Rearrangement of 3-alkylidene-2-siloxy-tetrahydro-1,2-oxazines (ASENA). A new approach toward the synthesis of 3-α-hydroxyalkyl-5,6-dihydro-4H-1,2-oxazines

Article abstract of DOI:10.1016/j.tet.2009.03.082

A new approach toward the synthesis of 3-α-hydroxyalkyl-5,6-dihydro-4H-1,2-oxazines 1 from available 5,6-dihydro-4H-1,2-oxazine N-oxides 2 has been described. The key step of the process-the rearrangement of 3-alkiliden-2-siloxy-tetrahydro-1,2-oxazines 3 (ASENA)-was thoroughly investigated. Optimal experimental conditions were developed. A possible pathway of the ASENA rearrangement was proposed.

Full text of DOI:10.1016/j.tet.2009.03.082

Tetrahedron 65 (2009) 4578–4592
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Rearrangement of 3-alkylidene-2-siloxy-tetrahydro-1,2-oxazines (ASENA). A new
approach toward the synthesis of 3-a-hydroxyalkyl-5,6-dihydro-4H-1,2-oxazines
,
a
b
a
Andrey A. Tabolin a, Alexey V. Lesiv a , Yulia A. Khomutova , Yulia V. Nelyubina , Sema L. Ioffe
*
a N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prosp. 47, Moscow 119991, Russian Federation
b A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov Str. 28, Moscow 119991, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach toward the synthesis of 3-
a-hydroxyalkyl-5,6-dihydro-4H-1,2-oxazines 1 from available
Received 21 November 2008
Received in revised form 10 March 2009
Accepted 26 March 2009
Available online 1 April 2009
5,6-dihydro-4H-1,2-oxazine N-oxides 2 has been described. The key step of the processdthe re-
arrangement of 3-alkiliden-2-siloxy-tetrahydro-1,2-oxazines 3 (ASENA)dwas thoroughly investigated.
Optimal experimental conditions were developed. A possible pathway of the ASENA rearrangement was
proposed.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1,2-Oxazines
1,2-Oxazine-N-oxides
Silylation
Prolinoles
1. Introduction
2. Results and discussion
1,2-Oxazine-N-oxides 2dthe products of [4þ2]-cycloaddition of
nitroalkenes to olefinesdare useful intermediates in organic chem-
istry. They were used as convenient precursors of pyrrolidines,1a,b
aminosugars,1c andothercompounds.Silylationisoneof thepossible
applications of 1,2-oxazine-N-oxides 2.2 It was found that theycan be
transformed into 3-halomethyl-derivatives of 1,2-oxazines,2b modi-
fied 1,2-oxazines,2c and tetrahydrooxazines2d (Scheme 1).
Recently, we have reported that 3-alkylidene-2-siloxy-tetrahydro-
oxazines 3 (ASENA) obtained by silylation of 1,2-oxazine-N-oxides 2
can undergo the rearrangement affording 3-(1-silyloxy)alkyl-5,6-
dihydro-4H-1,2-oxazines 4 (Scheme 1).2a On the one hand, this was
the only example of this reaction. On the other hand, the reaction
proceeded with a good yield and stereoselectivity. Also, the resulting
2.1. Rearrangement of 3-alkilidene-2-siloxy-tetrahydro-1,2-
oxazines 3 (ASENA) to 3-(1-silyloxy)alkyl-1,2-oxazines 4
The reaction sequence 2/1 consists of three steps (Scheme 1).
The first stepdsilylation of 1,2-oxazine-N-oxides 2 into ASENA
3dhas already been studied.2a,b The third stepddesilylation of the
siloxy derivative 4 of a-hydroxyoximedhas also been well-stud-
ied.5,6 Thus, at first, we focused on the second step of the process,
viz. the ASENA 3 rearrangement.
Previously it was reported that N,N-bis(silyloxy)enamines 5, i.e.,
acyclic analogues of ASENA 3, could undergo the acid-promoted
rearrangement affording derivatives of a-oxyoximes 6 (Scheme 2).
It was shown that the reaction proceeded with good yields both
under the silylation conditions7 and also upon treatment with
catalytic amounts of a weak Lewis acid, e.g., AgOTf or Zn(OTf)2.6
We attempted to use the same reaction conditions for the
ASENA 3 rearrangement (Scheme 3, Table 1, entries 1–4). Since in
the ASENA structure there are two non-equivalent oxy-groups
bound with the nitrogen atom, two products were expected to
form: the above-mentioned oxazines 4 (path a) and oximes of
tetrahydropyrans 7 (path b) (Scheme 3, Table 1). Oxazines 4 were
obtained under the non-nucleophilic conditions. In the case of the
nucleophile catalysis we obtained pyranone oximes 7 (entry 12,
vide infra). In all cases, yields of the rearrangement product did not
exceed 40%. Interestingly, treatment of model compound 3a with
Zn(OTf)2, successfully employed for the rearrangement of BENA 5
(Scheme 2), afforded 4a in rather low yields (entry 1).
3-a-hydroxyalkyl-5,6-dihydro-4H-1,2-oxazines 1 can be considered
as useful precursors of 2-hydroxyalkylpyrrolidines or 2-amino-1,5-
dialcohols that possess different biological activity.3
Given the foresaid, the goal of this research was the detailed
investigation of the rearrangement of 3 to 4 and elaboration of the
method for the transformation of 5,6-dihydro-4H-1,2-oxazine-N-
oxides
2 into 3-a-hydroxyalkyl-5,6-dihydro-4H-1,2-oxazines 1,
based on this rearrangement.4
* Corresponding author. Tel.: þ7 495 135 5329; fax: þ7 495 135 5328.
E-mail address: lesav@mail.ru (A.V. Lesiv).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.082

A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
4579
Scheme 1. Silylation of 1,2-oxazine-N-oxides 2.
In contrast to it was found that several ASENA, when diluted in
CDCl3 and kept in the NMR tube for some time, rearranged to
oxazines 4 in moderate to good yields. Also ASENA rearrangement
occurred in other solvents such as ethyl acetate, hexane, tetrahy-
drofuran or dichloromethane though in lower yields than in chlo-
roform. The highest yields were obtained where chloroform was
distilled from P2O5 with subsequent water addition (5%).
While using commercially available chloroform (stabilized by
ethanol) the formation of by-product 8 (13%) was observed
(Scheme 4, Table 2).
Scheme 2. Silylation of aliphatic nitro compounds.
Scheme 4. By-products of the ASENA 3 rearrangement.
The other by-products obtained were 3-vinyl-5,6-dihydro-4H-
1,2-oxazines 9 (Scheme 4, Table 2). Their yields generally did not
exceed 15%, and they could be easily separated from the target
derivatives 1 by column chromatography.
It was found that the nature of the substituent R at the double
bond had the most significant influence on the process rate. The
rearrangement of ASENA 3g with the electron-donating 4-
methoxyphenyl substituent occurred in situ, simultaneously with
silylation of initial 1,2-oxazine-N-oxide 2g. ASENA with less elec-
tron-donor substituents (R¼Me, Et, Ph) underwent the rearrange-
ment within 24 h. The ASENA rearrangement with R¼CH2CO2Me
proceeded in 30 days affording the target product in 76% yield.
ASENA with the terminal double bond (R¼H) gave bad yields under
the mentioned conditions (Scheme 5, Table 3). Desilylation of
derivatives 4 afford the target oxazines 1.
Scheme 3. Rearrangement of ASENA 3.
Table 1
Optimization of the conditions for the ASENA 3 rearrangement
Entry
Compound
Conditions
Product
Yielda, %
1
2
3
4
5
6
7
8
3a
3k
3a
3a
3a
3k
3a
3a
3a
3a
3k
3k
Zn(OTf)2 (5%), 1 h
Zn(OTf)2 (5%), 1 h
TsOH (10%), 1 h
TMSCl (10%), 1 h
CHCl3, 24 h
4a
4k
4a
4a
4a
d
16
15
40
35
61
0
53
15
CHCl3, 24 h
CHCl3/NEt3 (10%), 24 h
CHCl3 (abs), 24 h
Hexane, 24 h
4a
4a
4a
Table 2
By-products of the ASENA 3 rearrangement
9
11
19
Entry
3,4,8,9a
Solv.
Yield 4, %
Yield 8, %
Yield 9, %
10
11
12
EtOAc, 24 h
4a
1
2
a
b
CHCl3 (stab. EtOH)
CHCl3, H2O (5%)
47
74
13
d
10
14
CHCl3/H2O (5%), 24 h
TBAF (5%), 1 h
4k, 7k
7k
30 (4k), 30 (7k),
27
a
a
See Table 3.
According to NMR with the internal standard (CHCl]CCl2).

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A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
Scheme 5. Synthesis of oxazines 1 from oxazine N-oxides 2 via the ASENA 3 rearrangement.
Table 3
Synthesis of oxazines 1 from oxazine N-oxides 2 via the ASENA 3 rearrangement
Entry
1-4
R
R1
R2
R3
R4
de, %
Yield 2/3a, %
Yield 3/4,a
%
Yield 4/1, %
Yield 2/1, %
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
Me
Me
Me
Me
Me
Et
An
Ph
An
An
4-Cl-C6H4–
Ph
An
An
An
An
H
OMe
Me
H
>95
>95
>95
>95
16b
>95
71
88
>95
83
94
66
94
95
24c
98
dd
85
93
90
97
61
74
94
94
94
90
96
95
95
95
94
95
96
54
46
73
52
46
58
58
54
66
64
30
–(CH2)4–
H
H
H
H
H
H
H
H
H
OMe
OMe
Me
OMe
OMe
OMe
OMe
OMe
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
82
61
95
62
61e
67
76f
75
32
9
10
11
CH2CO2Me
Me
H
An
j
k
2-MeO-C6H4–
4-Cl-C6H4–
d
a
According to NMR with the internal standard (CHCl]CCl2) unless otherwise mentioned.
b
c
d
e
f
We cannot judge about the configuration of the major isomer.
In a mixture with 4eþ4e0 (3e/4eþ4e0¼1:1) according to NMR. Procedure: TMSOTf/EtN(i-Pr)2, CH2Cl2, ꢀ78 ꢁC to ꢀ30 ꢁC, 1 day.
Compound 3g was not detected due to the rearrangement in the reaction mixture (see in the text).
Yield 2g/4gþ4g0, purified product.
Reaction time 3i/4iþ4i0, 1 month.
The configuration of the CH(OH)R fragment in the obtained
use of ‘acidic’ chloroform (pH<5) led to significant initial ASENA
decomposition. We found that ASENA 3a was rather stable in ab-
solute chloroform at room temperature (the average conversion
was estimated at 10% for 24 h according to NMR), whereas the
addition of a small amount of water (5%) resulted in a 61% yield of
the rearrangement product 4a.
oxazines 1a–c,f was determined by X-ray diffraction analysis
(Fig. 1).8 It was found that the ASENA 3 rearrangement generally
proceeded with a high stereoselectivity and afforded a single iso-
mer of siloxy derivative 4. However the formation of both isomers
in almost equal ratio was observed in one experiment (see Table 3,
entry 5).
Considering high sensitivity of the reaction to the water we
suggest the following reaction pathway. We suppose that it should
2.2. The pathway of the ASENA 3 rearrangement to
derivatives 4
The ASENA rearrangement results could not be explained using
the model proposed previously for the similar BENA process
(Scheme 6).6 It was demonstrated that the acidic impurities present
in chloroform (hydrogen chloride, phosgene) had no influence on
the process rate because triethylamine addition to the reaction
mixture did not affect the outcome of the process. Moreover, the
Scheme 6. The BENA 5 rearrangement mechanism.
Figure 1. X-ray structure of oxazines 1a–c,f.

A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
4581
occur via initial water interaction with ASENA affording TMSOH
(Scheme 7). The obtained trimethylsilanol subsequently reacts with
ASENA yielding target siloxy derivative 4 through the pericyclic
transition state. Also ASENA can react with water through the
similar transition state affording derivatives 1 directly. Indeed, we
observed the formation of derivatives 1 in the rearrangement re-
action with a large excess of water. It is noteworthy that 4 did not
yield 1 under these reaction conditions. Unfortunately, we could
not directly confirm the participation of TMSOH in the reaction due
to instability of TMSOH.9 However, the reaction with ethanol (see
Scheme 4) can be similarly explained by this pathway that in-
directly confirms the supposed pathway.
Scheme 8. Dynamic processes in ASENA 3 and stereochemistry of its rearrangement.
intermediate.12 We also tried to induce the ASENA rearrangement
by treatment with tetrabutylammonium fluoride or triethylamine.
As a result, we observed the migration of the alkoxy group instead
of the siloxy group leading to derivatives 7 and 10 (Scheme 9).
Scheme 7. The ASENA 3 rearrangement reaction pathway.
It is known that ASENA can easily undergo two dynamic pro-
cesses at room temperature,10 namely inversions of the nitrogen
atom and cycle (E w60 kJ/mol) (Scheme 8). As mentioned above,
the rearrangement rate strongly depends on the nature of the
substituent R at the double bond (Table 3). Thus only those con-
formations with the siloxy group that occupy the axial position
should be considered as reacting ones (conformations B and C),
whereas the axial position provides the required orbital overlap of
the substituent R with the antibonding orbital of the N–O bond.
Moreover, in these conformations the N–O bond is weaker due to
the anomeric interaction with the lone pair of the cyclic oxygen
atom.
Considering the configuration of the formed stereocentre
CH(OH)R we suppose that reaction proceeded from conformation
B. Thus conformation C should lead to another diastereomer of the
derivative 4. The preference for this conformation B can be
explained in the following way. Where ASENA bear the alkoxy
group at C-6 of the oxazine cycle, conformation C is significantly
destabilized by the transannular interaction between the 6-alkoxy
and N-siloxy groups.
2.3. The rearrangement of 3-alkylidene-2-siloxy-tetrahydro-
1,2-oxazines 3 (ASENA) under treatment with nucleophiles11
Scheme 9. Nucleophile-promoted rearrangement of ASENA 3.
To explain this fact we may assume that the reaction includes
the generation of a nitroso alkene similar to the process described
for N,N-bis(siloxy)enamines (Scheme 10).12 The rearrangement
outcome significantly depends on the substituents R3 and R4 at C-6
As it was demonstrated previously, N,N-bis(siloxy)enamines can
be involved in the rearrangement by treatment with nucleophiles
via the formation of conjugated nitroso alkene as a key reaction

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A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
Scheme 10. The mechanism of the nucleophile-promoted rearrangement of ASENA 3.
of the oxazine cycle. Where R3 and R4sOAlk, the intermediate A
formed in the reaction course undergoes re-cyclization yielding
tetrahydropyranone oxime 7. If R3¼OAlk, elimination of the alkoxy
anion occurs followed by its addition to the double bond and
subsequent transformation into 1,2-oxazine 10. A further hydrolysis
of 7 and 10 affords derivatives 70 and 100, respectively.
Figure 2. Selected NOE interactions in the ASENA 3.
2.4. Synthesis of initial ASENA 3a–c,e,f,h–j
As mentioned above, the first step of the reaction sequen-
cedsilylation of N-oxides 2dwas thoroughly investigated in the
case of 3-methyl-5,6-dihydro-4H-1,2-oxazine-N-oxides.
Since only ASENA with the substituent R at the C]C double
bond underwent the rearrangement with good yields, it was nec-
essary to synthesize previously non-described ASENA. It was found
that silylation of 1,2-oxazin-N-oxides bearing an ethyl or even more
bulky substituent at C-3 of the oxazine cycle was complicated by
the formation of several by-products, primarily enoximes 11, due to
a competitive process of C-4 deprotonation of the oxazine cycle
(Scheme 11).2a
C(3)-methyl group (R¼H) for silylation of oxazine-N-oxides 2. On
the other hand, the ASENA 3 rearrangement proceeded efficiently
where RsH. This fact limits the number of oxazines 1 attainable by
this method.
To perform a one-stage transformation 2/1 it was necessary to
succeed in selective silylation of initial oxazine-N-oxides yielding
ASENA 3. The optimal conditions found for the silylation reaction
are shown in Scheme 5. Subsequent treatment of the reaction
mixture with water led to the formation of ASENA 3. The double
bond configuration in the products was determined by two-di-
mensional NOESY spectra revealing characteristic interactions
presented in Figure 2. In all cases only (E)-isomers were obtained.
2.5. Application of 1,2-oxazines 1
5,6-Dihydro-4H-1,2-oxazines have found numerous applications
in the total synthesis of natural and biologically active nitrogen-
containing compounds, e.g., alkaloids, unnatural amino acids, and
amino sugars. In these syntheses reduction of the oximino-fragment
plays the key role that makes it possible to transform oxazines into
a wide range of heterocyclic and acyclic products. Thus, depending
on the structure of oxazines and reaction conditions, reduction can
lead to substituted14a and fused14b pyrrolidines, pyrroles,14c five-
membered cyclic nitrones,14d -aminoalcohols,14e and diketones.14f
d
To demonstrate an application of synthesized oxazines 1 we
reduced 1a to pyrrolidine 12 in two steps by a known procedure15
via the formation of tetrahydrooxazine 13 (Scheme 12).
Scheme 11. Silylation of 1,2-oxazine-N-oxides 2.
The steric and electron properties of the substituent R3 obvi-
ously have a significant influence on the ratio of products 3 and 11.
It was found that even in the case of R3¼Me (2e) silylation using
triethylamine as a base afforded enoxime 11 as the single product.
Fortunately, the use of a more sterically hindered basedthe Hunig
base13dwas quite effective and gave an enhanced yield of target
ASENA 3.
However, our attempts to obtain siloxy derivative 3 of oxazine-
N-oxides with more branched substituents at C-3 of the oxazine
cycle (e.g., the 3-i-Pr derivative) failed.
Based upon the obtained results a conclusion was made on the
necessary presence of the sterically unhindered substituent R at the
Scheme 12. Reduction of derivative 1a.

A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
4583
Scheme 13. Structures of compounds 1–4, 7–10, 12, 13.
3. Conclusions
tetrahydrooxazines 3 was demonstrated. An efficient one-step
procedure for the transformation 2/1 was developed without
purifying intermediate products. The impact of different factors on
the reaction outcome was evaluated. Basing on the results the
pathway of the process was proposed.
A new approach to the synthesis of 3-a-hydroxymethyl-5,6-
dihydro-4H-1,2-oxazines 1 from 1,2-oxazin-N-oxides 2 via the
formation and subsequent rearrangement of 3-alkiliden-2-siloxy-

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A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
4. Experimental section
recrystallized from EtOH to give 12 g (53%) of title compound as
a yellow solid. Rf¼0.68 (hexane/EtOAc, 1:1). Mp¼55–56 ꢁC. Anal.
Calcd for C13H15NO5: C, 58.86; H, 5.70; N, 5.28. Found: C, 58.87; H,
5.78; N, 5.25. 1H NMR: 2.67 and 3.21 (t, J¼7.3, both 2H, CH2CH2),
3.69 (s, 3H, CO2Me), 3.85 (s, 3H, ArOMe), 6.97 (d, J¼8.8, 2H, CHAr,o-OMe),
7.43 (d, J¼8.8, 2H, CHAr,m-OMe), 8.08 (s, 1H, C]CH). 13C NMR: 23.1
and 31.8 (CH2CH2), 52.0 (CO2Me), 55.5 ArOMe), 114.8 (CHAr,o-OMe),
124.0 (CAr,p-OMe), 132.1 (CHAr,m-OMe), 135.2 (C]CH), 147.7 (C–NO2),
161.6 (CAr–OMe), 172.5 (CO2Me).
4.1. General information
All silylation reactions were performed in oven-dried (150 ꢁC)
glassware under an argon atmosphere. Melting points were de-
termined on a Koffler melting point apparatus and are uncorrected.
Chromatographic separations were performed on silica gel (Merck
Kieselgel 230–400 mesh) with analytical-grade solvents, driven by
a positive pressure of air. Analytical thin-layer chromatography was
performed on Merck silica gel plates with QF-254 indicator. Visu-
alization was accomplished with UV light and/or anisaldehyde and/
or ninhydrin. IR spectra were recorded on the spectrometer Bruker
Vector22 in the thin layer, nmax are reported in cmꢀ1. 1D and 2D
NMR spectra were recorded on the NMR-spectrometers Bruker
DRX-500 (1H: 500.13 MHz, NOESY), Bruker AM-300 (1H:
300.13 MHz, 13C: 75.47 MHz, 29Si: 59.63 MHz), and Bruker WM-250
(1H: 250 MHz, 13C: 62.5 MHz,) for CDCl3 solutions with residual
solvent peak as an internal standard.16 The INEPT pulse sequence
was used for observation of the 29Si signals. Multiplicities are in-
dicated by s (singlet), d (doublet), t (triplet), q (quartet), m (mul-
tiplet), and br (broad). Coupling constants, J, are reported in hertz.
Atom numbering is shown in Scheme 13. Elemental analyses were
performed by the analytical Centre of N.D. Zelinsky Institute of
Organic Chemistry.
4.2.1.3. 1-Chloro-4-(2-nitro-1-butenyl)benzene.22 The solution of 4-
chlorobenzaldehyde (28 g, 0.2 mol), 1-nitropropane (18 mL,
1 equiv, 0.2 mol), and butylamine (0.05 equiv, 1 mL) in EtOH
(20 mL) was refluxed for 16 h. The solution was cooled to 0 ꢁC. The
precipitate was filtered and washed with EtOH to give 10 g (23%) of
title compound as a light yellow solid. Mp¼72–73 ꢁC. (lit.22
mp¼77.5 ꢁC). 1H NMR: 1.28 (t, J¼7.3, 3H, CH2CH3), 2.85 (q, J¼7.3, 2H,
CH2), 7.35 and 7.45 (d, J¼8.8, both 2H, CHAr), 7.96 (s, 1H, ]CH). 13
C
NMR: 12.5 (CH2CH3), 20.7 (CH2), 129.3 and 130.9 (CHAr), 130.8 and
136.1 (CAr), 131.8 (]CH), 153.7 (C–NO2).
4.2.1.4. 1-Methoxy-4-(2-nitro-3-phenyl-1-propenyl)benzene. The
solution of 4-methoxybenzaldehyde (12 mL, 0.1 mol), 2-phenyl-
nitroethane (15 g, 1 equiv, 0.1 mol), and butylamine (0.05 equiv,
0.5 mL) in toluene (30 mL) was refluxed for 12 h with a Dean–Stark
trap. The solvent was removed in vacuum. The residue was
recrystallized from EtOH to give 24 g (90%) of title compound as
a light yellow solid. Mp¼53–58 ꢁC. Anal. Calcd for C16H15NO3: C,
71.36; H, 5.61; N, 5.20. Found: C, 71.37; H, 5.76; N, 5.20. 1H NMR:
3.85 (s, 3H, OMe), 4.31 (s, 2H, CH2), 6.95 (d, J¼8.8, 2H, CHAr,o-OMe),
7.20–7.39 (m, 5H, Ph), 7.45 (d, J¼8.8, 2H, CHAr,m-OMe), 8.35 (s,
1H,¼CH(6)). 13C NMR: 33.1 (CH2), 55.5 (OMe(1)), 114.7 (CHAr,o-OMe),
124.2 (CAr,p-OMe), 126.9, 127.6, and 129.0 (Ph), 132.0 (CHAr,m-OMe),
135.8 (]CH), 136.4 (CPh), 147.4 (C–NO2), 161.6 (C–OMe).
Hexane, EtOAc, toluene, EtOH, and MeOH were distilled without
drying agents. Glacial acetic acid was recrystallized twice. The fol-
lowing reaction solvents and reagents were distilled from the in-
dicated drying agents: methylene chloride (CaH2), CHCl3 (P2O5),
triethylamine (CaH2), ethyl-di-iso-propylamine (CaH2), tin tetra-
chloride (CaH2), cyclohexane (CaH2). The following chemicals were
purchased from the indicated sources: TMSBr (Acros), TMSOTf
(Acros), CaCl2 (Acros), 2-methoxypropene (Acros), ethylvinyl ether
(Acros), isobutylene (Aldrich), 4-methoxybenzaldehyde (Acros), 4-
chlorobenzaldehyde (Acros), 1-nitropropane (Acros), methyl-4-
nitrobutyrate (Aldrich), butylamine (Acros), NH4F$HF (Acros),
NaBH3CN (Acros), Raney Nickel (50% slurry in water) (Acros), Boc2O
(Acros). Brine refers to a saturated aqueous solution of NaCl.
The following compounds were prepared according to litera-
ture procedures: tetra-n-butylammonium fluoride (TBAF),17
methoxybenzaldehyde,18 2-phenylnitroethane, and 2-(4-methoxy-
4.2.1.5. 1-Methoxy-4-(3-(4-methoxyphenyl)-2-nitro-1-propenyl)ben-
zene.23 The solution of 4-methoxybenzaldehyde (4.2 mL, 35 mmol),
2-(4-methoxyphenyl)nitroethane (6.4 g, 1 equiv, 35 mmol), and
butylamine (0.08 equiv, 0.3 mL) in EtOH (4 mL) was refluxed for
16 h. The solvent was removed in vacuum. The residue was sub-
jected to column chromatography (eluent: hexane/toluene, 1:1) to
give 3.1 g (30%) of title compound as a yellow oil. Rf¼0.62 (toluene).
The spectral data (1H and 13C NMR) are identical to previously
reported.23
phenyl)nitroethane,19
1-methoxy-4-((E)-2-nitro-1-pentenyl)-
benzene,20 ASENA 3a,2b ASENA 3d,l,m, oxazine N-oxide 2k.2c
4.2. Preparation of oxazine N-oxides 2
4.2.1.6. 1-Methoxy-2-(2-nitro-1-butenyl)benzene.24 The solution of
2-methoxybenzaldehyde (10 g, 73 mmol), 1-nitropropane (7 mL,
1 equiv, 73 mmol), and butylamine (0.07 equiv, 0.5 mL) in EtOH
(8 mL) was refluxed for 16 h. The solvent was removed in vacuum.
The residue was subjected to column chromatography (eluent:
hexane/toluene, 1:1) to give 2.3 g (15%) of title compound as a yel-
low oil. Rf¼0.45 (toluene). 1H NMR: 1.26 (t, J¼7.4, 3H, CH2CH3), 2.81
(q, J¼7.4, 2H, CH2), 3.87 (s, 3H, OMe), 6.95 (d, J¼7.9, 1H, CHAr,o-OMe),
7.03 (t, J¼7.9, 1H, CHAr,p-OMe), 7.30 (d, J¼7.9, 1H, CHAr,o-CH]C), 7.41 (t,
J¼7.9, 1H, CHAr,p-CH¼C), 8.23 (s, 1H, ]CH). 13C NMR: 12.6 (CH2CH3),
20.9 (CH2), 55.6 (OMe), 110.9 (CHAr,o-OMe), 120.6 (CHAr,p-OMe),
121.5 (CAr,o-OMe), 129.3 and 129.4 (CHAr,m-OMe), 131.6 (]CH), 153.0
(C–NO2), 158.1 (C–OMe).
4.2.1. Preparation of nitroalkenes
4.2.1.1. 1-Methoxy-4-((E)-2-nitro-1-butenyl)benzene.21 The solution
of 4-methoxybenzaldehyde (24 mL, 0.2 mol), 1-nitropropane
(18 mL, 1 equiv, 0.2 mol), and butylamine (0.05 equiv, 1 mL) in tol-
uene (30 mL) was refluxed for 12 h with a Dean–Stark trap. Then
the Dean–Stark trap was replaced with the dropping funnel with
anhydrous CaCl2 (10 g). The reaction mixture was additionally
refluxed for 12 h. The solvent was removed in vacuum. The residue
was recrystallized from EtOH to give 24 g (58%) of title compound
as a yellow solid. Mp¼49–51 ꢁC (lit.21 mp¼55–57 ꢁC (MeOH)). 1H
NMR: 1.30 (t, J¼7.4, 3H, CH2CH3), 2.91 (q, J¼7.4, 2H, CH2), 3.87 (s, 3H,
OMe), 6.99 (d, J¼8.5, 2H, CHAr,o-OMe), 7.43 (d, J¼8.5, 2H, CHAr,m-OMe),
8.02 (s, 1H, ]CH).
4.2.2. [4þ2]-Cycloaddition of nitroalkenes to olefins. General
procedure for the preparation of oxazine N-oxides 2c,f–i
4.2.1.2. Methyl 5-(4-methoxyphenyl)-4-nitro-4-pentenoate. The so-
lution of 4-methoxybenzaldehyde (12 mL, 0.1 mol), methyl-4-
nitrobutyrate (14.7 g, 1 equiv, 0.1 mol), and butylamine (0.05 equiv,
0.5 mL) in toluene (15 mL) was refluxed for 12 h with a Dean–Stark
trap. The solvent was removed in vacuum. The residue was
SnCl4 (0.65 mL, 1.1 equiv, 5.5 mmol) was added to a stirred so-
lution of corresponding nitroalkene (5 mmol) in CH2Cl2 (25 mL) at
ꢀ78 ꢁC in dry argon. The temperature was decreased to ꢀ94 ꢁC and
2-methoxypropene (0.96 mL, 2 equiv, 10 mmol) was added drop-
wise. The reaction mixture was stirred for 5 min and then poured

A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
4585
into a mixture of EtOAc (150 mL) and saturated aqueous solution of
NaHCO3 (100 mL). The organic layer was washed with saturated
aqueous solution of NaHCO3 (50 mL), H2O (100 mL), and brine
(2ꢂ50 mL), and dried over Na2SO4. The solvents were removed in
vacuum and the residue was recrystallized from Hex/EtOAc¼3:1 to
give title compound as a white solid.
1.42 (s, 3H, CH3(12)), 1.88–2.15 (m, 3H, CH2b(8) and CH2(10)), 2.42
(dq, J¼14.4, 7.2, 1H, CH2a(8)), 3.66 (dd, J¼10.8, 8.1, 1H, CH(6)), 3.78
(s, 3H, CH3(1)), 6.85 (d, J¼8.5, 2H, CH(4)), 7.10 (d, J¼8.5, 2H, CH(3)).
13C NMR: 8.7 (CH3(9)), 21.9 (CH3(12)), 24.1 (CH2(8)), 27.9 (CH(13)),
41.0 (CH(6)), 41.8 (CH2(10)), 55.3 (CH3(1)), 81.1 (C(11)), 114.5
(CH(3)), 126.5 (C(7)), 129.2 (CH(4)), 132.1 (C(5)), 159.0 (C(2)).
4.2.2.1. rel-(4S,4aR,8aR)-3-Ethyl-4-(4-methoxyphenyl)-4a,5,6,7,8,8a-
hexahydro-4H-benzo[e][1,2]oxazine N-oxide 2b. SnCl4 (1.3 mL,
1.1 equiv, 11 mmol) was added to a stirred solution of 1-methoxy-4-
(2-nitro-1-butenyl)benzene (2.07 g, 10 mmol) in CH2Cl2 (50 mL) at
ꢀ78 ꢁC in dry argon. The temperature was decreased to ꢀ94 ꢁC and
cyclohexene (1.9 mL, 2 equiv, 20 mmol) was added for 1 min. The
reaction mixture was maintained for 1 day at ꢀ30 ꢁC and then
poured into a mixture of EtOAc (150 mL) and saturated aqueous
solution of NaHCO3 (100 mL). The organic layer was washed with
a saturated aqueous solution of NaHCO3 (50 mL), H2O (100 mL),
brine (2ꢂ50 mL), and dried over Na2SO4. The solvents were re-
moved in vacuum and the residue was recrystallized from hexane/
EtOAc, 3:1 to give 2.2 g (77%) of title compound as a white solid.
Rf¼0.26 (hexane/EtOAc, 1:1) (UV). Mp¼105–106 ꢁC (EtOAc). Anal.
Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.63; H,
8.29; N, 4.89. nmax: 2933, 2860, 1606, 1581, 1511, 1462, 1146, 1292,
1248, 1215, 1179, 1109, 1033, 965, 934, 885, 857, 733, 593 cmꢀ1. 1H
NMR: 1.26 (t, J¼7.5, 3H, CH3(9)), 1.20–1.83 (m, 8H, CH2(12–15)),
1.98–2.13 (m, 2H, CH2(8)), 2.60 (dq, J¼13.9, 7.4, 1H, CH(10)), 3.35 (s,
1H, CH(6)), 3.79 (s, 3H, CH3(1)), 4.58 (br s, 1H, CH(11)), 6.85 (d,
J¼8.5, 2H, CH(3)), 7.07 (d, J¼8.5, 2H, CH(4)). 13C NMR: 8.9 (CH3(9)),
28.8, 27.4, 25.6, 24.8, 19.8 (all CH2(8,12–15)), 39.7 (CH(10)), 47.7
(CH(6)), 55.4 (CH3(1)), 75.0 (CH(11)), 110.7 (CH(11)), 114.4 (CH(3)),
124.1 (C(7)), 129.0 (CH(4)), 133.6 (C(5)), 159.0 (C(2)).
4.2.2.4. rel-(4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-6-methyl-3-
propyl-5,6-dihydro-4H-1,2-oxazine N-oxide 2f. Oxazine N-oxide 2f
was prepared according to the general procedure from 1-
methoxy-4-((E)-2-nitro-1-pentenyl)benzene. Yield¼77%. Rf¼
0.23 (hexane/EtOAc, 1:1) (UV). Mp¼92–93 ꢁC (Et2O). Anal. Calcd
for C16H23NO4: C, 65.51; H, 7.90; N, 4.77. Found: C, 65.60; H, 7.85;
N, 4.70. nmax: 2993, 2962, 2941, 1608, 1512, 1462, 1379, 1304, 1277,
1252, 1230, 1178, 1148, 1085, 1035, 872, 834, 798, 534 cmꢀ1 1H
.
NMR: 0.84 (t, J¼7.3, 3H, CH3(14)), 1.48 (s, 3H, CH3(12)), 1.56 (m,
1H, CH2b(9)), 1.56 (m, 1H, CH2a(9)), 1.88 (ddd, J¼14.7, 8.8, 6.2, 1H,
CH2b(8)), 1.94 (dd, J¼14.0, 11.5, 1H, CH2ax(10)), 2.26 (dd, J¼14.0,
8.1, 1H, CH2eq(10)), 2.45 (ddd, J¼14.7, 8.8, 6.2, 1H, CH2a(8)), 3.44 (s,
3H, CH3(13)), 3.77 (s, 3H, CH3(1)), 3.79 (dd, J¼11.5, 8.1, 1H, CH(6)),
6.83 (d, J¼8.8, 2H, CH(3)), 7.07 (d, J¼8.8, 2H, CH(4)). 13C NMR: 13.6
(CH3(14)), 17.6 (CH2(9)), 20.8 (CH3(12)), 32.2 (CH2(8)), 40.3
(CH(6)), 40.5 (CH2(10)), 50.0 (CH3(13)), 55.3 (CH3(1)), 103.7
(C(11)), 114.4 (CH(3)), 126.4 (C(7)), 129.1 (CH(4)), 131.9 (C(5)),
158.9 (C(2)).
4.2.2.5. rel-(4S,6S)-6-Methoxy-3-(4-methoxybenzyl)-4-(4-methoxy-
phenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine N-oxide 2g. Oxazine
N-oxide 2g was prepared according to the general procedure from
1-methoxy-4-(3-(4-methoxyphenyl)-2-nitro-1-propenyl)benzene.
Yield¼50%. Rf¼0.30 (hexane/EtOAc, 1:1) (UV). Mp¼79–80 ꢁC (hex-
ane/EtOAc,1:1). Anal. Calcd for C21H25NO5: C, 67.91; H, 6.78; N, 3.77.
Found: C, 68.28; H, 6.80; N, 3.77. nmax: 2995, 2941, 2918, 2837, 1609,
4.2.2.2. rel-(4S,6S)-4-(4-Chlorophenyl)-3-ethyl-6-methoxy-6-methyl-
5,6-dihydro-4H-1,2-oxazine N-oxide 2c. Oxazine N-oxide 2c was
prepared according to the general procedure from 1-chloro-4-(2-
nitro-1-butenyl)benzene. Yield¼69%. Rf¼0.31 (hexane/EtOAc, 1:1)
(UV). Mp¼74–76 ꢁC (hexane/EtOAc, 3:1). Anal. Calcd for
C14H18ClNO3: C, 59.26; H, 6.39; N, 4.94. Found: C, 58.97; H, 6.47; N,
4.87. nmax: 2974, 2941, 1610, 1491, 1461, 1454, 1409, 1379, 1301, 1264,
1231, 1187, 1148, 1090, 1050, 1014, 852, 829, 771, 532 cmꢀ1. 1H NMR:
0.97 (t, J¼7.2, 3H, CH3(8)), 1.51 (s, 3H, CH3(11)), 1.94 (dd, J¼13.8, 11.2,
1H, CH2a(9)), 2.04 (dq, J¼14.5, 7.2, 1H, CH2a(7)), 2.29 (dd, J¼13.8, 7.8,
1H, CH2e(9)), 2.39 (dq, J¼14.5, 7.2,1H, CH2b(7)), 3.47 (s, 3H, CH3(12)),
3.87 (dd, J¼11.2, 7.8, 1H, CH(5)), 7.13 (d, J¼7.9, 2H, CH(3)), 7.32 (d,
J¼7.9, 2H, CH(2)). 13C NMR: 8.6 (CH3(8)), 20.9 (CH3(11)), 24.3
(CH2(7)), 40.3 (CH(5) and CH2(9)), 50.2 (CH3(12)), 103.9 (C(10)),
126.4 (CH(6)), 129.4 and 129.6 (CH(2) and CH(3)), 133.5 and 138.6
(C(1) and C(4)).
1511, 1458, 1301, 1248, 1178, 1139, 1082, 1065, 1035, 840, 534 cmꢀ1
.
1H NMR: 1.50 (s, 3H, CH3(12)), 2.25 (dd, J¼13.6, 11.0, 1H, CH2ax(10)),
2.25 (dd, J¼13.6, 8.1, 1H, CH2eq(10)), 3.03 (d, J¼15.1, 1H, CH2b(8)),
3.46 (s, 3H, CH3(13)), 3.77 and 3.80 (s, 6H, CH3(1) and CH3(17)), 3.74
(dd, J¼11.0, 8.1, 1H, CH(6)), 4.05 (d, J¼15.1, 1H, CH2a(8)), 6.76 and
6.83 (d, J¼8.8, 4H, CH(3) and CH(15)), 6.97 and 6.99 (d, J¼8.8, 4H,
CH(4) and CH(14)). 13C NMR: 20.8 (CH3(12)), 34.8 (CH2(8)), 39.4
(CH(6)), 40.5 (CH2(10)), 50.1 (CH3(13)), 55.2 and 55.3 (CH3(1) and
CH3(17)), 104.1 (C(11)), 113.8 and 114.5 (CH(3) and CH(15)), 126.1
(C(7)), 128.1 and 131.8 (C(5) and C(9)), 129.3 and 129.8 (CH(4) and
CH(14)), 158.3 and 158.9 (C(2) and C(16)).
4.2.2.6. rel-(4S,6S)-3-Benzyl-6-methoxy-4-(4-methoxyphenyl)-6-
methyl-5,6-dihydro-4H-1,2-oxazine N-oxide 2h. Oxazine N-oxide 2h
was prepared according to the general procedure from 1-methoxy-
4-(2-nitro-3-phenyl-1-propenyl)benzene. Yield¼76%. Rf¼0.29 (hex-
ane/EtOAc, 1:1) (UV). Mp¼80 ꢁC (EtOAc). Anal. Calcd for C20H23NO4:
C, 70.36; H, 6.79; N, 4.10. Found: C, 69.94; H, 6.87; N, 4.09. nmax: 3060,
3028, 2995, 2941, 2836,1607,1512,1453,1379,1300,1250,1231,1178,
1140, 1080, 1065, 1035, 984, 835, 798, 704, 536, 519 cmꢀ1. 1H NMR:
1.51 (s, 3H, CH3(12)), 1.99 (dd, J¼13.7, 11.2, 1H, CH2ax(10)), 2.26 (dd,
J¼13.7, 7.9, 1H, CH2eq(10)), 3.10 (d, J¼14.7, 1H, CH2b(8)), 3.46 (s, 3H,
CH3(13)), 3.77 (dd, J¼11.2, 7.9,1H, CH(6)), 3.80 (s, 3H, CH3(1)), 4.11 (d,
J¼14.7, 1H, CH2a(8)), 6.83 (d, J¼8.5, 2H, CH(3)), 6.99 (d, J¼8.5, 2H,
CH(4)), 7.06–7.09 and 7.19–7.27 (m, 5H, CH(14–16)). 13C NMR: 20.8
(CH3(12)), 55.3 (CH3(1)), 50.1 (CH3(13)), 35.6 (CH2(8)), 40.0 (CH(6)),
40.5 (CH2(10)), 104.2 (C(11)), 114.4 (CH(3)), 125.9 (C(7)), 131.7 (C(5)),
136.1 (C(9)), 128.4 and 129.3 (CH(14) and CH(15)), 128.8 (CH(3)),
159.0 (C(2)).
4.2.2.3. 3-Ethyl-4-(4-methoxyphenyl)-6,6-dimethyl-5,6-dihydro-4H-
1,2-oxazine N-oxide 2e. SnCl4 (1.3 mL, 1.1 equiv, 11 mmol) was
added to
a stirred solution of 1-methoxy-4-(2-nitro-1-bute-
nyl)benzene (2.07 g, 10 mmol) in CH2Cl2 (50 mL) at ꢀ78 ꢁC in dry
argon. The temperature was decreased to ꢀ94 ꢁC and isobutylene
(0.9 g, 2 equiv, 20 mmol) was added for 1 min. The reaction mixture
was stirred for 5 min and then poured into a mixture of EtOAc
(150 mL) and saturated aqueous solution of NaHCO3 (100 mL). The
organic layer was washed with a saturated aqueous solution of
NaHCO3 (50 mL), H2O (100 mL), brine (2ꢂ50 mL), and dried over
Na2SO4. The solvents were removed in vacuum and the residue was
recrystallized from hexane/EtOAc, 5:1 to give 2.11 g (80%) of title
compound as a white solid. Rf¼0.18 (hexane/EtOAc, 1:1) (UV).
Mp¼80–81 ꢁC (hexane/EtOAc, 5:1). Anal. Calcd for C15H21NO3: C,
68.42; H, 8.04; N, 5.32. Found: C, 68.51; H, 8.29; N, 5.33. nmax: 2977,
2933, 1602, 1512, 1462, 1372, 1297, 1247, 1177, 1033, 888, 856, 833,
529 cmꢀ1. 1H NMR: 0.96 (t, J¼7.4, 3H, CH3(9)), 1.38 (s, 3H, CH3(13)),
4.2.2.7. rel-(4S,6S)-6-Methoxy-3-(3-methoxy-3-oxopropyl)-4-(4-
methoxyphenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine N-oxide 2i.
Oxazine N-oxide 2i was prepared according to the general

4586
A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
procedure from methyl 5-(4-methoxyphenyl)-4-nitro-4-pente-
noate. Yield¼70%. Rf¼0.12 (hexane/EtOAc, 1:1) (UV). Mp¼60–62 ꢁC
(EtOAc). Anal. Calcd for C17H23NO6: C, 60.52; H, 6.87; N, 4.15. Found:
C, 60.37; H, 6.75; N, 4.17. nmax: 2995, 2948, 2837, 1737, 1608, 1513,
1462, 1438, 1380, 1362, 1302, 1252, 1231, 1178, 1143, 1084, 1072,
1036, 856, 836, 798, 536 cmꢀ1. 1H NMR: 1.50 (s, 3H, CH3(12)), 1.99
(dt, J¼13.5, 10.5, 1H, CH2a(8)), 2.28 (dd, J¼14.0, 8.1, 1H, CH2e(10)),
2.30–2.41 (2H), 2.49–2.58 (1H) and 2.77–2.88 (1H) (all m, CH2b(8),
CH2(9) and CHa(10)), 3.44 (s, 3H, CH3(13)), 3.80 (s, 3H, CH3(1)), 3.64
(s, 3H, CH3(15)), 3.91 (dd, J¼11.0, 7.3, 1H, CH(6)), 6.87 (d, J¼8.8, 2H,
CH(3)), 7.11 (d, J¼8.8, 2H, CH(4)). 13C NMR: 20.8 (CH3(12)), 27.7 and
26.2 (CH2(8) and CH2(9)), 40.3 (CH2(10)), 40.8 (CH(6)), 50.1
(CH3(13)), 51.7 (CH3(15)), 55.3 (CH3(1)), 104.2 (C(11)), 114.6 (CH(3)),
125.2 (C(7)), 129.3 (CH(4)), 131.4 (C(5)), 159.0 (C(2)), 173.0 ((C(14))).
J¼13.2, 6.6, 1H, CH2a(9)), 2.45 (dd, J¼13.2, 7.3, 1H, CH2b(9)), 3.27 (s,
3H, CH3(12)), 4.08 (br t, J¼7.0, 1H, CH(5)), 5.67 (q, J¼6.6, 1H, CH(7)),
7.25 (d, J¼8.1, 2H, CH(3)), 7.34 (d, J¼8.1, 2H, CH(2)). 13C NMR: ꢀ0.6
(CH3(13)), 12.1 (CH3(8)), 23.4 (CH3(11)), 36.9 (CH(5)), 39.5 (CH2(9)),
49.1 (CH3(12)), 101.3 (C(10)), 115.2 (CH(7)), 128.4 and 129.3 (CH(3)
and CH(2)), 131.8 (C(1)), 141.9 (C(4)), 146.3 (C(6)).
4.3.1.3. rel-(4S,6S)-(E)-6-Methoxy-4-(4-methoxyphenyl)-6-methyl-
3-propylidene-2-(trimethylsilyloxy)morpholine 3f. 1H NMR: 0.26 (s,
9H, CH3(14)), 0.80 (t, J¼7.3, 3H, CH3(15)), 1.10 (s, 3H, CH3(12)), 2.27
(dd, J¼13.2, 6.6, 1H, CH2b(10)), 2.41 (dd, J¼13.2, 8.1, 1H, CH2a(10)),
1.61–1.85 (m, 2H, CH2(9)), 3.28 (s, 3H, CH3(13)), 3.79 (s, 3H, CH3(1)),
4.07 (br t, 1H, CH(6)), 5.52 (t, J¼7.4, 1H, CH(8)), 6.81 (d, J¼8.1, 2H,
CH(3)), 7.31 (d, J¼8.1, 2H, CH(4)). 13C NMR: ꢀ0.6 (CH3(14)), 13.3
(CH3(15)), 20.0 (CH(9)), 23.3 (CH3(12)), 37.4 (CH(6)), 39.8 (CH2(10)),
49.1 (CH3(13)), 55.2 (CH3(1)), 101.6 (C(11)), 113.5 (CH(3)), 121.4
(CH(8)), 129.3 (CH(4)), 135.8 (C(5)), 145.6 (C(7)), 157.8 (C(2)).
4.2.2.8. rel-(4S,6S)-3-Ethyl-6-methoxy-4-(2-methoxyphenyl)-6-
methyl-5,6-dihydro-4H-1,2-oxazine N-oxide 2j. Oxazine N-oxide 2j
was prepared according to the general procedure from 1-methoxy-
2-(2-nitro-1-butenyl)benzene. Yield¼61%. Mp¼71–73 ꢁC (hexane/
EtOAc, 1:1) (UV). Rf¼0.11 (hexane/EtOAc, 1:1). Anal. Calcd for
C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.07; H, 7.70; N,
4.96. nmax: 2972, 2942, 2839, 1613, 1587, 1493, 1462, 1439, 1379,
4.3.1.4. rel-(4S,6S)-(E)-3-Benzylidene-6-methoxy-4-(4-methoxyphenyl)-
6-methyl-2-(trimethylsilyloxy)morpholine 3h. 1H NMR: 0.35 (s, 9H,
CH3(14)), 0.95 (s, 3H, CH3(12)), 2.35 (br s, 2H, CH2(10)), 3.30 (s, 3H,
CH3(13)), 3.79 (s, 3H, CH3(1)), 4.33 (br s, 1H, CH(6)), 6.60 (s, 1H,
CH(8)), 6.84 (d, J¼8.5, 2H, CH(3)), 7.05–7.20 (m, 5H, CH(15–17)),
7.33 (d, J¼8.5, 2H, CH(4)). 13C NMR: ꢀ0.5 (CH3(14)), 22.4 (CH3(12)),
38.8 and 40.6 (CH(6) and CH2(10)), 49.3 (CH3(13)), 55.2 (CH3(1)),
102.8 (C(11)), 113.8 (CH(3)), 115.9 (CH(8)), 126.6 (CH(17)), 128.2 and
129.3 (CH(15–16)), 128.8 (CH(4)), 135.4 and 135.1 (C(5) and C(9)),
149.0 (C(7)), 157.9 (C(2)).
1298, 1248, 1233, 1188, 1051, 1028, 828, 800, 756 cmꢀ1 1H NMR:
.
0.97 (t, J¼7.3, 3H, CH3(9)), 1.50 (s, 3H, CH3(12)), 1.98–2.09 (m, 2H,
CH2a(10) and CH2a(8)), 2.23 (dd, J¼13.2, 8.1, 1H, CH2e(10)), 2.45 (dq,
J¼14.0, 7.3, 1H, CH2a(8)), 3.48 (s, 3H, CH3(13)), 3.83 (s, 3H, CH3(1)),
4.21 (dd, J¼11.1, 8.1, 1H, CH(6)), 6.87–6.95 (m, 2H, CH(3) and
CH(14)), 7.11 (d, J¼8.1, 1H, CH(15)), 7.23–7.29 (m, 1H, CH(4)). 13C
NMR: 8.5 (CH3(9)), 21.0 (CH3(12)), 24.2 (CH2(8)), 35.2 (CH(6)), 37.7
(CH2(10)), 50.1 (CH3(13)), 55.5 (CH3(1)), 103.9 (C(11)), 110.9 and
121.0 (CH(3) and CH(14)), 127.7 and 127.8 (C(5) and C(7)), 128.8 and
129.6 (CH(4) and CH(15)), 157.2 (C(2)).
4.3.1.5. rel-(4S,6S)-(E)-Methyl 3-(6-methoxy-4-(4-methoxyphenyl)-
6-methyl-2-(trimethylsilyloxy)-morpholin-3-ylidene)propanoate 3i.
1H NMR: 0.27 (s, 9H, CH3(14)), 1.07 (s, 3H, CH3(12)), 2.35 (br s, 2H,
CH2(10)), 2.76 (dd, J¼18.0, 6.2, 1H CH2a(9)), 2.85 (dd, J¼18.0, 8.1, 1H,
CH2b(9)), 3.26 (s, 3H, CH3(13)), 3.57 (s, 3H, CH3(16)), 3.76 (s, 3H,
CH3(1)), 4.05 (br t, J¼5.9, 1H, CH(6)), 5.72 (t, J¼7.4, 1H, CH(8)), 6.79
(d, J¼8.5, 2H, CH(3)), 7.25 (d, J¼8.8, 2H, CH(4)). 13C NMR: ꢀ0.7
(CH3(14)), 22.9 (CH3(12)), 32.1 (CH2(9)), 37.7 (CH(6)), 40.0
(CH2(10)), 49.1 (CH3(13)), 51.6 (CH3(16)), 55.2 (CH3(1)), 102.1
(C(11)), 113.8 (CH(3)), 129.2 (CH(4)), 129.5 (CH(8)), 134.4 (C(5)),
149.4 (C(7)), 158.1 (C(2)), 171.6 (C(15)). 29Si NMR: 25.98.
4.3. Silylation of oxazine N-oxides 2
4.3.1. General procedure for the preparation of ASENA 3b,c,f,h–k
NEt3 (0.36 mL, 1.3 equiv, 2.6 mmol) was added to stirred solu-
tion of corresponding nitronate 2 (2 mmol) in CH2Cl2 (4 mL) at
ꢀ78 ꢁC. Then TMSBr (0.32 mL, 1.2 equiv, 2.4 mmol) was added. The
reaction mixture was maintained at the same temperature for 16 h,
diluted with hexane (15 mL) and poured into a mixture of hexane
(30 mL) and NaHSO4 aqueous solution (0.5 g in 30 mL of water).
The organic layer was washed with H2O (30 mL) and brine
(2ꢂ30 mL) and dried over Na2SO4. The solvents were removed in
vacuum to give title ASENA as colorless oil, which was used in the
next step without additional purification. For yields see Table 3.
4.3.1.6. rel-(4S,6S)-(E)-3-Ethylidene-6-methoxy-4-(2-methoxyphenyl)-
6-methyl-2-(trimethylsilyloxy)morpholine 3j. 1H NMR: 0.26 (s, 9H,
CH3(14)), 0.95 (s, 3H, CH3(12)), 1.29 (d, J¼6.6, 3H, CH3(9)), 2.23–2.35
(m, 2H, CH2(10)), 3.28 (s, 3H, CH3(13)), 3.86 (s, 3H, CH3(13)), 3.79–
3.86 (m, 1H, CH(6)), 4.44 (br s, 1H, CH(6)), 5.54 (q, J¼6.6, 1H, CH(8)),
6.77–6.87 (m, 2H, CH(3) and CH(15)), 7.14–7.22 (m, 1H, CH(4)), 7.45
(d, J¼6.6, 1H, CH(16)). 13C NMR: ꢀ0.6 (CH3(14)), 12.0 (CH3(9)), 23.1
(CH3(12)), 31.7 (CH(6)), 36.6 (CH2(10)), 49.2 (CH3(13)), 55.3
(CH3(1)), 102.2 (C(11)), 109.8 and 120.3 (CH(3) and CH(15)), 111.8
(CH(8)), 127.1 and 129.9 (CH(4) and CH(16)), 128.9 (C(5)), 147.7
(C(7)), 156.7 (C(2)). 29Si NMR: 24.59.
4.3.1.1. rel-(4S,4aR,8aR)-(E)-3-Ethylidene-4-(4-methoxyphenyl)-2-
(trimethylsilyloxy)-octahydro-2H-benzo[e][1,2]oxazine 3b. Two con-
formers in a ratio 3:1. 1H NMR: major conformer: 0.24 (s, 9H,
CH3(16)), 1.58 (d, J¼7.2, 3H, CH3(9)), 1.80–2.09 (m, 9H, CH2(12–15)
and CH(10)), 3.80 (s, 3H, CH3(1)), 4.35 (br s,1H, CH(6)), 4.82 (br s,1H,
CH(11)), 5.85 (q, J¼7.2, 1H, CH(8)), 6.84 (d, J¼9.2, 2H, CH(3)), 7.33 (d,
J¼8.6, 2H, CH(4)). Minor conformer: 0.16 (s, 9H, CH3(16)), 1.58 (d,
J¼7.2, 3H, CH3(9)), 1.80–2.09 (m, 9H, CH2(12–15) and CH(10)), 3.71
(s, 3H, CH3(1)), 4.35 (br s, 1H, CH(6)), 4.82 (br s, 1H, CH(11)), 5.93 (q,
J¼7.2,1H, CH(8)), 7.03 (d, J¼9.2, 2H, CH(3)), 7.41 (d, J¼8.6, 2H, CH(4)).
13C NMR (major conformer): ꢀ0.6 (CH3(16)), 11.4 (CH3(9)), 20.2,
25.8, 27.7, 30.0 (CH2(12–15)), 42.5 (CH(10)), 45.8 (CH(6)), 55.2
(CH3(1)), 71.8 (CH(11)), 108.1 (CH(8)), 113.4 (CH(3)), 129.0 (CH(4)),
135.2 (C(5)), 145.5 (C(7)), 157.8 (C(2)). Signals of the minor con-
former could not be unambiguously identified due to low intensity.
4.3.1.7. 4-(4-Chlorophenyl)-3-methylidene-6,6-dimethyl-2-(trimethyl-
silyloxy)morpholine 3k. 1H NMR: 0.24 (s, 9H, CH3(12)), 1.31 (s, 3H,
CH3(10 or 11)),1.50 (br s, 3H, CH3(10 or 11)),1.73 (dd, J¼12.6, 4.7,1H,
CH2a(8)), 1.96 (t, J¼12.6, 1H, CH2e(8)), 3.79 (br t, J¼12.6, 1H, CH(5)),
3.90 (s, 1H, CH2a(7)), 5.00 (s, 1H, CH2a(7)), 7.21 (d, J¼8.5, 2H, CH(6 or
7)), 7.31 (d, J¼8.5, 2H, CH(6 or 7)). 13C NMR: ꢀ0.7 (CH3(12)), 23.9
(br) and 28.9 (CH3(10) and CH3(11)), 42.3 (CH(5)), 43.5 (CH2(8)),
76.8 (C(9)), 97.3 (CH(7)), 128.6 and 130.2 (CH(2) and CH(3)), 132.6
(C(4)), 139.4 (C(1)), 158.0 (C(6)).
4.3.1.2. rel-(4S,6S)-(E)-4-(4-Chlorophenyl)-3-ethylidene-6-methoxy-
6-methyl-2-(trimethylsilyloxy)morpholine 3c. 1H NMR: 0.25 (s, 9H,
CH3(13)), 1.12 (s, 3H, CH3(11)), 1.34 (d, J¼6.6, 3H, CH3(8)), 2.30 (dd,
4.3.1.8. (E)-3-Ethylidene-4-(4-methoxyphenyl)-6,6-dimethyl-2-(tri-
methylsilyloxy)morpholine 3e. EtN(i-Pr)2 (0.78 mL, 1.5 equiv,
4.5 mmol) was added to a stirred solution of the oxazine N-oxide 2e

A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
4587
(0.79 g, 3 mmol) in CH2Cl2 (6 mL) at ꢀ78 ꢁC. Then TMSOTf (0.63 mL,
1.1 equiv, 3.3 mmol) was added. The reaction mixture was main-
tained at ꢀ30 ꢁC for 16 h, diluted with hexane (20 mL) and then
poured into a mixture of hexane (30 mL) and aqueous solution of
NaHSO4 (0.5 g in 30 mL of water). The organic layer was washed
with H2O (50 mL), brine (2ꢂ50 mL), and dried over Na2SO4. The
solvents were removed in vacuum to give mixture of 3e with 4e and
4e0. Overall yield 3eþ4eþ4e0¼48% (according to NMR). Two con-
formers in a ratio 1:1. Characteristic signals in 1H NMR: 4.01 (br t,
J¼7.3, 1H, CH(6)), 5.63 (q, J¼6.6, 1H, CH(8)) and 5.75 (q, J¼7.2, 1H,
CH(8)).
4.4.1.5. 4-(4-Methoxyphenyl)-6,6-dimethyl-3-(1-(trimethylsilyloxy)-
ethyl)-5,6-dihydro-4H-1,2-oxazines 4e and 4e0. Mixtures 4e and 4e0
in a ratio 1:1. 1H NMR: ꢀ0.09 and 0.15 (s, 9H, CH3(14)), 0.99 (d,
J¼6.6, 3H, CH3(9)), 1.26 and 1.32 (both s, both 3H, CH3(12) and
CH3(13)), 1.79–2.10 (m, 3H, CH2(10)), 3.51 and 3.60 (J¼10.8, 8.8,
1H, CH(6)), 3.80 (s, 3H, CH3(1)), 4.23 and 4.35 (both q, J¼6.6,
both 1H, CH(8)), 6.86 (both d, both J¼8.5, both 2H, CH(3)), 7.07
and 7.13 (d, J¼8.4, 2H, CH(4)). 13C NMR: 0.1 and 0.3 (CH3(14)),
22.6 and 22.9 (CH3(9) and CH3(12)), 28.5 and 29.7 (CH3(13)), 36.2
and 36.3 (CH(6)), 41.9 and 42.0 (CH2(10)), 55.3 (CH3(1)), 68.2 and
70.0 (CH(8)), 74.2 (C(11)), 114.1 and 114.4 (CH(3)), 129.5 and
130.0 (CH(4)), 132.6 and 133.3 (C(5)), 158.7 (C(2)), 160.2 and 161.8
(C(7)).
4.4. Preparation of siloxy derivatives 4a–f,h–k
4.4.1. General procedure for the rearrangement of ASENA 3a–f,h–k
Crude ASENA was dissolved in CHCl3 (10 mL). H2O (0.5 mL) was
added. The reaction mixture was maintained for 24 h, and the
solvents were removed in vacuum to give crude oxazine 4 as col-
orless or slightly yellow oil, which was used in the next step
without additional purification. For yields see Table 3.
4.4.1.6. rel-(4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-6-methyl-3-((1R)-
1-(trimethylsilyloxy)propyl)-5,6-dihydro-4H-1,2-oxazine 4f. 1H
NMR: ꢀ0.07 (s, 9H, CH3(14)), 0.84 (t, J¼7.3, 3H, CH3(15)), 1.44 (s, 2H,
CH3(12)), 1.60–1.74 (m, 2H, CH2(9)), 1.93 (dd, J¼13.5, 11.5, 1H,
CH2ax(10)), 2.27 (dd, J¼13.5, 8.2, 1H, CH2eq(10)), 3.27 (s, 3H,
CH3(13)), 3.70 (dd, J¼11.5, 8.2, 1H, CH(6)), 3.78 (s, 3H, CH3(1)), 4.06
(t, J¼6.6, 1H, CH(8)), 6.83 (d, J¼8.5, 2H, CH(3)), 7.08 (d, J¼8.5, 2H,
CH(4)). 13C NMR: 0.1 (CH3(14)), 9.7 (CH3(15)), 21.5 (CH3(12)), 27.8
(CH2(9)), 35.9 (CH(6)), 40.9 (CH2(10)), 49.3 (CH3(13)), 55.3 (CH3(1)),
74.5 (CH(8)), 97.5 (C(11)), 114.1 (CH(3)), 129.8 (CH(4)), 132.8 (C(5)),
158.5 (C(2)), 162.1 (C(7)).
4.4.1.1. rel-(4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-6-methyl-3-
((1R)-1-(trimethylsilyloxy)ethyl)-5,6-dihydro-4H-1,2-oxazine 4a. Title
compound can be additionally purified by column chromatography
(eluent: hexane/EtOAc, 10:1). Rf¼0.57 (hexane/EtOAc, 1:1) (UV). 1H
NMR: ꢀ0.09 (s, 9H, CH3(14)), 1.30 (d, J¼6.6, 3H, CH3(9)), 1.42 (s, 3H,
CH3(12)), 1.84 (dd, J¼13.2, 12.5, 1H, CH2ax(10)), 2.25 (dd, J¼13.2, 8.1,
1H, CH2eq (10)), 3.28 (s, 3H, CH3(13)), 3.72–3.80 (m, 1H, CH(6)), 3.78
(s, 3H, CH3(1)), 4.25 (q, J¼6.7, 1H, CH(8)), 6.83 (d, J¼8.4, 2H, CH(3)),
7.07 (d, J¼8.4, 2H, CH(4)). 13C NMR: 0.3 (CH3(14)), 20.5 (CH3(12)),
21.6 (CH3(9)), 35.6 (CH(6)), 40.3 (CH2(10)), 49.4 (CH3(13)), 55.3
(CH3(1)), 68.4 (CH(8)), 97.4 (C(11)), 114.2 (CH(3)), 129.7 (CH(4)),
132.9 (C(5)), 158.6 (C(2)), 162.5 (C(7)).
4.4.1.7. rel-(4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-6-methyl-3-
(phenyl(trimethylsilyloxy)methyl)-5,6-dihydro-4H-1,2-oxazine 4h.
1H NMR: ꢀ0.15 (s, 3H, CH3(14)), 1.40 (s, 3H, CH3(12)), 1.95 (dd,
J¼13.2, 10.8, 1H, CH2ax(10)), 2.19 (dd, J¼13.2, 8.2, 1H, CH2eq(10)),
3.28 (s, 3H, CH3(13)), 3.53 (dd, J¼10.8, 8.6, 1H, CH(6)), 3.81 (s, 3H,
CH3(1)), 5.31 (s, 1H, CH(8)), 6.83 (d, J¼7.9, 2H, CH(3)), 6.99 (d, J¼7.9,
2H, CH(4)), 7.20–7.30 (m, 5H, CH(15–17)). 13C NMR: ꢀ0.3 (CH3(14)),
21.4 (CH3(12)), 35.5 (CH(6)), 40.9 (CH2(10)), 49.3 (CH3(13)), 55.3
(CH3(1)), 75.3 (CH(8)), 97.8 (C(11)), 113.7 (CH(3)), 126.6 and 130.1
(CH(15) and CH(16)), 127.4 (CH(17)), 127.8 (CH(4)), 132.6 (C(5)),
141.0 (C(9)), 158.5 (C(2)), 163.3 (C(7)).
4.4.1.2. rel-(4S,4aR,8aR)-4-(4-Methoxyphenyl)-3-((1R)-1-(trimethyl-
silyloxy)ethyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2]oxazine 4b.
1H NMR: ꢀ0.12 (s, 9H, CH3(16)),1.37 (d, J¼6.6, 3H, CH3(9)),1.21–1.74
(m, 9H, CH(10) and CH2(12–15)), 3.36 (s, 1H, CH(6)), 3.79 (s, 3H,
CH3(1)), 4.00 (br s, 1H, CH(11)), 4.37 (q, J¼6.6, 1H, CH(8)), 6.85 (d,
J¼8.5, 2H, CH(4)), 7.03 (d, J¼8.5, 2H, CH(3)). 13C NMR: ꢀ0.1
(CH3(16)),19.9, 25.2, 27.6, and 29.5 (CH2(12–15)), 21.7 (CH3(9)), 38.7
(CH(10)), 41.8 (CH(6)), 55.3 (CH3(1)), 68.0 and 68.8 (CH(8) and
CH(11)), 113.9 (CH(3)), 129.3 (CH(4)), 134.6 (C(5)), 157.3 and 158.4
(C(2) and C(7)). 29Si NMR: 17.35.
4.4.1.8. rel-(4S,6S)-Methyl 3-(6-methoxy-4-(4-methoxyphenyl)-6-meth-
yl-5,6-dihydro-4H-1,2-oxazin-3-yl)-3-(trimethylsilyloxy)propanoate
4i. Oxazine 4i was prepared according to the general procedure
from ASENA 3i with one change: the reaction mixture was
maintained not for 1 day, but for 1 month. 1H NMR: ꢀ0.08 (s, 9H,
CH3(14)), 1.43 (s, 3H, CH3(12)), 1.82 (dd, J¼13.2, 12.5, 1H,
CH2a(10)), 2.27 (dd, J¼13.2, 8.1, 1H, CH2e(10)), 2.59 (dd, J¼16.1, 6.6,
1H, CH2a(9)), 2.91 (dd, J¼16.1, 8.8, 1H, CH2b(9)), 3.30 (s, 3H,
CH3(13)), 3.66 (s, 3H, CH3(16)), 3.75 (dd, J¼12.5, 8.1, 1H, CH(6)),
3.80 (s, 3H, CH3(1)), 4.67 (t, J¼6.6, 1H, CH(8)), 6.89 (d, J¼8.4, 2H,
CH(3)), 7.11 (d, J¼8.4, 2H, CH(4)). 13C NMR: 0.2 (CH3(14)), 21.4
(CH3(12)), 35.5 (CH(6)), 38.8 and 40.2 (CH2(9) and CH2(10)), 49.5
(CH3(13)), 51.5 (CH3(16)), 55.3 (CH3(1)), 68.7 (CH(8)), 97.5 (C(11)),
114.4 (CH(3)), 129.7 (CH(4)), 132.0 (C(5)), 158.7 (C(2)), 160.0 (C(7)),
171.6 (C(15)).
4.4.1.3. rel-(4S,6S)-4-(4-Chlorophenyl)-6-methoxy-6-methyl-3-((1R)-
1-(trimethylsilyloxy)ethyl)-5,6-dihydro-4H-1,2-oxazine 4c. 1H NMR:
ꢀ0.09 (s, 9H, CH3(13)), 1.33 (d, J¼6.6, 3H, CH3(8)), 1.43 (s, 3H,
CH3(11)), 1.84 (dd, J¼13.3, 12.5, 1H, CH2ax(9)), 2.28 (dd, J¼13.3, 8.1,
1H, CH2eq(9)), 3.29 (s, 3H, CH3(12)), 3.81 (dd, J¼12.5, 8.1, 1H, CH(5)),
4.28 (q, J¼6.6, 1H, CH(7)), 7.11 (d, J¼8.8, 2H, CH(3)), 7.29 (d, J¼8.8,
2H, CH(2)). 13C NMR: 0.2 (CH3(13)), 20.7 (CH3(11)), 21.4 (CH3(8)),
35.8 (CH(5)), 40.4 (CH2(9)), 49.4 (CH3(12)), 68.6 (CH(7)), 97.2
(C(10)), 128.8 and 129.9 (CH(2) and CH(3)), 132.6 (C(4)), 139.7
(C(1)), 162.0 (C(6)). 29Si NMR: 17.11.
4.4.1.9. rel-(4S,6S)-6-Methoxy-4-(2-methoxyphenyl)-6-methyl-3-(1-
(trimethylsilyloxy)ethyl)-5,6-dihydro-4H-1,2-oxazine 4j. 1H NMR:
ꢀ0.14 (s, 9H, CH3(14)), 1.33 (d, J¼6.5, 3H, CH3(9)), 1.43 (s, 3H,
CH3(12)), 1.94 (dd, J¼13.1, 11.8, 1H, CH2ax(10)), 2.17 (dd, J¼13.1,
7.9, 1H, CH2eq (10)), 3.31 (s, 3H, CH3(13)), 3.79 (s, 3H, CH3(1)),
4.09 (dd, J¼11.8, 7.9, 1H, CH(6)), 4.25 (q, J¼6.6, 1H, CH(8)), 6.84–
6.94 (m, 2H, CH(3) and CH(15)), 7.09 (d, J¼7.2, 1H, CH(16)), 7.23
(t, J¼7.2, 1H, CH(4)). 13C NMR: 0.1 (CH3(14)), 20.6 (CH3(12)), 21.7
(CH3(9)), 31.5 (CH(6)), 37.5 (CH2(10)), 49.4 (CH3(13)), 55.4
(CH3(1)), 68.5 (CH(8)), 97.3 (C(11)), 110.7 (CH(3)), 120.8 (CH(5)),
128.1 and 130.4 (CH(4) and CH(16)), 129.1 (C(5)), 157.1 (C(2)),
162.5 (C(7)). 29Si NMR: 20.6.
4.4.1.4. rel-(4S,6S)-4-Phenyl-6-methoxy-6-methyl-3-(1-(trimethylsi-
lyloxy)ethyl)-5,6-dihydro-4H-1,2-oxazine 4d2a 1H NMR: 0.12 (s,
.
9H, CH3(13)), 1.33 (d, J¼6.6, 3H, CH3(8)), 1.44 (s, 3H, CH3(11)),
1.88 (dd, J¼13.1, 12.5, 1H, CH2a(9)), 2.29 (dd, J¼13.1, 8.1, 1H,
CH2e(9)), 3.31 (s, 3H, CH3(12)), 3.84 (dd, J¼12.5, 8.1, 1H, CH(5)),
4.29 (q, J¼6.6, 1H, CH(7)), 7.15–7.28 (m, 5H, CH(1–3)). 13C NMR:
0.2 (CH3(6)), 20.6 and 21.5 (CH3(8) and CH3(11)), 36.4 (CH(5)),
40.5 (CH2(9)), 49.4 (CH3(12)), 68.4 (CH(7)), 97.3 (C(10)), 126.8
(CH(1)), 128.8 and 128.9 (CH(2) and CH(3)), 141.1 (C(4)), 162.3
(C(6)).

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A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
4.4.1.10. 4-(4-Chlorophenyl)-6,6-dimethyl-3-((trimethylsilyloxy)methyl)-
5,6-dihydro-4H-1,2-oxazine 4k. Oxazine 4k was prepared according
to the general procedure from ASENA 3k. Rf¼0.63 (hexane/EtOAc,
1:1) (UV). Purity was approximately 50% according to NMR. Spec-
troscopically pure sample was obtained from purified desilylated
product 1k (see Section 4.5.12) by the following procedure: NEt3
(0.063 mL, 3 equiv, 0.45 mmol) was added to a stirred solution of
the oxazine 1k (0.038 g, 0.15 mmol) in CH2Cl2 (1 mL) at 0 ꢁC in dry
argon. Then TMSCl (0.029 mL, 1.5 equiv, 0.23 mmol) was added.
After 10 min the cooling bath was removed and the reaction mix-
ture was maintained for 24 h and then the solvent was removed in
vacuum. The solid residue was washed with hexane (2ꢂ10 mL) and
hexane phase was evaporated in vacuum to give title oxazine 4k
(0.05 g, ca. 100%), which was NMR spectroscopically pure. 1H NMR:
ꢀ0.03 (s, 9H, CH3(12)), 1.30 and 1.35 (both s, 3H, CH3(10) and
CH3(11)), 1.84 (dd, J¼13.2, 11.7, 1H, CH2ax(8)), 2.05 (dd, J¼13.2, 8.1,
1H, CH2eq(8)), 3.63 (dd, J¼11.8, 8.1, 1H, CH(5)), 3.91 (d, J¼11.7, 1H,
CH2a(7)), 4.02 (d, J¼11.7, 1H, CH2b(7)), 7.13 and 7.31 (both d, J¼8.8,
both 2H, CH(2) and CH(3)). 13C NMR: ꢀ0.7 (CH3(12)), 22.7 and 28.5
(CH3(10) and CH3(11)), 36.2 (CH(5)), 40.3 (CH2(8)), 62.8 (CH2(7)),
74.4 (C(9)), 125.0 (C(4)), 128.9 and 129.9 (CH(2) and CH(3)), 138.9
(C(1)), 157.3 (C(6)).
EtOAc, from 10:1 to 3:1) to give title oxazines 1 as colorless oil
unless otherwise mentioned. For yields see Table 3.
4.5.1. rel-(1R)-1-((4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-
6-methyl-5,6-dihydro-4H-1,2-oxazin-3-yl)ethanol 1a
Oxazine 1a was prepared according to the general procedure
from oxazine 4a. Yield¼94% (total yield from oxazine 2a on three
steps¼54%). Rf¼0.26 (hexane/EtOAc, 1:1) (UV). Mp¼63–64 ꢁC
(hexane/EtOAc, 3:1). Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N,
5.01. Found: C, 64.42; H, 7.59; N, 4.83. nmax: 3442, 2987, 2938, 2835,
1612, 1513, 1463, 1378, 1302, 1245, 1198, 1178, 1151, 1082, 1070, 1036,
905, 876, 834, 797, 553 cmꢀ1. 1H NMR: 1.23 (d, J¼6.7, 3H, CH3(9)),
1.45 (s, 3H, CH3(12)), 1.94 (dd, J¼13.3, 12.6, 1H, CH2ax(10)), 2.06 (d,
J¼6.7, 1H, OH(14)), 2.27 (dd, J¼13.3, 8.1, 1H, CH2eq(10)), 3.28 (s, 3H,
CH3(13)), 3.79 (s, 3H, CH3(1)), 3.83 (dd, J¼12.6, 8.1, 1H, CH(6)), 4.12
(m, J¼6.7, 1H, CH(8)), 6.87 (d, J¼8.5, 2H, CH(3)), 7.13 (d, J¼8.5, 2H,
CH(4)). 13C NMR: 20.8 (CH3(12)), 21.5 (CH3(9)), 36.3 (CH(6)), 39.2
(CH2(10)), 49.5 (CH3(13)), 55.3 (CH3(1)), 67.7 (CH(8)), 97.7 (C(11)),
114.5 (CH(3)), 129.7 (CH(4)), 131.5 (C(5)), 158.8 (C(2)), 162.9 (C(7)).
4.5.2. rel-(1R)-1-((4S,4aR,8aR)-4-(4-Methoxyphenyl)-4a,5,6,7,8,8a-
hexahydro-4H-benzo[e][1,2]oxazin-3-yl)ethanol 1b
Oxazine 1b was prepared according to the general procedure
from oxazine 4b. Yield¼94% (total yield from oxazine 2b on three
steps¼46%). Rf¼0.46 (hexane/EtOAc, 1:1) (UV). Mp¼116–120 ꢁC
(hexane/EtOAc, 3:1). Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01; N,
4.84. Found: C, 70.58; H, 8.05; N, 4.85. nmax: 3411, 2932, 2858, 1610,
1511, 1462, 1445, 1299, 1248, 1180, 1110, 1034, 968, 941, 890, 876,
4.4.1.11. rel-(4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-3-((4-methoxy-
phenyl)(trimethylsilyloxy)methyl)-6-methyl-5,6-dihydro-4H-1,2-ox-
azine 4g and 4g0. NEt3 (0.36 mL, 2 equiv, 2.6 mmol) was added to
a stirred solution of the oxazine N-oxide 2g (0.48 g, 1.3 mmol) in
CH2Cl2 (5.2 mL) at ꢀ78 ꢁC in dry argon. Then TMSBr (0.22 mL,
1.3 equiv, 1.7 mmol) was added. The reaction mixture was main-
tained at the same temperature for 4.5 h, diluted with hexane
(20 mL), and then poured into a mixture of hexane (30 mL) and
aqueous solution of NaHSO4 (0.5 g in 30 mL of water). The organic
layer was washed with H2O (30 mL), brine (2ꢂ30 mL), and dried
over Na2SO4. The solvents were removed in vacuum, and the resi-
due was subjected to column chromatography (eluent: hexane/
EtOAc, 3:1) to give 0.35 g (61%) of title oxazines 4g and 4g0 (mixture
of two diastereomers, de¼71%) as colorless oil. Rf¼0.63 (hexane/
EtOAc, 1:1) (UV). Compound 4g: 1H NMR: ꢀ0.17 (s, 3H, CH3(14)),
1.40 (s, 3H, CH3(12)), 1.94 (dd, J¼13.9, 11.8, 1H, CH2ax(10)), 2.19 (dd,
J¼13.9, 8.1, 1H, CH2eq(10)), 3.28 (s, 3H, CH3(13)), 3.57 (dd, J¼11.8, 8.1,
1H, CH(6)), 3.79 and 3.80 (s, 6H, CH3(1) and CH3(18)), 5.24 (s, 1H,
CH(8)), 6.84 (d, J¼8.5, 4H, CH(3) and CH(16)), 7.00 and 7.12 (d, J¼8.5,
4H, CH(4) and CH(15)). 13C NMR: ꢀ0.3 (CH3(14)), 21.4 (CH3(12)),
35.5 (CH(6)), 40.9 (CH2(10)), 49.3 (CH3(13)), 55.2 and 55.3 (CH3(1)
and CH3(18)), 75.3 (CH(8)), 97.7 (C(11)), 113.2 and 113.7 (CH(3) and
CH(16)), 127.8 and 130.0 (CH(4) and CH(15)), 132.6 and 133.0 (C(5)
and C(9)), 158.4 and 158.9 (C(2) and C(17)), 163.4 (C(7)). Compound
4g0: 1H NMR: 0.09 (s, 3H, CH3(14)), 1.45 (s, 3H, CH3(12)), 1.92 (dd,
J¼13.9, 11.8, 1H, CH2ax(10)), 2.16 (dd, J¼13.9, 8.1, 1H, CH2eq(10)), 3.33
(s, 3H, CH3(13)), 3.52 (dd, J¼11.8, 8.1, 1H, CH(6)), 3.75 and 3.80 (s,
6H, CH3(1) and CH3(18)), 5.19 (s, 1H, CH(8)), 6.61 and 6.65 (d, J¼8.5,
4H, CH(3) and CH(16)), 6.78 and 6.94 (d, J¼8.5, 4H, CH(4) and
CH(15)). 13C NMR: ꢀ0.3 (CH3(14)), 21.3 (CH3(12)), 39.6 (CH(6)), 41.0
(CH2(10)), 49.3 (CH3(13)), 55.2 and 55.3 (CH3(1) and CH3(18)), 74.9
(CH(8)), 97.5 (C(11)), 113.1 and 113.5 (CH(3) and CH(16)), 126.9 and
130.2 (CH(4) and CH(15)), 131.1 and 133.1 (C(5) and C(9)), 158.6 and
158.9 (C(2) and C(17)), 162.5 (C(7)).
833 cmꢀ1
.
1H NMR: 1.26 (d, J¼6.6, 3H, CH3(9)), 1.20–1.75 (m, 8H,
CH2(12–15)), 2.05 (m, 1H, CH(10)), 2.58 (d, J¼6.6, 1H, OH(16)), 3.29
(s, 1H, CH(6)), 3.76 (s, 3H, CH3(1)), 4.01 (br s, 1H, CH(11)), 4.23 (m,
J¼6.6, 1H, CH(8)), 6.83 (d, J¼8.8, 2H, CH(3)), 7.03 (d, J¼8.8, 2H,
CH(4)). 13C NMR: 19.9, 25.1, 27.5 and 29.4 (CH2(12–15)), 21.2
(CH3(9)), 38.7 and 42.9 (CH(6) and CH(10)), 55.3 (CH3(1)), 68.5 and
69.0 (CH(8) and CH(11)), 114.2 (CH(3)), 129.2 (CH(4)), 133.7 (C(5)),
156.6 (C(7)), 158.6 (C(2)).
4.5.3. rel-(1R)-1-((4S,6S)-4-(4-Chlorophenyl)-6-methoxy-
6-methyl-5,6-dihydro-4H-1,2-oxazin-3-yl)ethanol 1c
Oxazine 1c was prepared according to the general procedure
from oxazine 4c. Yield¼94% (total yield from oxazine 2c on three
steps¼73%). Rf¼0.45 (hexane/EtOAc, 1:1) (UV). Mp¼74–75 ꢁC
(hexane/EtOAc, 5:1). Anal. Calcd for C14H18ClNO3: C, 59.26; H, 6.39;
N, 4.94. Found: C, 59.36; H, 6.45; N, 4.87. nmax: 3415, 2987, 2939,
2835,1672,1491,1454,1409,1378,1311,1239,1198,1182, 1152,1089,
1063, 1015, 941, 907, 877, 835, 776 cmꢀ1. 1H NMR: 1.25 (d, J¼6.6, 3H,
CH3(11)), 1.45 (s, 3H, CH3(8)), 1.84 (dd, J¼13.8, 12.1, 1H, CH2ax(9)),
1.91 (d, J¼6.6, 1H, OH(12)), 2.28 (dd, J¼13.8, 7.9, 1H, CH2eq(9)), 3.28
(s, 3H, CH3(8)), 3.87 (dd, J¼12.1, 7.9, 1H, CH(5)), 4.08 (m, J¼6.6, 1H,
CH(10)), 7.15 and 7.31 (both d, J¼8.6, both 2H, CH(2) and CH(3)). 13C
NMR: 20.6 (CH3(7)), 21.5 (CH3(11)), 36.5 (CH(5)), 39.3 (CH2(9)), 49.5
(CH3(8)), 67.8 (CH(10)), 97.8 (C(6)), 129.2 and 130.0 (CH(2) and
CH(3)), 133.2 (C(4)), 138.6 (C(1)), 162.1 (C(13)).
4.5.4. rel-1-((4S,6S)-6-Methoxy-6-methyl-4-phenyl-5,6-
dihydro-4H-1,2-oxazin-3-yl)ethanol 1d
Oxazine 1d was prepared according to the general procedure
from oxazine 4d. Yield¼90% (total yield from oxazine 2d on three
steps¼52%). Rf¼0.50 (hexane/EtOAc, 1:1) (UV). Mp¼86–87 ꢁC
(hexane/EtOAc, 7:1). Anal. Calcd for C14H19NO3: C, 67.45; H, 7.68; N,
5.62; Found: C, 64.40; H, 7.67; N, 5.59. nmax: 3427, 3028, 2987, 2939,
2834,1602,1494,1454,1378,1311,1239,1198,1184, 1150, 1097,1073,
1038, 1008, 944, 916, 900, 876, 837, 758, 704, 551 cmꢀ1. 1H NMR:
1.17 (d, J¼5.9, 3H, CH3(8)), 1.39 (s, 3H, CH3(11)), 1.90 (dd, J¼13.3,
12.5, 1H, CH2ax(9)), 1.99 (d, J¼7.3, 1H, OH(13)), 2.24 (dd, J¼13.3, 8.1,
1H, CH2eq(9)), 3.23 (s, 3H, CH3(12)), 3.81 (dd, J¼12.5, 8.1, 1H, CH(5)),
4.5. General procedure for desilylation. Preparation
of hydroxy derivatives 1a–k
Crude oxazine 4 was dissolved in MeOH (4 mL). NH4F$HF
(11 mg, 0.1 equiv, 0.2 mmol) was added. The reaction mixture was
maintained for 24 h, the solvents were removed in vacuum, and the
residue was separated by column chromatography (eluent: hexane/

A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
4589
4.04 (m, J¼5.9, 1H, CH(7)), 7.14–7.29 (m, 5H, CH(1–3)). 13C NMR:
20.8 and 21.6 (CH3(8) and CH3(11)), 37.3 (CH(5)), 39.5 (CH2(9)), 49.6
(CH3(12)), 67.8 (CH(7)), 97.8 (C(10)), 127.6 (CH(1)), 128.8 and 129.3
(CH(2) and CH(3)), 140.1 (C(4)), 162.8 (C(6)).
1611, 1585, 1513, 1463, 1443, 1421, 1379, 1358, 1303, 1248, 1176, 1153,
1112, 1083, 1072, 1034, 951, 899, 832, 798, 770, 736, 551 cmꢀ1. 1g
(major isomer): 1H NMR: 1.47 (s, 3H, CH3(12)), 1.98 (t, J¼13.9, 1H,
CH2ax(10)), 2.20 (dd, J¼13.9, 7.9, 1H, CH2eq(10)), 2.85 (d, J¼7.2, 1H,
OH(14)), 3.33 (s, 3H, CH3(13)), 3.71 (dd, J¼13.9, 7.9, 1H, CH(6)), 3.76
(s, 6H, CH3(1) and CH3(18)), 5.03 (d, J¼7.2, 1H, CH(8)), 6.67 and 6.70
(d, J¼8.6, 4H, CH(3) and CH(16)), 6.85 and 6.95 (d, J¼8.6, 4H, CH(4)
and CH(15)). 13C NMR: 21.5 (CH3(12)), 36.8 (CH(6)), 39.1 (CH2(10)),
49.5 (CH3(13)), 55.3 (CH3(1) and CH3(18)), 74.6 (CH(8)), 98.1 (C(11)),
113.6 and 114.1 (CH(3) and CH(16)), 127.8 and 130.1 (CH(4) and
CH(15)), 132.8 (C(5) and C(9)), 158.9 (C(2) and C(17)), 162.1 (C(7)).
1g0 (minor isomer): 1H NMR: 1.47 (s, 3H, CH3(12)), 1.90 (dd, J¼13.9,
11.8, 1H, CH2ax(10)), 2.17 (dd, J¼13.9, 7.9, 1H, CH2eq(10)), 3.20 (dd,
J¼11.8, 8.5, 1H, CH(6)), 3.44 (s, 3H, CH3(13)), 3.81 (s, 6H, CH3(1) and
CH3(18)), 4.37 (br s,1H, OH(14)), 4.82 (br s,1H, CH(8)), 6.67 and 6.70
(d, J¼8.6, 4H, CH(3) and CH(16)), 6.85 and 6.97 (d, J¼8.6, 4H, CH(4)
and CH(15)). 13C NMR: 21.5 (CH3(12)), 36.2 (CH(6)), 40.5 (CH2(10)),
50.3 (CH3(13)), 55.3 (CH3(1) and CH3(18)), 72.6 (CH(8)), 98.2 (C(11)),
114.0 and 114.5 (CH(3) and CH(16)), 129.0 and 129.8 (CH(4) and
CH(15)), 132.1 (C(5) and C(9)), 158.9 (C(2) and C(17)), 160.7 (C(7)).
4.5.5. 1-(4-(4-Methoxyphenyl)-6,6-dimethyl-5,6-dihydro-
4H-1,2-oxazin-3-yl)ethanol 1e
Oxazine 1e was prepared according to the general procedure
from the mixture of oxazines 4e and 4e0. Yield¼40% (total yield
from oxazine 2e on three steps¼19%). Rf¼0.46 (hexane/EtOAc, 1:1)
(UV). Mp¼92–94 ꢁC (hexane/EtOAc, 10:1). Anal. Calcd for
C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C, 68.32; H, 8.27; N,
5.28. nmax: 3470, 2975, 2930, 1612, 1513, 1462, 1385, 1370, 1304,
1263, 1248, 1179, 1130, 1111, 1035, 960, 926, 898, 833, 554 cmꢀ1. 1H
NMR: 1.24 (d, J¼6.6, 3H, CH3(9)), 1.26 and 1.36 (both s, both 3H,
CH3(12) and CH3(13)), 1.86 (dd, J¼13.7, 11.8,1H, CH2ax(10)), 2.05 (dd,
J¼13.7, 7.4, 1H, CH2eq(10)), 3.39 (J¼11.8, 7.4, 1H, CH(6)), 3.80 (s, 4H,
CH3(1) and OH(14)), 4.09 (m, J¼6.6, 1H, CH(8)), 6.87 (d, J¼8.5, 2H,
CH(3)), 7.09 (d, J¼8.5, 2H, CH(4)). 13C NMR: 21.9 and 22.4 (CH3(9)
and CH3(12)), 28.4 (CH3(13)), 36.5 (CH(6)), 41.1 (CH2(10)), 55.3
(CH3(1)), 66.5 (CH(8)), 75.1 (C(11)), 114.6 (CH(3)), 129.3 (CH(4)),
131.5 (C(5)), 158.9 and 159.2 (C(2) and C(7)).
4.5.9. rel-((4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-6-methyl-
5,6-dihydro-4H-1,2-oxazin-3-yl)(phenyl)methanol 1h
4.5.6. 1-(4-(4-Methoxyphenyl)-6,6-dimethyl-5,6-dihydro-
4H-1,2-oxazin-3-yl)ethanol 1e0
Oxazine 1h was prepared according to the general procedure
from oxazine 4h. Yield¼95% (total yield from oxazine 2h on three
steps¼54%). Rf¼0.45 (hexane/EtOAc, 1:1) (UV). Anal. Calcd for
C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C, 70.30; H, 6.42; N,
4.20. nmax: 3444, 3061, 3030, 2991, 2939, 2908, 2835, 1611, 1513,
1454, 1378, 1303, 1246, 1178, 1152, 1083, 1072, 1035, 900, 835, 797,
Oxazine 1e0 was prepared according to the general procedure
from the mixture of oxazines 4e and 4e0. Yield¼56% (total yield
from oxazine 2e on three steps¼27%). Rf¼0.37 (hexane/EtOAc, 1:1)
(UV). nmax: 3384, 2976, 2933, 2839, 1711, 1682, 1609, 1512, 1462,
1444, 1421, 1383, 1371, 1304, 1250, 1179, 1129, 1111, 1034, 953, 926,
833 cmꢀ1. 1H NMR: 1.24 (d, J¼6.5, 3H, CH3(9)), 1.25 and 1.33 (both s,
both 3H, CH3(12) and CH3(13)), 1.89 (dd, J¼13.7, 11.8, 1H, CH2ax(10)),
2.00–2.08 (m, 2H, CH2eq(10) and OH(14)), 3.63 (J¼11.8, 7.8, 1H,
CH(6)), 3.78 (s, 3H, CH3(1)), 4.09 (m, J¼6.6, 1H, CH(8)), 6.85 (d,
J¼8.5, 2H, CH(3)), 7.11 (d, J¼8.5, 2H, CH(4)). 13C NMR: 20.5 and 22.6
(CH3(9) and CH3(12)), 28.6 (CH3(13)), 37.0 (CH(6)), 40.9 (CH2(10)),
55.3 (CH3(1)), 67.5 (CH(8)), 74.4 (C(11)),114.5 (CH(3)),129.5 (CH(4)),
132.0 (C(5)), 158.6 (C(2)), 160.7 (C(7)).
733, 710, 700, 551 cmꢀ1 1H NMR: 1.48 (s, 3H, CH3(12)), 1.99 (dd,
.
J¼13.8, 12.5, 1H, CH2ax(10)), 2.21 (dd, J¼13.8, 7.9, 1H, CH2eq(10)),
2.88 (d, J¼7.6, 1H, OH(14)), 3.34 (s, 3H, CH3(13)), 3.71 (dd, J¼12.5,
7.9,1H, CH(6)), 3.76 (s, 3H, CH3(1)), 5.11 (s,1H, CH(8)), 6.67 (d, J¼8.6,
2H, CH(3)), 6.85 (d, J¼8.6, 2H, CH(4)), 7.05 (br s, 2H, CH(15)), 7.17 (br
s, 3H, CH(16–17)). 13C NMR: 21.4 (CH3(12)), 36.8 (CH(6)), 39.1
(CH2(10)), 49.5 (CH3(13)), 55.3 (CH3(1)), 75.1 (CH(8)), 98.2 (C(11)),
114.2 (CH(3)), 126.5 and 129.9 (CH(15) and CH(16)), 127.4 (CH(17)),
127.7 (CH(4)), 129.9 (C(5)), 140.5 (C(9)), 158.9 (C(2)), 162.0 (C(7)).
4.5.7. rel-(1R)-1-((4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-6-
methyl-5,6-dihydro-4H-1,2-oxazin-3-yl)propan-1-ol 1f
4.5.10. Methyl rel-3-hydroxy-3-((4S,6S)-6-methoxy-4-
(4-methoxyphenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazin-
3-yl)propanoate 1i
Oxazine 1f was prepared according to the general procedure
from oxazine 4f. After column chromatography title compound was
obtained as a slightly brown solid. Yield¼95% (total yield from
oxazine 2f on three steps¼58%). Rf¼0.27 (hexane/EtOAc, 1:1) (UV).
Mp¼92–93 ꢁC. Anal. Calcd for C16H23NO4: C, 65.51; H, 7.90; N, 4.77.
Found: C, 65.67; H, 8.13; N, 4.66. nmax: 3454, 2964, 2938, 2877, 2835,
1611, 1513, 1462, 1378, 1302, 1246, 1178, 1151, 1105, 1083, 1066, 1035,
899, 834, 796, 553 cmꢀ1. 1H NMR: 0.81 (t, J¼7.5, 3H, CH3(15)), 1.44
(s, 2H, CH3(12)), 1.43–1.72 (m, 2H, CH2(9)), 1.79 (d, J¼7.2, 1H,
OH(14)), 1.96 (t, J¼13.1, 1H, CH2ax(10)), 2.27 (dd, J¼13.1, 7.9, 1H,
CH2eq(10)), 3.30 (s, 3H, CH3(13)), 3.79 (m, 1H, CH(6)), 3.79 (s, 3H,
CH3(1)), 3.88 (dd, J¼7.2, 5.9, 1H, CH(8)), 6.86 (d, J¼8.5, 2H, CH(3)),
7.13 (d, J¼8.5, 2H, CH(4)). 13C NMR: 9.8 (CH3(15)), 21.5 (CH3(12)),
27.3 (CH2(9)), 36.4 (CH(6)), 39.5 (CH2(10)), 49.4 (CH3(13)), 55.3
(CH3(1)), 73.2 (CH(8)), 97.7 (C(11)), 114.5 (CH(3)), 129.7 (CH(4)),
131.5 (C(5)), 158.9 (C(2)), 162.0 (C(7)).
Oxazine 1i was prepared according to the general procedure
from oxazine 4i. Yield¼94% (total yield from oxazine 2i on three
steps¼66%). Rf¼0.42 (hexane/EtOAc, 1:1) (UV). Anal. Calcd for
C17H23NO6: C, 60.52; H, 6.87; N, 4.15. Found: C, 60.78; H, 7.01; N,
3.99. nmax: 3479, 2991, 2942, 2836, 1737, 1612, 1514, 1462, 1439,
1379, 1302, 1246, 1203, 1178, 1153, 1080, 1065, 1035, 902, 834, 797,
552 cmꢀ1. 1H NMR: 1.39 (s, 3H, CH3(12)), 1.86 (dd, J¼13.2, 12.5, 1H,
CH2ax(10)), 2.24 (dd, J¼13.2, 8.1, 1H, CH2eq(10)), 2.67 (d, J¼5.9, 2H,
CH2(9)), 3.21 (s, 3H, CH3(13)), 3.37 (d, J¼6.5,1H, OH(14)), 3.59 (s, 3H,
CH3(16)), 3.73 (s, 3H, CH3(1)), 3.86 (dd, J¼12.5, 8.1, 1H, CH(6)), 4.25
(q, J¼6.5, 1H, CH(8)), 6.81 (d, J¼8.5, 2H, CH(3)), 7.09 (d, J¼8.5, 2H,
CH(4)). 13C NMR: 21.2 (CH3(12)), 35.6 (CH(6)), 37.0 and 39.1 (CH2(9)
and CH2(10)), 49.3 (CH3(13)), 51.6 (CH3(16)), 55.2 (CH3(1)), 67.1
(CH(8)), 97.6 (C(11)), 114.4 (CH(3)), 129.6 (CH(4)), 131.8 (C(5)), 158.7
(C(2)), 160.1 (C(7)), 173.2 (C(15)).
4.5.8. rel-((4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-6-methyl-
5,6-dihydro-4H-1,2-oxazin-3-yl)(4-methoxyphenyl)methanol
1g and 1g0
Oxazines 1g and 1g0 were prepared according to the general
procedure from the mixture of oxazines 4g and 4g0. Yield¼95%
(total yield from oxazine 2g on three steps¼58%). Rf¼0.43 (hexane/
EtOAc, 1:1) (UV). Anal. Calcd for C21H25NO5: C, 67.91; H, 6.78; N,
3.77. Found: C, 68.05; H, 6.74; N, 3.85. nmax: 3458, 2993, 2937, 2835,
4.5.11. rel-1-((4S,6S)-6-Methoxy-4-(2-methoxyphenyl)-6-
methyl-5,6-dihydro-4H-1,2-oxazin-3-yl)ethanol 1j and 1j0
Oxazines 1j and 1j0 were prepared according to the general
procedure from the mixture of oxazines 4j and 4j0. Yield¼95% (total
yield from oxazine 2j on three steps¼64%, de¼83%). Major isomer:
Rf¼0.35 (hexane/EtOAc, 1:1) (UV). Mp¼38–42 ꢁC. Anal. Calcd for
C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.88; H, 7.60; N,
4.77. Minor isomer: Rf¼0.46 (hexane/EtOAc, 1:1) (UV). Major

4590
A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
diastereomer 1j: nmax: 3442, 2987, 2940, 2836, 1745, 1599, 1587,
1494,1463,1446,1377,1377,1290,1245,1198, 1183, 1151, 1082,1052,
1028, 907, 877, 842, 756 cmꢀ1. 1H NMR: 1.24 (d, J¼6.5, 3H, CH3(9)),
1.45 (s, 3H, CH3(12)), 2.04–2.22 (m, 3H, CH2ax(10), CH2eq(10) and
OH(14)), 3.30 (s, 3H, CH3(13)), 3.82 (s, 3H, CH3(1)), 4.08 (m, J¼6.5,
1H, CH(8)), 4.17 (dd, J¼11.7, 8.1, 1H, CH(6)), 6.88–6.96 (m, 2H, CH(3)
and CH(15)), 7.15 (dd, J¼7.3, 1.5, 1H, CH(16)), 7.26 (td, J¼6.5, 1.5, 1H,
CH(4)). 13C NMR: 20.3 and 21.8 (CH3(9) and CH3(12)), 31.9 (CH(6)),
36.8 (CH2(10)), 49.5 (CH3(13)), 55.5 (CH3(1)), 68.0 (CH(8)), 97.8
(C(11)), 111.3 (CH(3)), 121.4 (CH(15)), 127.9 (C(5)), 128.9 and 130.3
(CH(4) and CH(16)), 157.4 (C(2)), 162.8 (C(7)). Minor diastereomer
1j0: nmax: 3472, 2981, 2972, 2940, 2836, 1599, 1587, 1494, 1463, 1441,
1377, 1319, 1290, 1245, 1183, 1152, 1118, 1086, 1061, 1029, 948, 906,
840, 796, 757 cmꢀ1. 1H NMR: 1.19 (d, J¼6.5, 3H, CH3(9)), 1.47 (s, 3H,
CH3(12)), 2.00 (dd, J¼13.1, 11.2, H, CH2ax(10)), 2.15 (dd, J¼13.1, 8.1,
1H, CH2eq(10)), 3.31 (s, 3H, CH3(13)), 3.82 (s, 3H, CH3(1)), 3.94 (dd,
J¼11.2, 8.1, 1H, CH(6)), 4.05 (m, J¼6.5, 1H, CH(8)), 6.87–6.96 (m, 2H,
CH(3) and CH(15)), 7.11 (d, J¼7.9, 1H, CH(16)), 7.23–7.29 (m, 1H,
CH(4)). 13C NMR: 21.5 and 22.0 (CH3(9) and CH3(12)), 31.6 (CH(6)),
36.8 (CH2(10)), 49.4 (CH3(13)), 55.4 (CH3(1)), 66.7 (CH(8)), 98.0
(C(11)), 111.1 (CH(3)), 121.2 (CH(15)), 127.4 (C(5)), 128.8 and 130.2
(CH(4) and CH(16)), 157.1 (C(2)), 162.1 (C(7)).
O-trimethylsilyl pyranone oximes 7 (yields: 7kd85%, 7ld67%),
which were NMR spectroscopically pure.
4.6.2. 4-(4-Chlorophenyl)-6,6-dimethyl-dihydro-2H-pyran-
3(4H)-one O-trimethylsilyl oxime 7k
Rf¼0.71 (hexane/EtOAc,1:1) (UV). 1H NMR: 0.05 (s, 9H, CH3(12)),
1.10 and 1.26 (both s, both 3H, CH3(6) and CH3(7)), 1.97 (dd, J¼14.7,
6.6, 1H, CH2a(4)), 2.09 (dd, J¼14.7, 7.3, 1H, CH2b(4)), 4.27 (d, J¼13.6,
1H, CH2a(1)), 4.32 (dd, J¼7.3, 6.6, 1H, CH(3)), 4.45 (d, J¼13.6, 1H,
CH2b(1)), 7.11 and 7.27 (both d, J¼8.0, both 2H, CH(9) and CH(10)).
13C NMR: ꢀ1.0 (CH3(12)), 27.7 and 28.2 (CH3(6) and CH3(7)), 37.1
(CH(3)), 41.3 (CH2(4)), 62.2 (CH2(1)), 72.6 (C(5)), 128.4 and 128.6
(CH(9) and CH(10)), 131.7 (C(8)), 140.1 (C(11)), 160.5 (C(2)).
4.6.3. rel-(4S,4aR,8aR)-4-(4-Methoxyphenyl)-hexahydro-2H-
chromen-3(4H)-one O-trimethylsilyl oxime 7l
Rf¼0.73 (hexane/EtOAc, 1:1) (UV). Mixture of two isomers in
a ratio 4:3 (cis:trans). cis-Isomer: 1H NMR: 0.24 (s, 9H, CH3(15)),
1.27–1.91 (m, 8H, CH2(6–9)), 2.15–2.25 (m,1H, CH(4)), 3.53 (br s,1H,
CH(3)), 3.80 (s, 3H, CH3(14)), 3.80 (br s, 1H, CH(5)), 3.83 (d, J¼14.0,
1H, CH2a(1)), 5.23 (d, J¼14.0, 1H, CH2b(1)), 6.87 (d, J¼8.8, 2H,
CH(12)), 7.17 (d, J¼8.8, 2H, CH(11)), 8.91 (br s, 1H, OH(15)). trans-
Isomer: 1H NMR: 0.21 (s, 9H, CH3(15)), 1.27–1.91 (m, 8H, CH2(6–9)),
2.15–2.25 (m,1H, CH(4)), 3.80 (s, 3H, CH3(14)), 3.90 (br s,1H, CH(5)),
4.13 (d, J¼12.8, 1H, CH2a(1)), 4.29 (d, J¼12.8, 1H, CH2b(1)), 4.48 (br s,
1H, CH(3)), 6.87 (d, J¼8.8, 2H, CH(12)), 7.13 (d, J¼8.8, 2H, CH(11)),
8.91 (br s, 1H, OH(15)). 13C NMR (cisþtrans): ꢀ0.7 and ꢀ0.6
(CH3(15)), 20.0 and 20.1, 25.8 and 26.1, 27.1 and 27.4, 31.0 and 31.2
(CH2(6–9)), 41.0, 41.2, 42.2 and 47.5 (CH(3) and CH(4)), 55.2
(CH3(14)), 60.3, 67.2, 70.6 and 71.5 (CH2(1) and CH(5)), 113.8 and
114.0 (CH(12)), 128.6 (CH(11)), 132.1 and 132.6 (C(10)), 158.0 (C(2)),
159.3 and 159.7 (C(2) and C(13)).
4.5.12. (4-(4-Chlorophenyl)-6,6-dimethyl-5,6-dihydro-4H-
1,2-oxazin-3-yl)methanol 1k
Oxazine 1k was prepared according to the general procedure
from oxazine 4k. Yield¼96% (total yield from oxazine 2k on three
steps¼30%). Rf¼0.38 (hexane/EtOAc, 1:1) (UV). Mp¼53–57 ꢁC. Anal.
Calcd for C13H16ClNO2: C, 61.54; H, 6.36; N, 5.52. Found: C, 61.48; H,
6.33; N, 5.67. nmax: 3360, 2976, 2930, 2875, 1492, 1454, 1410, 1385,
1370, 1315, 1271, 1228, 1181, 1123, 1093, 1045, 1015, 995, 976, 941,
923, 860, 829, 783, 736, 714, 541 cmꢀ1. 1H NMR: 1.27 and 1.36 (both
s, 3H, CH3(10) and CH3(11)), 1.86 (dd, J¼13.8, 11.8, 1H, CH2ax(8)),
2.07 (dd, J¼13.8, 7.6, 1H, CH2eq(8)), 3.06 (br s, 1H, OH(12)), 3.52 (dd,
J¼11.8, 7.6, 1H, CH(5)), 3.93 (br s, 2H, CH(7)), 7.12 and 7.31 (both d,
J¼8.3, both 2H, CH(2) and CH(3)). 13C NMR: 22.6 and 28.2 (CH3(10)
and CH3(11)), 36.8 (CH(5)), 40.0 (CH2(8)), 62.1 (CH2(7)), 74.8 (C(9)),
129.1 and 129.5 (CH(2) and CH(3)), 133.2 (C(4)), 137.8 (C(1)), 156.3
(C(6)).
4.6.4. 4-(4-Chlorophenyl)-6,6-dimethyl-dihydro-2H-pyran-
3(4H)-one oxime 70k
Rf¼0.48 (hexane/EtOAc, 1:1) (anisaldehyde). Mp¼42–47 ꢁC.
Anal. Calcd for C13H16ClNO2: C, 61.54; H, 6.36; N, 5.52. Found: C,
61.51; H, 6.56; N, 5.40. nmax: 3317, 3103, 2973, 2931, 1492, 1462,
1446, 1408, 1384, 1369, 1257, 1234, 1215, 1178, 1126, 1091, 1014, 947,
827, 751, 530 cmꢀ1. 1H NMR: 1.07 and 1.25 (both s, both 3H, CH3(6)
and CH3(7)), 2.00 (dd, J¼14.7, 6.6, 1H, CH2a(4)), 2.09 (dd, J¼14.7, 7.3,
1H, CH2b(4)), 4.19 (d, J¼13.9, 1H, CH2a(1)), 4.33 (dd, J¼7.3, 6.6, 1H,
CH(3)), 4.40 (d, J¼13.9, 1H, CH2b(1)), 7.13 and 7.29 (both d, J¼8.5,
both 2H, CH(9) and CH(10)), 8.66 (br s, 1H, OH(12)). 13C NMR: 27.5
and 28.3 (CH3(6) and CH3(7)), 36.5 (CH(3)), 41.3 (CH2(4)), 62.0
(CH2(1)), 72.7 (C(5)), 128.5 and 128.9 (CH(9) and CH(10)), 132.2
(C(8)), 139.3 (C(11)), 156.7 (C(2)).
4.6. General procedure for the preparation of pyranone
oximes 70k,l
The solution of the corresponding ASENA (3 mmol) in CH2Cl2
(6 mL), was added dropwise for 10 min at ꢀ78 ꢁC to the stirred
solution of catalytic amount of TBAF in CH2Cl2 (12 mL). After 40 min
the cooling bath was removed. The mixture was stirred for an ad-
ditional 1 h and then poured into a mixture of EtOAc (100 mL)/
brine (50 mL). The organic layer was dried over Na2SO4. The sol-
vents were removed in vacuum to give crude 7k,l (purity was ap-
proximately 40–50% according to NMR). The residue was dissolved
in MeOH (24 mL) and NH4F$HF (0.02 g, 0.1 equiv, 0.3 mmol) was
added. The reaction mixture was maintained for 24 h, the solvent
was removed in vacuum, and the residue was subjected to column
chromatography (eluent: hexane/EtOAc, 3:1) to give title pyranone
oximes 70k,l as colorless oils (yields: 70kd27%, 70ld17%).
4.6.5. rel-(4S,4aR,8aR)-4-(4-Methoxyphenyl)-hexahydro-2H-
chromen-3(4H)-one oxime 70l
Rf¼0.58 (hexane/EtOAc, 1:1) (anisaldehyde). Anal. Calcd for
C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 70.22; H, 8.00; N,
4.71. Mixture of two isomers in a ratio 4:3 (cis:trans) nmax: 3287,
3101, 3001, 2932, 2854, 1610, 1582, 1512, 1462, 1444, 1298, 1248,
1181, 1111, 1087, 1051, 1035, 1007, 982, 946, 930, 920, 897, 837,
737 cmꢀ1. cis-Isomer: 1H NMR: 1.25–1.95 (m, 8H, CH2(6–9)), 2.14–
2.21 (m, 1H, CH(4)), 3.49 (br s, 1H, CH(3)), 3.81 (s, 3H, CH3(14)), 3.88
(br s, 1H, CH(5)), 4.05 (d, J¼15.0, 1H, CH2a(1)), 5.12 (d, J¼15.0, 1H,
CH2b(1)), 6.87 (d, J¼8.8, 2H, CH(12)), 7.17 (d, J¼8.8, 2H, CH(11)), 8.91
(br s, 1H, OH(15)). trans-Isomer: 1H NMR: 1.25–1.95 (m, 8H, CH2(6–
9)), 2.14–2.21 (m, 1H, CH(4)), 3.81 (s, 3H, CH3(14)), 3.90 (br s, 1H,
CH(5)), 4.17 (d, J¼12.8, 1H, CH2a(1)), 4.29 (d, J¼12.8, 1H, CH2b(1)),
4.41 (br s, 1H, CH(3)), 6.87 (d, J¼8.8, 2H, CH(12)), 7.17 (d, J¼8.8, 2H,
CH(11)), 8.91 (br s, 1H, OH(15)). 13C NMR (cisþtrans): 19.8 and 20.2,
25.1 and 25.9, 27.1 and 27.4, 30.4 and 31.0 (CH2(6–9)), 41.1, 41.3, 41.9
and 47.3 (CH(3) and CH(4)), 55.1 (CH3(14)), 59.9, 68.9, 70.7 and 71.3
4.6.1. Spectroscopically pure samples of 7k,l were obtained from
purified desilylated product 70k,l by the following procedure
NEt3 (0.056 mL, 2 equiv, 0.4 mmol) was added to a stirred so-
lution of the pyranone oximes 70 (0.2 mmol) in CH2Cl2 (1.5 mL) at
0 ꢁC in dry argon. Then TMSCl (0.038 mL, 1.5 equiv, 0.3 mmol) was
added. After 15 min the cooling bath was removed and the reaction
mixture was maintained for 24 h and then the solvent was removed
in vacuum. The solid residue was washed with hexane (2ꢂ5 mL)
and hexane phase was evaporated in vacuum to give title

A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
4591
(CH2(1) and CH(5)), 113.8 and 114.0 (CH(12)), 128.4 and 128.5
(CH(11)), 130.3 and 132.2 (C(10)), 156.2 (C(2)), 158.0 (C(13)).
2.10 (br d, J¼14.7, 1H, CH(10)), 3.44 (s, 1H, CH(6)), 3.79 (s, 3H,
CH3(1)), 4.04 (br s, 1H, CH(11)), 5.23 (d, J¼11.0, 1H, CH2cis(9)), 5.23
(d, J¼17.7, 1H, CH2trans(9)), 6.45 (dd, J¼17.7, 11.0, 1H, CH(8)), 6.85 (d,
J¼8.5, 2H, CH(3)), 7.08 (d, J¼8.5, 2H, CH(4)). 13C NMR: 19.8, 25.3,
27.6, 29.4 (CH2(12–15)), 39.1, 42.3 (CH(6,10)), 55.3 (CH3(1)), 68.9
(CH(11)), 114.1 (CH(3)), 118.3 (CH2(9)), 129.0 (CH(4)), 134.2 (CH(8)),
134.5 (C(5)), 153.3 (C(7)), 158.3 (C(2)).
4.7. Preparation of oxazines 10
4.7.1. 3-(Methoxymethyl)-6-methyl-4-phenyl-6-(trimethyl-
silyloxy)-5,6-dihydro-4H-1,2-oxazine 10m
The solution of ASENA 3m (3 mmol) in CH2Cl2 (3 mL) was added
dropwise to the stirred solution of NEt3 (0.042 mL, 0.03 equiv,
0.1 mmol) in CH2Cl2 (3 mL), looking for the temperature didn’t
exceed 30 ꢁC. The reaction mixture was stirred for an additional
20 min. The solvent was removed in vacuum, and then the residue
was subjected to column chromatography (eluent: hexane/EtOAc,
10:1) to give 0.20 g (22%) of title oxazine 10m as colorless oil.
Rf¼0.73 (hexane/EtOAc, 1:1) (UV). 1H NMR: 0.02 (s, 9H, CH3(11)),
1.21 (s, 3H, CH3(10)), 2.17 (dd, J¼13.9, 8.1, 1H, CH2a(8)), 2.29 (dd,
J¼13.9, 7.3, 1H, CH2b(8)), 3.26 (s, 3H, CH3(10)), 4.37–4.51 (m, 3H,
4.8.3. rel-(4S,6S)-3-(1-(Ethyloxy)ethyl)-6-methoxy-4-(4-
methoxyphenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine 8
Oxazine 8 was obtained as a by-product in the preparation of
oxazine 1a from ASENA 3a via oxazine 4a with one changedin the
stage 3a/4a CHCl3 (tech. grade) was used instead of mixture
CHCl3(anhydrous)/water. The product was purified by column chro-
matography (eluent: hexane/EtOAc, from 10:1 to 3:1). Yield¼13%.
Rf¼0.57 (hexane/EtOAc,1:1) (ninhydrin). nmax: 2974, 2937, 2837,1713,
1689, 1681, 1666, 1602, 1512, 1463, 1454, 1443, 1423, 1373, 1360, 1302,
1248,1174,1113,1084,1065,1032, 899, 833, 548 cmꢀ1.1H NMR: 1.05 (t,
J¼7.0, 3H, CH3(15)), 1.27 (d, J¼6.2, 3H, CH3(9)), 1.45 (s, 3H, CH3(12)),
1.92 (dd, J¼13.2, 12.5, 1H, CH2ax(10)), 2.27 (dd, J¼13.2, 8.1, 1H,
CH2eq(10)), 2.99 (m, J¼7.4,1H, CH2a(14)), 3.29 (s, 3H, CH3(13)), 3.31 (m,
J¼7.4, 1H, CH2b(14)), 3.77 (dd, J¼12.5, 8.1, 1H, CH(6)), 3.79 (s, 3H,
CH3(1)), 4.12 (q, J¼6.2, 1H, CH(8)), 6.85 (d, J¼8.5, 2H, CH(3)), 7.11 (d,
J¼8.5, 2H, CH(4)). 13C NMR: 15.4 and 16.2 (CH3(9) and CH3(15)), 21.5
(CH3(12)), 36.4 (CH(6)), 39.7 (CH2(10)), 49.4 (CH3(13)), 55.3 (CH3(1)),
62.8 (CH2(14)), 74.2 (CH(8)), 97.5 (C(11)), 114.2 (CH(3)), 129.7 (CH(4)),
132.5 (C(5)), 158.6 (C(2)), 161.5 (C(7)).
CH(5) and CH2(7)), 7.17–7.30 (m, 5H, CH(1), CH(2) and CH(3)). 13
C
NMR: ꢀ1.0 (CH3(11)), 23.4 (CH3(10)), 37.4 (CH(5)), 41.1 (CH2(8)),
48.4 (CH3(12)), 62.2 (CH2(7)), 98.9 (C(9)), 126.1 (CH(1)), 127.7 and
128.2 (CH(2) and CH(3)), 141.5 (C(4)), 161.6 (C(6)).
4.7.2. 3-(Methoxymethyl)-6-methyl-4-phenyl-5,6-dihydro-
4H-1,2-oxazin-6-ol 100m
The solution of the ASENA 3m (3 mmol) in CH2Cl2 (6 mL), was
added dropwise in 10 min at ꢀ78 ꢁC to the stirred solution of cata-
lytic amount of TBAF in CH2Cl2 (12 mL). After 40 min the cooling
bath was removed. The mixture was stirred for an additional 1 h and
poured into a mixture of EtOAc (100 mL)/brine (50 mL). The organic
layer was dried over Na2SO4. The solvents were removed in vacuum
to give crude 10m, which was dissolved in MeOH (24 mL) and
NH4F$HF (0.02 g, 0.1 equiv, 0.3 mmol) was added. The reaction
mixture was maintained for 4 h, the solvent was removed in vac-
uum, and then the residue was subjected to column chromatogra-
phy (eluent: hexane/EtOAc, 3:1) to give 0.16 g (23%) of title oxazine
4.9. Reduction of oxazine 1a
4.9.1. rel-(1R)-1-((3R,4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-
6-methyl-1,2-oxazinan-3-yl)-1-ethanol 13
NaBH3CN (0.19 g, 3 equiv, 3 mmol) was added to a stirred so-
lution of oxazine 1a (0.29 g, 1 mmol) in AcOH (4.4 mL). The reaction
mixture was stirred for 1 h and then poured into a mixture of EtOAc
(100 mL) and K2CO3 (aqueous solution) (100 mL). The aqueous
phase was washed with EtOAc (2ꢂ30 mL). Combined organic layer
was washed with brine (50 mL) and dried over Na2SO4. The sol-
vents were removed in vacuum, and then the residue was subjected
to column chromatography (eluent: hexane/EtOAc, 1:2) to give
0.24 g (83%) of title oxazine 13 as colorless oil. Rf¼0.11 (hexane/
EtOAc, 1:1). Mp¼63–64 ꢁC. Anal. Calcd for C15H23NO4: C, 64.03; H,
8.24; N, 4.98. Found: C, 64.32; H, 8.25; N, 4.76. nmax: 3417, 3261,
2987, 2930, 2835, 1611, 1513, 1462, 1443, 1377, 1304, 1271, 1246,
1236, 1180, 1147, 1107, 1068, 1051, 1035, 885, 845, 831, 799, 783, 736,
550 cmꢀ1. 1H NMR: 1.15 (d, J¼6.6, 3H, CH3(9)), 1.30 (s, 3H, CH3(12)),
1.82 (t, J¼13.2, 1H, CH2ax(10)), 2.01 (dd, J¼13.1, 4.4, 1H, CH2eq(10)),
2.88 (dd, J¼11.1, 2.0, 1H, CH(7)), 3.18 (td, J¼12.1, 4.4, 1H, CH(6)), 3.27
(s, 3H, CH3(13)), 3.57 (qd, J¼6.6, 2.0, 1H, CH(8)), 3.74 (s, 3H, CH3(1)),
6.81 (d, J¼8.5, 2H, CH(3)), 7.09 (d, J¼8.5, 2H, CH(4)). 13C NMR: 21.1
and 21.6 (CH3(9)) and (CH3(12)), 37.9 (CH2(10)), 42.5 (CH(6)), 48.6
(CH3(13)), 55.2 (CH3(1)), 65.2 and 65.6 (CH(7) and CH(8)), 99.1
(C(11)), 114.1 (CH(3)), 128.6 (CH(4)), 134.4 (C(5)), 158.2 (C(2)).
100m as colorless oil. Rf¼0.48 (hexane/EtOAc,1:1) (ninhydrin). nmax
:
3333, 3086, 3060, 2987, 2940, 2858, 2831, 1601, 1494, 1451, 1379,
1230, 1213, 1181, 1150, 1112, 1099, 1056, 1002, 943, 878, 832, 745,
699 cmꢀ1
.
1H NMR: 1.15 (s, 3H, CH3(10)), 2.17 (dd, J¼14.3, 7.3, 1H,
CH2a(8)), 2.30 (dd, J¼14.3, 7.3, 1H, CH2b(8)), 3.24 (s, 3H, CH3(10)),
4.31–4.48 (m, 3H, CH(5) and CH2(7)), 7.20–7.34 (m, 5H, CH(1), CH(2)
and CH(3)), 8.83 (br s, 1H, OH(11)). 13C NMR: 23.4 (CH3(10)), 36.8
(CH(5)), 41.1 (CH2(8)), 48.4 (CH3(12)), 61.9 (CH2(7)), 99.1 (C(9)),126.5
(CH(1)),127.4 and 128.5 (CH(2) and CH(3)),140.7 (C(4)),157.4 (C(6)).
4.8. By-products of the synthesis of oxazines 1
4.8.1. rel-(4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-6-methyl-
3-vinyl-5,6-dihydro-4H-1,2-oxazine 9a
Vinyloxazine 9a was obtained as a by-product in the preparation
of oxazine 1a from ASENA 3a via oxazine 4a with one changedin
the stage 3a/4a CHCl3 (tech. grade) was used instead of mixture
CHCl3(anhydrous)/water. The product was purified by column
chromatography (eluent: hexane/EtOAc, from 10:1 to 3:1).
Yield¼10%. Rf¼0.61 (hexane/EtOAc, 1:1) (UV). 1H NMR: 1.48 (s, 3H,
CH3(13)), 1.86 (dd, J¼13.2, 12.5, 1H, CH2a(10)), 2.35 (dd, J¼13.2, 8.5,
1H, CH2e(10)), 3.30 (s, 3H, CH3(12)), 3.79 (s, 3H, CH3(1)), 3.81 (dd,
J¼12.5, 8.5, 1H, CH(6)), 5.21 (d, J¼11.0, 1H, CH2cis(9)), 5.26 (d, J¼17.6,
1H, CH2trans(9)), 6.20 (dd, J¼17.6, 11.0, 1H, CH(8)), 6.85 (d, J¼8.1, 2H,
CH(3)), 7.06 (d, J¼8.1, 2H, CH(4)).
4.9.2. rel-tert-Butyl (2R,3S)-2-((1R)-1-hydroxyethyl)-3-
(4-methoxyphenyl)-5-methyl-tetrahydro-1H-pyrrole-
1-carboxylate 12
One milliliter of 50% slurry Raney Nickel in water was washed
with anhydrous methanol (5ꢂ5 mL), diluted with methanol (1 mL)
and added tothe solution of oxazine 13 (68 mg, 0.26 mmol) in MeOH
(2.5 mL). The suspension was hydrogenated at 50 bar H2 at room
temperature with intensive stirring for 8 h, filtered and concen-
trated in vacuum. The residue was dissolved in CH2Cl2 (2 mL) and
Boc2O (0.17 mL, 3 equiv, 0.8 mmol) was added. The reaction mixture
was stirred for 2 h, concentrated invacuum and then the residuewas
subjected to column chromatography (eluent: hexane/EtOAc, from
4.8.2. rel-(4S,4aR,8aR)-4-(4-Methoxyphenyl)-3-vinyl-
4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2]oxazine 9b
Vinyloxazine 9b was obtained as a by-product in the preparation
of oxazine 1b from ASENA 3b via oxazine 4b. Yield¼14%. Rf¼0.67
(hexane/EtOAc, 1:1) (UV). 1H NMR: 1.26–1.78 (m, 8H, CH2(12–15)),

4592
A.A. Tabolin et al. / Tetrahedron 65 (2009) 4578–4592
4. In the literature there are only two examples of the synthesis of 3-hydroxy-
methyl-5,6-dihydro-4H-1,2-oxazines by reduction of the corresponding ester.
(a) Lee, V. J.; Woodward, R. B. J. Org. Chem. 1979, 44, 2487–2491; (b) Zimmer, R.;
Homann, K.; Reissig, H. U. Liebigs Ann. Chem. 1993, 10, 1155–1158.
5. Bal, G.; Van der Veken, P.; Antonov, D.; Lambeir, A. M.; Grellier, P.; Croft, S. L.;
Augustyns, K.; Haemers, A. Bioorg. Med. Chem. Lett. 2003, 13, 2875–2878.
6. Tabolin, A. A.; Lesiv, A. V.; Khomutova, Yu. A.; Belyakov, P. A.; Strelenko, Yu. A.;
Ioffe, S. L. Synthesis 2005, 10, 1656–1662.
5:1 to 3:1) to give 54 mg (67%) of title pyrrolidine 12 as colorless oil.
Rf¼0.45 (major diastereomer) and 0.41 (minor diastereomer) (hex-
ane/EtOAc, 1:1). Mp¼72–74 ꢁC. Anal. Calcd for C19H29NO4: C, 68.03;
H, 8.71; N, 4.18. Found: C, 67.98; H, 8.72; N, 3.84. nmax: 3443, 2973,
2931, 1690, 1666, 1613, 1514, 1455, 1395, 1367, 1251, 1177, 1120, 1095,
1078, 1035, 832 cmꢀ1 1H NMR: 1.13–1.16 (m, 6H, CH3(9) and
.
CH3(12)),1.15 (s, 9H, CH3(16)),1.70 (dt, J¼12.8, 3.7,1H, CH2a(10)), 2.54
(dt, J¼12.8, 8.0, 1H, CH2b(10)), 3.10–3.15 (m, 1H, CH(6)), 3.79 (s, 3H,
CH3(1)), 3.86–3.99 (m,1H, CH(7) and CH(11)), 4.26 (dd, J¼7.4, 2.8,1H,
CH(8)), 6.85 (d, J¼8.2, 2H, CH(3)), 7.19 (d, J¼8.2, 2H, CH(4)).13C NMR:
20.8 and 21.5 (CH3(9)) and (CH3(12)), 28.5 (CH3(16)), 41.5 and 43.6
(CH(6) and (CH2(10)), 54.1 (CH(11)), 55.2 (CH3(1)), 69.1 and 71.1
(CH(7) and CH(8)), 80.2 (C(15)), 114.0 (CH(3)), 128.2 (CH(4)), 136.2
(C(5)), 158.1 (C(2)).
7. Feger, H.; Simchen, G. Liebigs Ann. Chem. 1986, 3, 428–437.
8. Crystallographic data for the structures 1a, 1b, 1c, 1f have been deposited with
the Cambridge Crystallography Data Centre as supplementary publication
numbers CCDC-701851, CCDC-701852, CCDC-701850, and CCDC-701849, re-
spectively. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk).
9. Vorbruggen, H. Silicon-Mediated Transformations of Functional Groups; Wiley-
VCH, Verlag GmbH & Co. KgaA: Weinheim, 2004; pp 7–9.
10. Khomutova, Yu. A., Ph.D. Thesis, N.D. Zelinsky Institute of Organic Chemistry:
Moscow, 2008.
11. Has been done in collaboration with A.D. Dilman and A.V. Ustinov.
12. Lesiv, A. V.; Ioffe, S. L.; Strelenko, Yu. A.; Tartakovsky, V. A. Helv. Chim. Acta 2002,
85, 3489–3507.
Acknowledgements
13. The impact of the base on the silylation process outcome is discussed in Ref. 2a.
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This work was supported by RFBR (grant 06-03-32607).
Supplementary data
NMR spectra for compounds 1–4, 7–10, 12, 13. Supplementary
data associated with this article can be found in the online version,
at doi:10.1016/j.tet.2009.03.082.
References and notes
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