdd, J = 2.5, 7.5, 13.5 Hz, 1 H, 5¢-He), 1.91
(dddd, J = 2.5, 6.5, 12.5, 13.5 Hz, 1 H, 5¢-Ha), 1.19 (t, J = 7 Hz, 3 H,
OCH2CH3).
13C NMR (CDCl3, 50.3 MHz): d = 166.4, 51.8 (s, q, CO2CH3),
155.4 (s, C-3¢), 141.6 (d, C-3), 121.5 (d, C-2), 95.7 (d, C-6¢), 63.8,
14.9 (t, q, OCH2CH3), 22.0 (t, C-5¢), 15.1 (t, C-4¢).
1H NMR (CDCl3, 200 MHz): d = 7.36, 6.13 (2 d, J = 16 Hz, 1 H
each, 3-H, 2-H), 3.77 (s, 3 H, CO2CH3), 2.63 (dd, J = 7, 17.5 Hz, 1
H, 4¢-H), 2.19–2.15, 1.91–1.79, 1.66–1.43, 1.29–0.96 (4 m, 1 H, 1
H, 5 H, 2 H, 4a¢-H, 5¢-H, 6¢-H, 7¢-H, 8¢-H), 1.90 (br d, J = 17.5 Hz,
1 H, 4¢-H), 0.08 [s, 9 H, OSi(CH3)3].
13C NMR (CDCl3, 50.3 MHz): d = 166.5, 51.8 (s, q, CO2CH3),
153.2 (s, C-3¢), 142.0 (d, C-3), 121.2 (d, C-2), 97.4 (d, C-8a¢), 37.3
(t, C-8¢), 34.8 (d, C-4a¢), 29.3 (t, C-4¢), 24.6, 23.6, 23.3 (3 t, C-5¢, C-
6¢, C-7¢), 1.4 [q, OSi(CH3)3].
Anal. Calcd for C10H15NO4 (213.2): C, 56.33; H, 7.09; N, 6.57.
Found: C, 56.54; H, 7.43; N, 6.56.
Methyl (E)-3-[5¢,6¢-Dihydro-6¢-(trimethylsiloxy)-4¢H-1¢,2¢-ox-
azin-3¢-yl]propenoate (4b)
Anal. Calcd for C15H25NO4Si (311.5): C, 57.85; H, 8.09; N, 4.50.
Found: C, 58.09; H, 8.65; N, 4.39.
According to general procedure 1, a mixture of 1b (2.88 g, 24.8
mmol), oxime 3 (1.10 g, 4.96 mmol), and Na2CO3 (3.07 g, 29.8
mmol) in t-BuOMe (50 mL) was stirred for 5 d at r.t. The resulting
crude product was purified by column chromatography (hexane–
EtOAc, 4:1) to give 1,2-oxazine 4b (0.317 g, 25%) as colorless
crystals; mp 97–98 °C.
Methyl (E)-3-[5¢,6¢-Dihydro-6¢-[(trimethylsilyl)methyl]-4¢H-
1¢,2¢-oxazin-3¢-yl]propenoate (6) and (E,E)-5,6,7,7a-Tetrahy-
dro-2,7a-bis[2-(methoxycarbonyl)ethenyl]-1-oxy-5-[(trimethyl-
silyl)methyl]-3H-4-oxa-1,3a-diazaindole (7)
Analogous to general procedure 1, a mixture of 5 (1.14 g, 10.0
mmol), oxime 3 (0.111 g, 0.50 mmol), and Na2CO3 (0.318 g, 6.00
mmol) in CH2Cl2 (20 mL) was stirred for 20 h at 60 °C in an ACE
pressure tube. The resulting crude product was purified by column
chromatography (hexane–EtOAc, 4:1) to provide 3 fractions: frac-
tion 1, 1,2-oxazine 6 (0.052 g, 41%) as colorless crystals; fraction
2, a 1:2 mixture of 6 and 7 (0.029 g); and fraction 3, product 7 (0.009
g, 5%) as a colorless oil.
IR (KBr): 3060–2850 (=C–H, C–H), 1715 (C=O), 1635 (C=C),
1570 cm–1 (C=N).
1H NMR (CDCl3, 200 MHz): d = 7.33, 6.16 (2 d, J = 16 Hz, 1 H
each, 3-H, 2-H), 5.47 (t, J = 2.5 Hz, 1 H, 6¢-H), 3.77 (s, 3 H,
CO2CH3), 2.44 (ddd, J = 7.5, 12, 17.5 Hz, 1 H, 4¢-Ha) 2.23 (ddd,
J = 2.5, 6.5, 17.5 Hz, 1 H, 4¢-He), 1.86–1.76 (m, 1 H, 5¢-He), 1.81
(dddd, J = 2.5, 6.5, 12, 13 Hz, 1 H, 5¢-Ha), 0.15 [s, 9 H, OSi(CH3)3].
13C NMR (CDCl3, 50.3 MHz): d = 166.5, 51.9 (s, q, CO2CH3),
154.7 (s, C-3¢), 141.7 (d, C-3), 121.4 (d, C-2), 91.1 (d, C-6¢), 23.8
(t, C-5¢), 14.7 (t, C-4¢), –0.2 [q, OSi(CH3)3].
Compound 6
Mp 79–81 °C.
IR (KBr): 3080–2800 (=C–H, C–H), 1720 (C=O), 1635 (C=C),
1560 cm–1 (C=N).
Anal. Calcd for C11H19NO4Si (257.3): C, 51.34; H, 7.44; N, 5.44.
Found: C, 51.45; H, 7.58; N, 5.46.
1H NMR (CDCl3, 200 MHz): d = 7.30, 6.06 (2 d, J = 16 Hz, 1 H
each, 3-H, 2-H), 3.84 (dtd, J = 2, 7.5, 10.5 Hz, 1 H, 6¢-H), 3.74 (s, 3
H, CO2CH3), 2.34–2.24, 2.00–1.87, 1.69–1.52 (3 m, 2 H, 1 H, 1 H,
4¢-H, 5¢-H), 1.09, 0.86 (2 dd, J = 7.5, 14.5 Hz, 1 H each, CH2SiMe3),
0.50 [s, 9 H, Si(CH3)3].
13C NMR (CDCl3, 50.3 MHz): d = 166.5, 51.8 (s, q, CO2CH3),
153.7 (s, C-3¢), 141.9 (d, C-3), 120.9 (d, C-2), 75.2 (d, C-6¢), 26.2,
22.7, 20.4 (3 t, C-4¢, C-5¢, CH2SiMe3), –0.9 [q, Si(CH3)3].
Methyl (E)-3-[5¢,6¢-Dihydro-t-5¢,r-6¢-bis(trimethylsiloxy)-4¢H-
1¢,2¢-oxazin-3¢-yl]propenoate (4c)
According to general procedure 1, a mixture of 1c (1.19 g, 5.80
mmol, E/Z = 60:40), oxime 3 (0.444 g, 2.00 mmol), and Na2CO3
(0.636 g, 12.0 mmol) in t-BuOMe (75 mL) was stirred for 10 d at
r.t. The resulting crude product was purified by column chromatog-
raphy (hexane–EtOAc, 4:1) to give 1,2-oxazine 4c (0.572 g, 83%)
as colorless crystals; mp 101–103 °C.
Anal. Calcd for C12H21NO3Si (255.4): C, 56.44; H, 8.29; N, 5.48.
Found: C, 56.80; H, 8.22; N, 5.21.
IR (KBr): 3060–2900 (=C–H), 1715 (C=O), 1635 (C=C), 1580
cm–1 (C=N).
Compound 7
Mixture of two diastereomers, 56:44.
1H NMR (CDCl3, 300 MHz): d = 7.39, 6.15 (2 d, J = 16.5 Hz, 1 H
each, 3-H, 2-H), 5.08 (d, J = 3 Hz, 1 H, 6¢-H), 3.92 (ddd, J = 2.5, 3,
5 Hz, 1 H, 5¢-He), 3.79 (s, 3 H, CO2CH3), 2.56 (dd, J = 5, 17.5 Hz,
1 H, 4¢-Ha), 2.17 (dd, J = 2.5, 17.5 Hz, 1 H, 4¢-He), 0.17, 0.13 [2 s,
9 H each, OSi(CH3)3].
13C NMR (CDCl3, 75.5 MHz): d = 166.4, 51.9 (s, q, CO2CH3),
153.1 (s, C-3¢), 141.9 (d, C-3), 121.5 (d, C-2), 93.3 (d, C-6¢), 62.6
(d, C-5¢), 24.5 (t, C-4¢), 0.0, –0.2 [2 q, OSi(CH3)3].
IR (KBr): 3050–2800 (=C–H, C–H), 1725, 1720 (C=O), 1645, 1635
(C=C), 1525 cm–1 (C=N).
Major Isomer
1H NMR (CDCl3, 300 MHz): d = 7.61, 6.88, 6.34, 6.22 (4 d, J = 16
Hz, 1 H each, HC=), 4.21–3.84 (m, 3 H, 3-H, 5-H), 3.79, 3.76 (2 s,
3 H each, CO2CH3), 2.74–2.66, 2.36–2.26, 2.07–1.81 (3 m, 1 H, 1
H, 2 H, 6-H, 7-H), 1.31 (dd, J = 8, 14.5 Hz, 1 H, CH2SiMe3), 0.97
(dd, J = 6.5, 14.5 Hz, 1 H, CH2SiMe3), 0.05 [s, 9 H, Si(CH3)3].
Anal. Calcd for C14H27NO5Si2 (345.6): C, 48.66; H, 7.88; N, 4.05.
Found: C, 47.98; H, 7.78; N, 4.01.
13C NMR (CDCl3, 75.5 MHz): d = 166.4, 165.6, 52.0 (2 s, q,
CO2CH3), 141.7, 128.4, 123.5, 123.2 (4 d, HC=), 135.2 (s, C-2),
95.9 (s, C-7a), 75.1 (d, C-5), 57.2 (t, C-3), 27.9, 26.5, 23.2 (3 t, C-
6, C-7, CH2SiMe3), –0.8 [q, CH2Si(CH3)3].
Methyl (E)-3-[4a¢,5¢,6¢,7¢,8¢,8a¢-Hexahydro-8a¢-(trimethyl-
siloxy)-4¢H-1¢,2¢-benzoxazin-3¢-yl]propenoate (4d)
According to general procedure 1, a mixture of 1d (1.36 g, 8.00
mmol), oxime 3 (0.222 g, 1.00 mmol), and Na2CO3 (0.318 g, 6.00
mmol) in t-BuOMe (10 mL) was stirred for 6 d at r.t. The resulting
crude product was purified by column chromatography (hexane–
EtOAc, 9:1) to give 1,2-oxazine 4d (0.130 g, 42%) as colorless
crystals; mp 117–118 °C.
Additional Signals Assigned to the Minor Isomer
1H NMR (CDCl3, 300 MHz): d = 7.66, 6.82, 6.36, 6.13 (4 d, J = 16
Hz, 1 H each, HC=), 3.80, 3.74 (2 s, 3 H each, CO2CH3), 0.82, 0.71
(2 dd, J = 7, 14.5 Hz, 1 H each, CH2SiMe3), 0.02 [s, 9 H, Si(CH3)3].
13C NMR (CDCl3, 75.5 MHz): d = 166.5, 165.7, 51.7 (2 s, q,
CO2CH3), 139.9, 128.0, 123.8, 123.0 (4 d, HC=), 134.3 (s, C-2),
98.2 (s, C-7a), 74.5 (d, C-5), 56.4 (t, C-3), 26.1, 25.5, 23.1 (3 t, C-
6, C-7, CH2SiMe3), –1.0 [q, Si(CH3)3].
IR (KBr): 3080–2800 (=C–H, C–H), 1715 (C=O), 1640 (C=C),
1580 cm–1 (C=N).
Synthesis 2008, No. 2, 237–244 © Thieme Stuttgart · New York