Synthesis and [3+2] cycloadditions of 3-bromo-5,6-dihydro-4 H -1,2-oxazine N -oxides

Article abstract of DOI:10.1055/s-0029-1218594

A number of 3-bromo-5,6-dihydro-4H-1,2-oxazine N-oxides have been synthesized and subjected to [3+2] cycloaddition with alkenes affording various types of products: 3-vinyloxazolines, isoxazoline N-oxides, and 3-functionalized 1,2-oxazine N-oxides. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218594

PAPER
407
Synthesis and [3+2] Cycloadditions of 3-Bromo-5,6-dihydro-4H-1,2-oxazine
N-Oxides
3
-Bromo-5,6-di
e
hydro-4
H
-1
o
,2-oxazine
Nn
-Oxides id V. Romashov,a Yulya A. Khomutova,b Vitaliy M. Danilenko,a Sema L. Ioffe,b Alexey V. Lesiv*a
a
Moscow Chemical Lyceum, Tamojenny pr. 4, 111033 Moscow, Russian Federation
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 119991 Moscow, Russian Federation
Fax +7(495)3623440; E-mail: Lesav@mail.ru
b
Received 14 September 2009; revised 16 October 2009
Between 1970 and 1980, it was reported by Chlenov and
co-workers that 3-nitro-1,2-oxazine N-oxides undergo
[3+2] cycloaddition with alkenes to give the products of
various rearrangements of cyclic nitroso acetals3
(Scheme 2). The reaction was not broadly introduced into
organic synthesis due to the poor availability of the re-
quired 3-nitro derivatives4 (5 stages starting from tri-
nitromethane).
Abstract: A number of 3-bromo-5,6-dihydro-4H-1,2-oxazine N-
oxides have been synthesized and subjected to [3+2] cycloaddition
with alkenes affording various types of products: 3-vinyloxazo-
lines, isoxazoline N-oxides, and 3-functionalized 1,2-oxazine N-ox-
ides.
Key words: 1,2-oxazine N-oxide, isoxazoline, cycloaddition,
nitronates, nitroso acetals
The goal of the current work became the investigation of
3-bromo-1,2-oxazine N-oxides, the analogues of previ-
ously studied 3-nitro-1,2-oxazine N-oxides. Only two rep-
resentatives of 3-halo-1,2-oxazine N-oxides have been
previously reported in the literature.5
5,6-Dihydro-4H-1,2-oxazine N-oxides (referred to in the
text simply as 1,2-oxazine N-oxides) are widely used in
organic synthesis.1 The main practical application of these
compounds is their [3+2] cycloaddition with alkenes fol-
lowed by further reduction (Scheme 1).2 This strategy was
successfully used by Denmark and co-workers in their
asymmetrical total syntheses of more than 20 natural com-
pounds.
There are two main synthetic approaches to 1,2-oxazine
N-oxides: intramolecular cyclization and [4+2] cycloaddi-
tion of nitroalkenes to olefins.1 In the current work the lat-
ter route was explored as it is easier and more convenient
compared to the former (Scheme 3, Table 1). Initial 1-
bromo-1-nitroalkenes were obtained from available b-ni-
trostyrenes in one step.
3-Substituted derivatives of 1,2-oxazine N-oxides have
been, as yet, poorly investigated although the presence of
a functional group incorporated directly into the reactive
centre of such compounds can significantly alter their
chemical properties and subsequently increase their syn-
thetic value.
The configuration of the 3-bromo-1,2-oxazine N-oxides 1
obtained was determined by comparison of their spectral
R
R
O
R
R
R
O
R
R
R
N
R
R
N
R
R
R
R
O
R
R
R
R
[H]
[3+2]
[4+2]
R
O
R
OH
R
R
N
R
O
N
O
R
O
R
R
Scheme 1 Synthesis and [3+2] cycloadditions of 1,2-oxazine N-oxides
OMe
NO2
Nu
BF3⋅OEt2
or Nu
NO2
O
R
R
O
[3+2]
[3+2]
5 steps
3 steps
HC(NO2)3
R
R
R
or
or
or ...
N
N
N
N
O
N
O
O
O
O
O
O
O
Br
N
Br
O
MeNO2
?
N
O
O
O
Scheme 2 Synthesis and [3+2] cycloaddition of 3-nitro-1,2-oxazine N-oxides
SYNTHESIS 2010, No. 3, pp 0407–0414
x
x
.
x
x
.2
0
1
0
Advanced online publication: 07.12.2009
DOI: 10.1055/s-0029-1218594; Art ID: P12709SS
© Georg Thieme Verlag Stuttgart · New York

408
L. V. Romashov et al.
PAPER
and trans-isomers in almost equal ratio,6a while the reac-
tion of b-bromo-4-methoxy-b-nitrostyrene under similar
conditions afforded exclusive formation of the trans-ad-
duct 1h (Table 1 entry 8). A similar result was previously
reported by Denmark.5
R2
R3
R1
O
1. NaOH R1
2. HCl
1. Br2
2. Et3N
R1
R2
R3
Br
O
R1CHO
R4
Br
NO2
+
N
LA
MeNO2
NO2
R4
However the rate of [4+2] cycloaddition of 1-bromo-1-
nitroalkenes is significantly lower than that observed for
1-methyl-1-nitroalkenes. Therefore, 2-nitro-3-(4-nitro-
phenyl)prop-1-ene was treated with cyclohexene at –30 °C
for one hour6a to give the corresponding product in 45%
yield (70% conversion); while starting from the analogous
1-bromo-1-nitroalkene afforded the target product 1f in
5% yield (50% conversion) after one week under the same
conditions (Table 1 entry 6).
1a–h
Scheme 3 Synthesis of 3-bromo-1,2-oxazine N-oxides 1a–h
Table 1 Synthesis of 3-Bromo-1,2-oxazine N-Oxides 1a–h
(Scheme 3)
Entry ProductR1
R2
R3
R4
Methoda Yield
(%)
1
2
3
1a
1b
1c
4-MeOC6H4
4-MeOC6H4
H
H
Me
Me
A
B
C
90
97
86
[4+2] Cycloaddition of 1-bromo-1-nitroalkenes is quite
sensitive to the reaction conditions. The increase of tem-
perature or exposition time leads to the formation of 3-
chloro-1,2-oxazine N-oxides 1¢ as byproducts (Scheme 4).
OMe Me
4-MeOC6H4 –(CH2)4–
4-MeOC6H4
H
H
An attempt to obtain 3-bromo-1,2-oxazine N-oxides 1
from 2-alkyl-1-bromo-1-nitroethenes failed due to their
instability under the described reaction conditions.
4
1d
C
81
5
6
7
8
1e
1f
Ph
–(CH2)4–
–(CH2)4–
OMe
H
B
D
A
E
61
5
Unlike 3-methyl-1,2-oxazine N-oxides, which can be
stored at room temperature for long periods, the similar 6-
alkoxy-substituted 3-bromo-1,2-oxazine N-oxides are
very labile products that undergo spontaneous decompo-
sition at room temperature within several hours.
4-O2NC6H4
Ph
1g
H
H
Me
OEt
Me
H
77
61
1h
4-MeOC6H4
a A: SnCl4, alkene (10 equiv), –78 °C, 10 min; B: SnCl4, alkene (2
equiv), –92 °C, 10 min; C: SnCl4, alkene (5 equiv), –30 °C, 1 h; D:
SnCl4, alkene (10 equiv), –30 °C, 1 week; E: TiCl2(Oi-Pr)2, alkene (2
equiv), –78 °C, 1 h.
Usually [3+2] cycloaddition of 1,2-oxazine N-oxides with
alkenes is carried out by stirring the mixture of reagents
(possibly at a raised temperature).7 However an attempt to
subject 3-bromo-1,2-oxazine N-oxides 1 to this transfor-
characteristics with those obtained for the 3-methyl- and mation led to intensive resinification of the reaction mix-
3-unsubstituted analogues.6
ture after addition of the alkene.
It was found that the stereoselectivity of the [4+2] cy- The treatment of 3-bromo-1,2-oxazine N-oxide 1a with a
cloaddition of 1-bromo-1-nitronates was higher than the 100-fold excess of methyl acrylate at 20 °C afforded lac-
selectivity observed for their 3-methyl- and 3-unsubstitut- tone 2a as the sole isolated product in poor yield (29%).
ed analogues. Thus dichlorodiisopropoxytitanium(IV)- Notably the resulting pH of reaction mixture was very
promoted cycloaddition of 4-methoxy-b-methyl-b-ni- acidic. The proposed mechanism of this transformation is
trostyrene with ethyl vinyl ether provided a mixture of cis- presented in Scheme 5.
R1
R1
R1
R1
Cl
N
R2
R3
Br
O
R2
R3
Br
O
R2
R3
Br
O
R2
R3
Cl
O
SnCl4
Cl
– SnCl3Br
N
N
SnCl3
SnCl3
N
O
O
O
O
R4
R4
R4
R4
1
1'
Scheme 4 Formation of 3-chloro-1,2-oxazine N-oxides 1¢ in [4+2] cycloadditions
An
An
An
O
An
An
OH
N
Br
O
Br
H+
Br
O
H2O
– H+
– HBr
– "HNO"
O
N
N
N
O
O
O
O
OH
OH
OH
2a, 29%
1a
An = 4-MeOC6H4
Scheme 5 Hydrolysis of 3-bromo-1,2-oxazine N-oxides under standard conditions required for the [3+2]-cycloaddition process
Synthesis 2010, No. 3, 407–414 © Thieme Stuttgart · New York

PAPER
3-Bromo-5,6-dihydro-4H-1,2-oxazine N-Oxides
409
We suggest that methyl acrylate is essential for generation bromo N-oxides 1c–f with methyl acrylate gave no results
of ‘the first molecule’ of HBr (see the mechanism for even under reflux for one week in toluene. Cycloaddition
[3+2] cycloaddition, Scheme 7). A low yield of 2a could of 6-methoxy-substituted substrate 1b and styrene afford-
be explained by intensive decomposition of 1 on exposure ed predominantly isoxazoline N-oxide 4a instead of the 3-
to HBr formed in the course of the reaction.
vinyloxazoline 3b observed for 1a (Scheme 6).
To avoid hydrolysis of N-oxides 1, a set of experiments The suggested mechanism of the reaction of 3-bromo N-
was carried out involving the treatment of a model N-ox- oxide 1 with alkenes proceeds through initial formation of
ide 1a with styrene in the presence of various bases bicyclic bromo nitroso acetal A¢ followed by rapid proton
(K2CO3, NaOMe, NaHCO3, pyridine, Et3N). It was found elimination to afford derivatives B and C (Scheme 7). No-
that the sole reagent capable of suppressing the polymer- tably, in all experiments performed, deprotonation was
ization process was triethylamine. However, the reaction exclusively regioselective. Further fragmentation of B or
afforded almost quantitative formation of 3-vinyloxazine double bond migration in C provides the target products 3
3b instead of the expected nitroso acetal A¢ (Scheme 6, and 5, respectively. The bromo nitroso acetal arising from
Table 2). It was also shown that 3-bromo-1,2-oxazine N- 6-methoxy derivative 1b underwent ring opening result-
oxides 1a,g provided derivatives 3 when treated not only ing in the formation of a more stable cation D, which sub-
with styrene, but with other donor and acceptor alkenes sequently afforded the target nitronate 4a after hydrolysis.
(Table 2).
Cation A is suggested to be the key intermediate of the
The data obtained revealed that 3-bromo-1,2-oxazine N- process although we could not trap it with such external
oxides undergo cycloaddition under milder conditions nucleophiles as sodium azide, sodium cyanide, or sodium
compared to the analogous 3-methyl- and 3-unsubstituted methoxide in methanol. Our attempts to detect the inter-
derivatives.8
mediately formed cycloadducts A¢ or cation A itself by
careful NMR monitoring of the reaction mixture also met
with no success.
Similarly to the analogous 3-alkyl N-oxides, 3-bromo N-
oxides could not be subjected to intramolecular coupling
with internal alkenes such as dimethyl maleate, dimethyl We suggest that removal of anion Br– proceeds through
fumarate, and methyl cinnamate. Surprisingly the reaction interaction of the nitrogen atom lone-electron pair with an
between 3-bromo N-oxide 1a and maleic anhydride pro- antibonding orbital of C–Br (Scheme 8),9 which can be
ceeded under mild conditions (toluene, reflux, 1 h) to give achieved only in the case of ‘trans’-connection of the
N-oxide 5a.
rings. The isomers of 1,2-oxazine N-oxides with ‘trans’-
and ‘cis’-fused rings are capable of interconversion by ni-
trogen atom inversion, which could easily occur under the
reaction conditions10 (110 °C). Thus, the initially formed
conformation of nitroso acetal A¢ does not affect the out-
come of the reaction (Scheme 8). In the case of tricyclic
The nature of substituents at the 5th and 6th positions of
oxazine cycle has a dramatic effect on the reaction rate
and outcome of 3-bromo N-oxide [3+2] cycloaddition
with alkenes. Thus, treatment of bicyclic derivatives of 3-
R5
O
O
R1
R1
R1
R1
O
R5
R5
O
Br
R6
R4
or
R6
or
R6
N
N
R3
O
O
N
R3
O
O
N
O
O
R4
O
R4
1a,b,g
3a–f
4a
5a
Scheme 6 [3+2] Cycloaddition of 3-bromo-1,2-oxazine N-oxides
Table 2 Cycloaddition of 1 (Scheme 6)
Entry
Substate
1a
R1
R3
R4
R5
H
H
H
H
H
H
H
R6
Product
3a
Time (h)
Yield (%)
1
2
3
4
5
6
7
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
Me
Me
Me
Me
Me
Me
OMe
Me
Me
Me
Me
Me
Me
Me
CO2Me
Ph
0.5
1
99
98
98
95
99
93
1a
3b
1a
OBu
3c
1
1g
CH2OH
CO2Me
COMe
Ph
3d
1.3
0.5
3
1g
Ph
3e
1g
Ph
3f
1b
4-MeOC6H4
3b + 4a
3
10 (3b)
58 (4a)
8
1a
4-MeOC6H4
Me
Me
C(O)OC(O)
5a
1
61
Synthesis 2010, No. 3, 407–414 © Thieme Stuttgart · New York

410
L. V. Romashov et al.
PAPER
R1
O
Alk
R1
O
O
R5
O
R5
H2O
R4
R4
R6
R6
– AlkOH
N
N
O
O
D
4
R3 = OAlk
R5
R1
O
R1
R1
O
R1
R5
R5
R1
R5
R5
Br
R6
Br
O
base
H+
R6
R6
R6
R6
N
[3+2]
N
N
R3
N
R3
O
R3
O
O
R3
O
– Br
O
N
R4
O
R4
R4
R4
A
A'
B
1
3
base
H+
R5, R6 = C(O)OC(O)
O
R1
O
O
O
R1
O
O
N
O
R3
O
N
R3
O
O
R4
R4
C
5
Scheme 7 Proposed mechanism for [3+2] cycloaddition of 1
N
nitroso acetals previously synthesized by Denmark, by
contrast, the initially conformer formed cannot be inter-
converted to give one with an antiperiplanar orientation of
the nitrogen atom lone-electron pair and C–Br bond due to
the rigidity of their cycle structure. Consequently, these
compounds cannot produce cation A to undergo subse-
quent rearrangements and thereby are quite stable and can
be isolated from the reaction mixture in a pure state.
R
N
O
H
N
R
SO2NH2
O
NHt-Bu
O
OH
6
7
Figure 1 Pharmacologically active analogues of isoxazolines 3
Various compounds bearing the 3-vinyloxazoline frag-
ment possess significant biological activity. For example,
compounds related to 6 (Figure 1) represent human b-ad-
renergic receptor agonists and antagonists (b-AR), with
potential use in cardiovascular (coronary heart disease,
cardiac insufficiency) and respiratory therapy.11 In recent
years, active development of drugs against diabetes and
obesity based on b-AR has been carried out. The data li-
brary of agents inhibiting Xa factor (preventing thrombo-
sis formation) was created using compounds related to 7.
In conclusion, the present report describes a new synthesis
of 3-bromo-1,2-oxazine N-oxides via a [4+2]-cycloaddi-
tion reaction and a thorough investigation of their [3+2]
cycloadditions with alkenes has been carried out.
All [4+2]-cycloaddition reactions were performed in oven-dried
(150 °C) glassware under an argon atmosphere. Melting points were
determined on a Koffler melting point apparatus. Chromatographic
separations were performed on silica gel (Merck Kieselgel 230–400
mesh) with analytical grade solvents. Analytical TLC was per-
Ar
OG*
Ar
Hal
O
O
[3+2]
O
A
N
N
O
Hal
*GO
Br
H
R5
R5
Br
R5
R6
Ar
R3
Ar
N
R6
–Br
O
N
R3
O
O
R6
R4
N
O
O
R3
cis
trans
R4
A'
R4
A
Scheme 8 Structure of the earlier obtained bicyclic and tricyclic a-halo nitroso acetals
Synthesis 2010, No. 3, 407–414 © Thieme Stuttgart · New York

PAPER
3-Bromo-5,6-dihydro-4H-1,2-oxazine N-Oxides
411
formed on Merck silica gel plates with QF-254 indicator. Visualiza-
tion was accomplished with UV light and/or anisaldehyde–MeOH–
H2SO4 and/or ninhydrin. NMR spectras were recorded on an NMR
spectrometer AM-300 (1H: 300.13 MHz, 13C: 75.47 MHz) for
CDCl3 solns with residual solvent peak as an internal standard. El-
emental analyses were performed by the analytical center of N. D.
Zelinsky Institute of Organic Chemistry.
the residue was recrystallized (hexane–EtOAc, 3:1) to give color-
less crystals.
(R/S)-3-Bromo-4-(4-methoxyphenyl)-6,6-dimethyl-5,6-dihy-
dro-4H-1,2-oxazine N-Oxide (1a)
Mp 124–125 °C (Et2O); Rf = 0.37 (hexane–EtOAc, 1:1) (UV).
1H NMR: d = 1.42 (s, 3 H, CH3), 1.51 (s, 3 H, CH3), 2.18 (m, 2 H,
CH2), 3.79 (s, 3 H, OCH3), 3.99 (dd, J = 11.1, 8.4 Hz, 1 H, CH),
6.88 (d, J = 8.5 Hz, 2 H, CHAr), 7.10 (d, J = 8.5 Hz, 2 H, CHAr).
13C NMR: d = 22.2, 27.4 (CH3), 43.4 (CH2), 46.7 (Ar-CH), 55.4
(OCH3), 83.3 (C), 111.2 (C=N), 114.5, 129.0 (CHAr), 131.9 (CAr),
159.3 (COCH3).
Hexane, EtOAc, toluene, Et2O, EtOH, and MeOH were distilled
without drying agents. The following reaction solvents and reagents
were distilled from the indicated drying agents: CH2Cl2, Et3N,
SnCl4 (CaH2), CHCl3 (P2O5). The following chemicals were pur-
chased from the indicated sources: 2-methoxypropene, ethyl vinyl
ether, methyl acrylate, cyclopentene, butyl vinyl ether, TiCl4,
Ti(Oi-Pr)4, MVK, cyclohexene, styrene, maleic anhydride, allyl al-
cohol (Acros), isobutylene, norbornene (Aldrich). b-Nitrostyrene,
and p-nitro-b-nitrostyrene were prepared according to the literature
procedure for b-nitrostyrene.12 Brine refers to sat. aq NaCl soln.
Anal. Calcd for C13H16BrNO3: C, 49.70; H, 5.13; N, 4.46. Found: C,
49.75; H, 5.18; N, 4.43.
rel-(4R,6R)-3-Bromo-6-methoxy-4-(4-methoxyphenyl)-6-meth-
yl-5,6-dihydro-4H-1,2-oxazine N-Oxide (1b)
Mp 57–61 °C (Et2O); Rf = 0.44 (hexane–EtOAc, 1:1) (UV).
1-(2-Bromo-2-nitrovinyl)-4-methoxybenzene
1H NMR: d = 1.55 (s, 3 H, CH3), 2.18 (dd, J = 11.8, 13.8 Hz, 1 H,
CH2), 2.41 (dd, J = 7.2, 13.8 Hz, 1 H, CH2), 3.51 (s, 3 H, OCH3),
3.81 (s, 3 H, Ar-OCH3), 4.14 (dd, J = 7.2, 11.8 Hz, 1 H, CH), 6.89
(d, J = 8.5 Hz, 2 H, CHAr), 7.12 (d, J = 8.5, 2 H, CHAr).
13C NMR: d = 20.4 (CH3), 42.2 (CH2), 45.5 (Ar-CH), 50.6 (OCH3),
55.3 (Ar-OCH3), 105.4 (C), 112.2 (C=N), 114.5, 129.2 (CHAr),
131.8 (CAr), 159.3 (COCH3).
To a stirred soln of p-methoxy-b-nitrostyrene (15.57 g, 87 mmol) in
CHCl3 (100 mL), Br2 (4.5 mL, 88 mmol) was added at r.t. within 5
min. The mixture was refluxed for 20 min. The temperature was de-
creased to 8 °C and soln of Et3N (15.7 mL, 113 mmol) was added
dropwise during 20 min. The mixture was maintained for 10 min
and poured into a mixture of EtOAc (300 mL) and H2O (300 mL).
The organic layer was washed with, H2O (200 mL), brine (2 × 150
mL) and dried (Na2SO4). The solvents were removed in vacuo and
the residue was recrystallized (EtOH) to give the product (20.4 g,
91%) as yellow crystals; Rf = 0.76 (hexane–EtOAc, 1:1) (UV); mp
60–62 °C (EtOH) (Lit.13 67–68 °C).
Anal. Calcd for C13H16BrNO4: C, 47.29; H, 4.88; N, 4.24. Found: C,
47.35; H, 4.77; N, 4.15.
rel-(4R,4aS,8aS)-3-Bromo-4-(4-methoxyphenyl)-4a,5,6,7,8,8a-
hexahydro-4H-1,2-benzoxazine N-Oxide (1c)
Mp 123–124 °C (Et2O); Rf = 0.47 (hexane–EtOAc, 1:1) (UV).
1H NMR: d = 1.13–2.18 (m, 9 H, CH, CH2), 3.76 (s, 1 H, Ar-CH),
3.81 (s, 3 H, OCH3), 4.75 (br s, 1 H, OCH), 6.91 (d, J = 8.5 Hz, 2 H,
CHAr), 7.12 (d, J = 8.5 Hz, 2 H, CHAr).
13C NMR: d = 19.9, 24.5, 27.4, 28.6 (CH2), 42.1 (Ar-CH), 53.8
(CH), 55.3 (OCH3), 77.2 (OCH), 107.6 (C=N), 114.5, 128.6 (CHAr),
132.9 (CAr), 159.2 (COCH3).
1-(2-Bromo-2-nitrovinyl)benzene
To a stirred soln of b-nitrostyrene (42.9 g, 0.288 mol) in CHCl3 (300
mL) was added a soln of Br2 (14.9 mL, 0.29 mol) in CHCl3 (10 mL)
at r.t. over 5 min; the mixture was refluxed for 35 min. The temper-
ature was decreased to 8 °C and soln of Et3N (52.0 mL, 0.374 mol)
in CHCl3 (50 mL) was added dropwise over 30 min. The mixture
was maintained for 15 min and poured into a mixture of CHCl3 (100
mL) and H2O (400 mL). The organic layer was washed with H2O
(400 mL) and brine (2 × 250 mL) and dried (Na2SO4). The solvent
was removed in vacuo and the residue was recrystallized (EtOH) to
give the product (49.9 g, 76%) as yellow crystals; mp 67 °C (EtOH)
(Lit.13 67 °C); Rf = 0.62 (hexane–EtOAc, 1:1) (UV).
Anal. Calcd for C15H18BrNO3: C, 52.96; H, 5.33; N, 4.12. Found: C,
52.56; H, 5.29; N, 4.04.
rel-(4R,4aS,5S,8aS)-3-Bromo-4-(4-methoxyphenyl)-
4a,5,6,7,8,8a-hexahydro-4H-5,8-methano-1,2-benzoxazine N-
Oxide (1d)
1-(2-Bromo-2-nitrovinyl)-4-nitrobenzene
To a stirred soln of p-nitro-b-nitrostyrene (6.53 g, 34.0 mmol) in
CH2Cl2 (150 mL) was added Br2 (1.73 mL, 34 mmol) at r.t. over 2
min. The mixture was refluxed for 3 h. The temperature was de-
creased to 8 °C and soln of Et3N (6.12 mL, 43.9 mmol) in CH2Cl2
(50 mL) was added dropwise over 30 min. The mixture was main-
tained for 15 min and poured into a mixture of EtOAc (250 mL) and
H2O (300 mL). The organic layer was washed with H2O (200 mL)
and brine (2 × 200 mL) and dried (Na2SO4). The solvent was re-
moved in vacuo and the residue was recrystallized (EtOH) to give
the product (5.66 g, 61%) as yellow crystals; mp 130–134 °C
(EtOH) (Lit.14 134–136 °C); Rf = 0.63 (hexane–EtOAc, 1:1) (UV).
Mp 134–136 °C (Et2O); Rf = 0.51 (hexane–EtOAc, 1:1) (UV).
1H NMR: d = 1.03–1.76 (m, 6 H, CH2), 2.03 (br s, 1 H, CH2CH),
2.43 (dd, J = 10.5, 6.6 Hz, 1 H, CH), 2.56 (d, J = 5.3 Hz, 1 H,
CH2CH), 3.71 (d, J = 10.5 Hz, 1 H, Ar-CH), 3.83 (s, 3 H, OCH3),
4.57 (d, J = 6.6 Hz, 1 H, OCH), 6.89 (d, J = 8.5 Hz, 2 H, CHAr), 7.13
(d, J = 8.5 Hz, 2 H, CHAr).
13C NMR: d = 24.1, 28.5, 33.0 (CH2), 39.9, 41.5 (CHCH2), 49.6
(Ar-CH), 55.3 (OCH3), 56.6 (CH), 89.1 (OCH), 114.1 (CHAr), 115.6
(C=N), 129.8 (CHAr), 130.9 (CAr), 159.5 (COCH3).
Anal. Calcd for C16H18BrNO3: C, 54.56; H, 5.15; Br, 3.98. Found:
C, 54.37; H, 5.26; N, 3.91.
3-Bromo-5,6-dihydro-4H-1,2-oxazine N-Oxides 1; General Pro-
cedure
SnCl4 (0.65 mL, 5.5 mmol) was added to a stirred soln of nitroalk-
ene (5 mmol) in CH2Cl2 (25 mL) at –78 °C in dry argon and the mix-
ture stirred at this temperature for 5 min. The alkene (see Table 1)
was added dropwise at the temperature indicated in Table 1 and
stirred for the indicated time; it was then poured into EtOAc (150
mL) and sat. aq NaHCO3 (100 mL). The organic layer was washed
with sat. aq NaHCO3 (50 mL), H2O (100 mL), and brine (2 × 50
mL) and dried (Na2SO4). The solvents were removed in vacuo and
rel-(4R,4aS,8aS)-3-Bromo-8a-methoxy-4-phenyl-4a,5,6,7,8,8a-
hexahydro-4H-1,2-benzoxazine N-Oxide (1e)
Mp 121–125 °C (Et2O); Rf = 0.50 (hexane–EtOAc, 1:1) (UV).
1H NMR: d = 1.10–1.79 (m, 8 H, CH2), 2.20–2.35 (m, 1 H, CH),
3.48 (s, 3 H, OCH3), 3.70 (d, J = 11.2 Hz, 1 H, Ph-CH), 7.1–7.44
(m, 5 H, CHPh).
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L. V. Romashov et al.
PAPER
13C NMR: d = 22.0, 24.7, 26.5, 28.45 (CH2), 48.1, 49.5 (PhCH),
52.0 (OCH3), 108.6 (C=N), 111.6 (CO), 127.0 (p-CPh), 128.6, 128.9
(CHPh), 139.1 (CPh).
of EtOAc (50 mL) and H2O (50 mL). The organic layer was washed
with H2O (2 × 50 mL) and brine (2 × 40 mL) and dried (Na2SO4).
The solvents were removed in vacuo and the residue was recrystal-
lized (Et2O) to give 2a (0.064 g, 29%) as a white solid; mp 60–62
°C; Rf = 0.51 (EtOAc–MeOH, 2:1).
1H NMR: d = 1.46, 1.52 (2 s, 6 H, CH3), 2.18 (t, J = 12.6 Hz, 1 H,
CH2), 2.54 (dd, J = 12.6, 9.2 Hz, 1 H, CH2), 3.78 (s, 3 H, OCH3),
3.97 (dd, J = 11.7, 9.2 Hz, 1 H, CH), 6.88 (d, J = 8.8 Hz, 2 H, CHAr),
7.19 (d, J = 8.8 Hz, 2 H, CHAr).
Anal. Calcd for C15H18BrNO3: C, 52.96; H, 5.33; N, 4.12. Found: C,
52.99; H, 5.78; N, 4.15.
rel-(4R,4aS,8aS)-3-Bromo-4-(4-nitrophenyl)-4a,5,6,7,8,8a-
hexahydro-4H-1,2-benzoxazine N-Oxide (1f)
Mp 147–153 °C (Et2O); Rf = 0.57 (hexane–EtOAc, 5:1) (UV).
1H NMR: d = 1.21–2.19 (m, 9 H, CH, CH2), 3.95 (s, 1 H, Ar-CH),
4.72 (s, 1 H, OCH), 7.41 (d, J = 8.5 Hz, 2 H, CHAr), 8.26 (d, J = 8.5
Hz, 2 H, CHAr).
13C NMR: d = 26.8, 28.9 (CH3), 44.1 (CH), 46.0 (CH2), 55.2
(OCH3), 81.8 [C(CH3)2], 114.2 (CHAr), 128.9 (CAr), 129.0 (CHAr),
158.8 (COCH3), 176.7 (C=O).
13C NMR: d = 19.8, 24.4, 27.6, 28.5 (CH2), 41.9 (CH), 53.4 (Ar-
CH), 77.3 (OCH), 105.4 (C=N), 124.5, 128.6 (CHAr), 147.6, 147.8
(CAr).
Anal. Calcd for C13H16O3: C, 70.89; H, 7.32; Found: C, 70.66; H,
7.24.
3-Vinylisoxazolines 3; General Procedure
Anal. Calcd for C14H15BrN2O4: C, 47.34; H, 4.26; N, 7.89. Found:
C, 47.43; H, 4.60; N, 8.00.
A soln of 1,2-oxazine N-oxide 1 (1 mmol), Et3N (0.42 mL, 3 mmol),
and alkene (5 mmol) in toluene (10 mL) was refluxed for the time
indicated in Table 2. The mixture was poured into a mixture of
EtOAc (50 mL) and H2O (50 mL). The organic layer was washed
with H2O (2 × 50 mL) and brine (2 × 40 mL) and dried (Na2SO4).
Solvents were removed in vacuo and the residue was subjected to
column chromatography (hexane–EtOAc, from 10:1 to 1:1).
(R/S)-3-Bromo-6,6-dimethyl-4-phenyl-5,6-dihydro-4H-1,2-ox-
azine N-Oxide (1g)
Mp 125–126 °C (Et2O); Rf = 0.41 (hexane–EtOAc, 1:1) (UV).
1H NMR: d = 1.40 (s, 3 H, CH3), 1.49 (s, 3 H, CH3), 2.15 (m, 2 H,
CH2), 3.69 (dd, J = 11.0, 8.3 Hz, 1 H, Ar-CH), 7.09–7.40 (m, 5 H,
CHPh).
Methyl (R/S)-3-[1-(4-Methoxyphenyl)vinyl]-4,5-dihydroisox-
azole-5-carboxylate (3a)
Yellowish oil; Rf = 0.59 (hexane–EtOAc, 1:1) (UV).
13C NMR: d = 22.1, 27.3 (CH3), 43.1 (CH2), 48.0 (PhCH), 83.4 (C),
110.6 (C=N), 126.1, 127.5, 126.4 (CHPh), 138.9 (CPh).
1H NMR: d = 3.53 (d, J = 9.2 Hz, 2 H, CH2), 3.81 (s, 3 H, OCH3),
3.82 (s, 3 H, Ar-OCH3), 5.14 (t, J = 9.2 Hz, 1 H, CH), 5.49, 5.60 (2
s, 2 H, H2C=), 6.88 (d, J = 8.5 Hz, 2 H, CHAr), 7.40 (d, J = 8.5 Hz,
2 H, CHAr).
13C NMR: d = 39.4 (CH2), 52.9 (OCH3), 55.3 (Ar-OCH3), 78.7
(CH), 113.6 (CHAr), 121.0 (CH2=), 129.8 (CHAr), 130.0 (CAr), 139.0
(C=), 157.4 (COCH3), 163.1 (C=N), 170.7 (CO2CH3).
Anal. Calcd for C12H14BrNO2: C, 50.72; H, 4.97; N, 4.93. Found: C,
50.81; H, 5.13; N, 4.72.
rel-(4R,6R)-3-Bromo-6-ethoxy-4-(4-methoxyphenyl)-5,6-dihy-
dro-4H-1,2-oxazine N-Oxide (1h)
Mp 105–107 °C (Et2O); Rf = 0.44 (hexane–EtOAc, 1:1) (UV).
1H NMR: d = 1.30 (t, J = 7.1 Hz, 3 H, CH2CH3), 2.34 (m, 2 H, CH2),
3.74 (dd, J = 9.8, 7.1 Hz, 1 H, CH2CH3), 3.81 (s, 3 H, OCH3), 4.08
(dd, J = 9.8, 7.1 Hz, 1 H, CH2CH3), 4.16 (dd, J = 11.0, 8.1 Hz, 1 H,
Ar-CH), 5.46 (br s, 1 H, OCH), 6.88 (d, J = 8.5 Hz, 2 H, CHAr), 7.12
(d, J = 8.5 Hz, 2 H, CHAr).
13C NMR: d = 15.1 (CH2CH3), 36.3 (CH2), 44.4 (Ar-CH), 55.3
(OCH3), 65.4 (CH2CH3), 102.0 (CO), 111.5 (C=N), 114.5, 129.1
(CHAr), 131.9 (CAr), 159.3 (COCH3).
Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C,
64.66; H, 5.93; N, 5.76.
(R/S)-3-[1-(4-Methoxyphenyl)vinyl]-5-phenyl-4,5-dihydroisox-
azole (3b)
Yellowish oil; Rf = 0.65 (hexane–EtOAc, 1:1) (UV).
1H NMR: d = 3.23 (dd, J = 16.2, 8.1 Hz, 1 H, CH2), 3.69 (dd,
J = 16.2, 11.0 Hz, 1 H, CH2), 3.82 (s, 3 H, OCH3), 5.49, 5.60 (2 s, 2
H, H2C=), 5.71 (dd, J = 11.0, 8.1 Hz, 1 H, CH), 6.92 (d, J = 8.8 Hz,
2 H, CHAr), 7.46 (d, J = 8.8 Hz, 2 H, CHAr), 7.28–7.42 (m, 5 H,
CHPh).
13C NMR: d = 29.8 (CH2), 55.3 (OCH3), 82.7 (CH), 113.5 (CHAr),
120.2 (CH2=), 125.8, 128.1, 128.7, 129.8, 130.4, 130.5 (CAr), 139.8
(C=), 157.4 (COCH3), 159.6 (C=N).
Anal. Calcd for C13H16BrNO4: C, 47.29; H, 4.88; N, 4.24. Found: C,
47.19; H, 5.20; N, 4.33.
rel-(4R,6R)-3-Bromo-6-ethoxy-4-(4-methoxyphenyl)-5,6-dihy-
dro-4H-1,2-oxazine N-Oxide (1h) Using TiCl2(Oi-Pr)2
To a stirred soln of 1-(2-bromo-2-nitrovinyl)-4-methoxybenzene
(3.10 g, 12.0 mmol) and ethyl vinyl ether (2.3 mL, 24.0 mmol) in
CH2Cl2 (36 mL) was added a soln of Ti(Oi-Pr)2Cl2 (11.38 g, 48.0
mmol) in CH2Cl2 (30 mL) at –78 °C under an argon atmosphere.
The mixture was maintained at –78 °C for 1 h and then quenched
with 0.5 M NaOH in MeOH (96 mL) and poured into a mixture of
CH2Cl2 (200 mL), sat. aq Na2CO3 (150 mL), and aq 0.1 M NaOH
(200 mL). The organic layer was washed with aq 0.1 M NaOH (150
mL). The aqueous layer was washed with CH2Cl2 (150 mL). The
combined organic layers were washed with aq 0.1 M NaOH (100
mL), sat. aq NaHCO3 (2 × 150 mL), and brine (3 × 150 mL) and
dried (Na2SO4). The solvents were removed in vacuo to give 1h as
white crystals.
Anal. Calcd for C18H17NO2: C, 77.40; H, 6.13; N, 5.01. Found: C,
77.09; H, 6–15; N, 4.89.
(R/S)-5-Butoxy-3-[1-(4-methoxyphenyl)vinyl]-4,5-dihydroisox-
azole (3c)
Yellowish oil; Rf = 0.51 (hexane–EtOAc, 1:1) (UV).
1H NMR: d = 0.92 (t, J = 7.3 Hz, 3 H, CH3), 1.23–1.60 (m, 4 H,
CH2CH2CH3), 3.10 (dd, J = 17.1, 1.3 Hz, 1 H, CH2), 3.32 (dd,
J = 17.1, 6.6 Hz, 1 H, CH2), 3.53 (m, 1 H, OCH2), 3.82 (s, 3 H,
OCH3), 3.85 (m, 1 H, OCH2), 5.50, 5.59 (2 s, 2 H, H2C=), 5.62 (dd,
J = 6.6, 1.3 Hz, 1 H, CH), 6.89 (d, J = 8.5 Hz, 2 H, CHAr), 7.42 (d,
J = 8.5 Hz, 2 H, CHAr).
3-(4-Methoxyphenyl)-5,5-dimethyldihydrofuran-2(3H)-one
(2a)
The soln of 1a (0.314 g, 1 mmol) in methyl acrylate (9.05 mL, 100
mmol) was stirred for 1 d. The mixture was poured into a mixture
13C NMR: d = 13.9 (CH3), 19.3 (CH2CH3), 31.6 (CH2CH2CH3),
41.9 (CH2), 55.4 (OCH3), 68.2 (OCH2), 103.3 (CH), 113.6 (CHAr),
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3-Bromo-5,6-dihydro-4H-1,2-oxazine N-Oxides
413
120.5 (H2C=), 129.8 (CHAr), 131.8 (CAr), 139.7 (C=), 158.3
(C=N), 126.0, 128.8, 128.9 (CHAr), 130.5 (CPh), 138.7 (CAr), 159.2
(COCH3), 164.4 (C=N).
(COCH3), 206.2 (C=O).
Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C,
70.03; H, 7.93; N, 4.90.
14N NMR: d = –72.
Anal. Calcd for C20H21NO4: C, 70.78; H, 6.24; N, 4.13. Found: C,
70.46; H, 6.07; N, 4.12.
(R/S)-[3-(1-Phenylvinyl)-4,5-dihydroisoxazol-5-yl]methanol
(3d)
Yellowish oil; Rf = 0.27 (hexane–EtOAc, 1:1) (UV).
1H NMR: d = 2.57 (br s, 1 H, OH), 3.20 (m, 2 H, CH2O), 3.62 (dd,
J = 11.8, 4.6 Hz, 1 H, CH2), 3.79 (dd, J = 11.8, 3.3 Hz, 1 H, CH2),
4.77 (m, 1 H, CH), 5.53 (s, 1 H, HC=), 5.60 (s, 1 H, HC=), 7.23–
7.48 (m, 5 H, CHPh).
3-(2,5-Dioxo-2,5-dihydrofuran-3-yl)-4-(4-methoxyphenyl)-6,6-
dimethyl-5,6-dihydro-4H-1,2-oxazine N-Oxide (5a)
The soln of 1a (0.314 g, 1 mmol), Et3N (0.28 mL, 2 mmol), and ma-
leic anhydride (0.294 g, 3 mmol) in toluene (10 mL) was refluxed
for 2 h. The mixture was poured into a mixture of EtOAc (50 mL)
and H2O (50 mL). The organic layer was washed with H2O (2 × 50
mL) and brine (2 × 40 mL) and dried (Na2SO4). The solvents were
removed in vacuo and the residue was subjected to column chroma-
tography (hexane–EtOAc, from 10:1 to 1:1) to give 5a (0.20 g,
61%) as a yellowish oil; Rf = 0.55 (hexane–EtOAc, 1:1) (UV).
1H NMR: d = 1.46, 1.52 (2 s, 6 H, 2 CH3), 2.05 (dd, J = 14.3, 9.9
Hz, 1 H, CH2), 3.36 (dd, J = 14.3, 8.8 Hz, 1 H, CH2), 3.77 (s, 3 H,
OCH3), 4.84 (t, J = 9.2 Hz, 1 H, CH), 6.81 (d, J = 8.8 Hz, 2 H,
CHAr), 7.07 (d, J = 8.8 Hz, 2 H, CHAr), 7.74 (s, 1 H, HC=).
13C NMR: d = 36.9 (CH2), 63.7 (CH2O), 81.5 (CH), 121.5 (C=),
128.3, 128.62, 129.1 (CHPh), 138.1 (CPh), 139.0 (C=), 163.0 (C=N).
Anal. Calcd for C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C,
71.19; H, 6.67; N, 6.70.
Methyl (R/S)-3-(1-Phenylvinyl)-4,5-dihydroisoxazole-5-carbox-
ylate (3e)
Yellowish oil; Rf = 0.59 (hexane–EtOAc, 1:1) (UV).
1H NMR: d = 3.51 (d, J = 9.2 Hz, 2 H, CH2), 3.82 (s, 3 H, OCH3),
5.13 (t, J = 9.2 Hz, 1 H, CH), 5.51, 5.62 (2 s, 2 H, H2C=), 7.21–7.43
(m, 5 H, CHPh).
13C NMR: d = 22.2, 27.6 (2 CH3), 37.9, 42.2 (CH, CH2), 55.3
(OCH3), 85.2 [C(CH3)2], 114.6 (CHAr), 119.3 (C=N), 128.8 (CHAr),
132.7 (CAr), 136.5, 137.8 (C=, CH=), 158.7 (COCH3), 163.8 (C=O).
Anal. Calcd for C17H17NO6: C, 61.63; H, 5.17; N, 4.23. Found: C,
61.88; H, 5.28; N, 4.03.
13C NMR: d = 39.9 (CH2), 53.4 (OCH3), 78.7 (CH), 121.0 (CH2=),
128.9, 129.2, 130.0 (CHPh), 138.6 (CPh), 160.1 (C=N), 171.0 (C=O).
Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C,
67.52; H, 5.90; N, 5.89.
Acknowledgment
This work was supported by RFFI (#06-03-32607).
rel-(S)-1-[3-(1-Phenylvinyl)-4,5-dihydroisoxazol-5-yl]ethanone
(3f)
Yellowish oil; Rf = 0.63 (hexane–EtOAc, 1:1) (UV).
References
1H NMR: d = 2.33 (s, 3 H, CH3), 3.38 (dd, J = 16.9, 11.7 Hz, 1 H,
CH2), 3.52 (dd, J = 16.9, 6.2 Hz, 1 H, CH2), 4.98 (dd, J = 11.7, 6.2
Hz, 1 H, CH), 5.57, 5.64 (2 s, 2 H, H2C=), 7.30–7.46 (m, 5 H, CHPh).
(1) Ioffe, S. L. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis, In Novel Strategies in Synthesis, 2nd ed.;
Feuer, H., Ed.; John Wiley & Sons: New Jersey, 2008, 658.
(2) Denmark, S. E.; Montgomery, J. I.; Kramps, L. A. J. Am.
Chem. Soc. 2006, 128, 11620; and references therein.
(3) (a) Chlenov, I. E.; Petrova, I. M.; Hasanov, B. N.;
Stepanyanc, A. U.; Chigov, O. C.; Tartakovskiy, V. A. Bull.
Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1978, 27,
2278; and references therein. (b) Chlenov, I. E.; Petrova, I.
M.; Shitkin, V. M.; Tartakovskiy, V. A. Bull. Acad. Sci.
USSR, Div. Chem. Sci. (Engl. Transl.) 1975, 24, 1365.
(c) Chlenov, I. E.; Sokolova, I. L.; Hasanov, B. N.; Novikov,
V. M.; Karpenko, N. F.; Stepanyanc, A. U.; Tartakovskiy, V.
A. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.)
1974, 23, 347.
(4) Chlenov, I. E.; Hudak, V. M.; Kolymagina, L. N.;
Morozova, N. S.; Tartakovskiy, V. A. Bull. Acad. Sci. USSR,
Div. Chem. Sci. (Engl. Transl.) 1970, 1757.
(5) Denmark, S. E.; Guagnano, V.; Dixon, J. A.; Stolle, A.
J. Org. Chem. 1997, 62, 4610.
(6) (a) Tishkov, A. A.; Lesiv, A. V.; Khomutova, Yu. A.;
Strelenko, Yu. A.; Nesterov, I. D.; Antipin, M. Yu.; Ioffe, S.
L.; Denmark, S. E. J. Org. Chem. 2003, 68, 9477.
(b) Sukhorukov, A. Yu.; Klenov, M. S.; Ivashkin, P. E.;
Lesiv, A. V.; Khomutova, Yu. A.; Ioffe, S. L. Synthesis
2007, 97.
(7) Brook, M. A.; Seebach, D. Can. J. Chem. 1987, 65, 836.
(8) Cycloaddition of 3-methyl-1,2-oxazine N-oxide proceeded
at reflux in xylene within 8 h. This fact corresponds with the
results obtained for [3+2] cycloaddition between alkenes
and 3-halo silyl nitronates [k(F) >> k(Br) ≈ k(Cl) > k(I)].
Kunetsky, R. A.; Dilman, A. D.; Struchkova, M. I.;
13C NMR: d = 26.3 (CH3), 37.2 (CH2), 84.5 (CH), 122.2 (CH2=),
128.1, 128.2, 128.4 (CHPh), 137.7 (CPh), 139.7 (C=), 157.6 (C=N),
207.1 (C=O).
Anal. Calcd for C13H13NO3: C, 72.54; H, 6.09; N, 6.51. Found: C,
72.64; H, 6.35; N, 6.57.
(R/S)-3-[1-(4-Methoxyphenyl)vinyl]-5-phenyl-4,5-dihydroisox-
azole (3b) and 3-[1-(4-Methoxyphenyl)-3-oxobutyl]-5-phenyl-
4,5-dihydroisoxazole 2-Oxide (4a)
The soln of 1,2-oxazine N-oxide 1b (0.33 g, 1 mmol), K2CO3 (0.14
g, 1 mmol), and styrene (0.57 mL, 5 mmol) in DMF (10 mL) was
kept for 3 h. The mixture was poured into a mixture of EtOAc (50
mL) and H2O (50 mL). The organic layer was washed with H2O
(2 × 50 mL) and brine (2 × 40 mL) and dried (Na2SO4). The sol-
vents were removed in vacuo and the residue was subjected to col-
umn chromatography (hexane–EtOAc, from 10:1 to 1:1) to give 3b
(0.028 g, 10%) and 4a (0.19 g, 58%) as a colorless oil; Rf = 0.31
(hexane–EtOAc, 1:1) (UV).
Isoxazole N-oxide 4a
1H NMR: d = 2.18 (s, 3 H, CH3), 2.96 (dd, J = 17.7, 5.9 Hz, 1 H,
CH2), 3.06 (dd, J = 16.6, 7.8 Hz, 1 H, isoxazole-CH2), 3.38 (dd,
J = 16.6, 8.5 Hz, 1 H, isoxazole-CH2), 3.38 (dd, J = 17.7, 9.2 Hz, 1
H, CH2), 3.75 (s, 3 H, OCH3), 4.14 (dd, J = 9.2, 5.9 Hz, 1 H, Ar-
CH), 4.14 (dd, J = 7.8, 8.5 Hz, 1 H, OCH), 6.82 (d, J = 8.5 Hz, 2 H,
CHAr), 7.20 (d, J = 8.5 Hz, 2 H, CHAr), 7.30 (m, 5 H, CHPh).
13C NMR: d = 29.7 (CH3), 37.7 (CHAr), 41.1 (isoxazole-CH2), 45.0
(CH2), 55.3 (OCH3), 76.3 (OCH), 114.2, 128.7 (CHAr), 117.2
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414
L. V. Romashov et al.
PAPER
Belyakov, P. A.; Tartakovsky, V. A.; Ioffe, S. L. Synthesis
2006, 2265.
(9) Kirby, A. J. Stereolectronic Effects; Oxford: New York,
1996, 24.
(10) (a) Rudchenko, V. F. Chem. Rev. 1993, 93, 725.
(b) Lambert, J. B.; Takeuchi, Y. Cyclic Organonitrogen
Stereodynamics; VCH: New York, 1992, Chap. 7.1.1 and
7.2.1, and references therein.
(11) (a) Conti, P.; Dallanoce, C.; Amici, M. D.; Micheli, C. D.;
Klotz, K.-N. Bioorg. Med. Chem. 1998, 6, 401. (b) Lam, P.
Y. S.; Adams, J. J.; Clark, C. G.; Calhoun, W. J.; Luettgen,
J. M.; Knabb, R. M.; Wexler, R. R. Bioorg. Med. Chem. Lett.
2003, 13, 1795.
(12) Worrall, D. E. Org. Synth. Coll. Vol. 1; John Wiley & Sons:
London, 1941, 413.
(13) Aleksiev, D. I.; Ivanova, S. M. Russ. J. Org. Chem. 1993, 29,
1845.
(14) Pfeiffer, P. Chem. Ber. 1914, 47, 1755; see p. 1768.
Synthesis 2010, No. 3, 407–414 © Thieme Stuttgart · New York