One-pot conversion of serine derivatives and amino sugars into oxazine derivatives of γ-aryl-γ-(hydroxy)amines

Article abstract of DOI:10.1002/ejoc.201101274

A one-pot process for the transformation of relatively inexpensive serine derivatives into oxazine derivatives of γ-aryl-γ-hydroxy-α- amino acids is described. The reaction preferentially afforded 4,6-cis oxazines. The method can also be applied to the tr

Full text of DOI:10.1002/ejoc.201101274

FULL PAPER
DOI: 10.1002/ejoc.201101274
One-Pot Conversion of Serine Derivatives and Amino Sugars into Oxazine
Derivatives of γ-Aryl-γ-(hydroxy)amines
Alicia Boto,*[a] Juan A. Gallardo,[a] and Eleuterio Álvarez[b]
Keywords: Sequential processes / Radical reactions / Nucleophilic addition / Heterocycles / Amino alcohols
A one-pot process for the transformation of relatively inex-
tially afforded 4,6-cis oxazines. The method can also be ap-
pensive serine derivatives into oxazine derivatives of γ-aryl-
plied to the transformation of amino sugars into highly func-
γ-hydroxy-α-amino acids is described. The reaction preferen- tionalized oxazines, which are precursors of chiral amines.
Introduction
Results and Discussion
The starting materials for this one-pot process were inex-
pensive serine derivatives, such as the methyl ester 1
(Scheme 1). Under treatment with (diacetoxyiodo)benzene
(DIB) and iodine, a radical scission took place,[2] giving C
radical 2, which underwent oxidation to acyliminium ion
3.[9] This intermediate was trapped by acetate ions from the
reagent to yield N,O-acetal 4. Under treatment of this acetal
with Lewis acid, the acyliminium ion was regenerated and
reacted with vinyl arenes to afford the intermediates 5.[10]
Sequential processes have proven very valuable in syn-
thetic chemistry for preparing a variety of compounds from
simpler and often inexpensive precursors.[1] In these pro-
cesses several reactions take place sequentially without the
need to isolate synthetic intermediates, thus saving time,
materials and energy with respect to conventional processes.
In recent years, we have developed different sequential
processes[2] that couple radical and ionic reactions[3] and
allow the direct conversion of readily available amino acids,
hydroxy amines and carbohydrates into amino acid or nu-
cleoside analogues and alkaloid precursors. These reactions
are carried out under mild conditions and generally proceed
in good to excellent yields.
This paper describes the one-pot preparation of 6-aryl-
5,6-dihydro-4H-1,3-oxazines from inexpensive serine deriv-
atives and amino sugars by using a sequential radical scis-
sion/oxidation /nucleophilic addition/intramolecular cycli-
zation process. 5,6-Dihydro-4H-1,3-oxazines[4,5] are present
in bioactive natural products[4] and drugs,[6] and are also
valuable synthetic intermediates.[4,7] Thus, they have been
used in the syntheses of the Taxol side-chain,[7a] unsaturated
amino acids,[7b] alkylhomoserines and homocysteines,[7c]
sphingosines,[7d,7e] amino alcohols,[7f] jasmonic acid deriva-
tives[7g] and a variety of hydroxy amines, aldehydes, ketones,
acids, olefins and pyrroles.[8] Their value as chiral amine
precursors will be described in this work.
[a] Instituto de Productos Naturales y Agrobiología CSIC,
Avda. Astrofísico Fco. Sánchez 3, 38206 La Laguna, Tenerife,
Spain
Fax: +34-922-260135
E-mail: alicia@ipna.csic.es
[b] Instituto de Investigaciones Químicas (CSIC-USe),
Isla de la Cartuja,
Avda. Américo Vespucio 49, 41092 Sevilla, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101274.
Scheme 1. One-pot conversion of serine derivatives into 6-aryl-5,6-
dihydro-4H-1,3-oxazines.
Eur. J. Org. Chem. 2012, 391–397
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
391

A. Boto, J. A. Gallardo, E. Álvarez
FULL PAPER
This addition was followed by intramolecular cyclization to
The reaction worked well with a variety of nucleophiles
yield 6-aryl-5,6-dihydro-4H-1,3-oxazines 6.
(7–11), affording the oxazines 12–20 in good global yields
The process was optimized by using different Lewis ac- (70–91%). Remarkably, good results were obtained even
ids, solvents, temperatures, reaction times and amounts of with highly hindered and strained products, such as the
reagent. Under the optimized conditions, the substrate 1 polycyclic systems 18 and 19,[11,12] and the 2,2-diaryl com-
(Table 1) was treated with DIB and iodine in CH2Cl2 at pound 20. These oxazines are protected derivatives of un-
room temperature in the presence of visible light. Then the usual γ-hydroxy amino acids.
reaction mixture was cooled to 0 °C and the vinyl arene and
boron trifluoride or TMSOTf were added.
When the hindered nucleophile 11 was used, the unsatu-
rated product 21 was also isolated. This product could be
formed either from intermediate 5 or from the oxazine 20.
The stereochemistries of products 12–19 were determined
Table 1. Conversion of serine derivatives into 6-aryl-5,6-dihydro-
4H-1,3-oxazines.
1
according to their H NMR coupling constants. Thus, the
cis isomers presented J4,5 ≈ 4.8, 11.5 Hz and J5,6 ≈ 3.0,
11.5 Hz, whereas the values for the trans isomers were J4,5
≈ 4.0, 5.7 Hz and J5,6 ≈ 3.5, 9.5 Hz. The stereochemistries
were confirmed by X-ray analysis of the major naphthyl
derivative 16 (Figure 1), which displayed a cis relationship
between the aryl and methoxycarbonyl groups.
Figure 1. X-ray analysis of the major 6-naphthyl isomer 16, dis-
playing a 4,6-cis relationship. The ORTEP drawing shows thermal
ellipsoids at the 30% probability level. Most hydrogen atoms have
been omitted for clarity.
When vinyl arenes 7–10 were used as nucleophiles, the
more hindered cis product (compounds 12, 14, 16 and 18)
predominated over the trans isomers (products 13, 15, 17
and 19). A possible explanation is that the addition of the
olefin to the iminium ion generates a chair-like intermediate
such as 5a (Scheme 2) in which the bulky substituents
[a] Substrate/DIB/I2 [mmol] 1:2:1, hν, CH2Cl2, 26 °C, 2 h; then
0 °C, vinyl arene (5 equiv.), BF3·OEt2 (3 equiv.), 0 to 26 °C, 4 h. [b]
BF3·OEt2 was replaced by TMSOTf (3 equiv.). In both procedures,
the yields are given for products purified by chromatography.
Scheme 2. Stereoselectivity of the cyclization process: formation of
the cis diastereomers as the major products.
392
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 391–397

Oxazine Derivatives of γ-Aryl-γ-(hydroxy)amines
(CO2Me, Ar) are in equatorial dispositions.[13] Intramolecu- conditions with alkene 11 as nucleophile. The scission/oxi-
lar cyclization followed to give cis oxazines such as com- dation step generated acyliminium intermediate 23, which
pound 16. Note that the addition and cyclization steps are was trapped by the alkene. According to the Felkin–Anh
probably not concerted because in some cases a consider- model, the approach of the nucleophile as shown for 23a
able amount of the minor trans isomer was also formed.
is less favoured than as shown for 23b. In the first case,
The process is versatile and can be extended to other sub- intermediate 24a was formed, which underwent intramolec-
strates. For instance, the amino sugar 22 (Scheme 3) was ular cyclization to give the 6,6-diphenyl-5,6-dihydro-4H-
treated under the scission/oxidation/alkylation/cyclization 1,3-oxazine 25 (4R, 11%). In the second case, the intermedi-
ate 24b cyclized to the major product 26 (4S, 54%). The
diastereomeric oxazines were readily separated by
chromatography.
As commented upon before, the oxazines are valuable
synthetic intermediates. Compounds 25 and 26 present
highly functionalized chains and could serve as precursors
of alkaloids and nucleoside analogues (particularly acyclic
C-nucleosides).
To study their use as chiral synthetic intermediates, oxa-
zine 26 was heated leading to ring-opening and amine[14] 27
(Scheme 4) in almost quantitative yield. X-ray analysis of
compound 27 confirmed the assigned stereochemistry.
Scheme 4. Conversion of oxazine 26 into chiral amine 27.
Conclusions
An efficient sequential process for the one-pot conver-
sion of readily available serine derivatives into 6-aryl-5,6-
dihydro-4H-1,3-oxazines has been developed. These ox-
azines are protected forms of γ-aryl-γ-hydroxy-α-amino ac-
ids. A variety of aryl groups can be introduced by this pro-
cess, which couples a radical scission with an oxidation, a
nucleophilic addition and a cyclization. The method uses
mild conditions and affords the dihydrooxazines in good-
to-excellent yields. Interestingly, the 4,6-cis isomers were the
major products.
The process is versatile and can be applied to different
substrates. For instance, the 2,3,4,6-tetraacetate of d-glu-
cosamine underwent the process to afford substituted ox-
azines which are analogues of C-nucleosides. The value of
oxazines as synthetic intermediates was illustrated by the
conversion of a sugar-derived oxazine into a chiral amine.
Experimental Section
General Methods: Commercially available reagents and solvents
were analytical grade or were purified by standard procedures prior
to use. All reactions involving air- or moisture-sensitive materials
were carried out under a nitrogen atmosphere. The spray reagents
for TLC analysis were either 0.5% vanillin in H2SO4/EtOH (4:1)
or Fleet’s reagent [Ce(SO4)2 (0.5 g) and ammonium phosphomolyb-
Scheme 3. Direct conversion of amino sugar 22 into oxazines 25
and 26.
Eur. J. Org. Chem. 2012, 391–397
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
393

A. Boto, J. A. Gallardo, E. Álvarez
FULL PAPER
date hydrate (2.5 g) in H2SO4 (5 mL) and water (65 mL)]. Once
sprayed, the TLC was heated until development of color. Merck
silica gel 60 (0.063–0.2 mm) was used for column chromatography.
Melting points were determined with a hot-stage apparatus. Optical
rotations were measured at the sodium line at ambient temperature
(26 °C).
CDCl3, 26 °C): δ = 2.18 (ddd, J = 11.5, 11.5, 13.7 Hz, 1 H, 5-Ha),
2.60 (ddd, J = 2.9, 4.9, 13.7 Hz, 1 H, 5-Hb), 3.81 (s, 3 H, OMe),
4.64 (dd, J = 4.8, 11.5 Hz, 1 H, 4-H), 5.39 (dd, J = 2.8, 11.7 Hz, 1
H, 6-H), 7.36 (dd, J = 7.4, 7.5 Hz, 1 H, Ar), 7.41 (dd, J = 7.0,
7.6 Hz, 2 H, Ar), 7.46 (dd, J = 7.0, 7.5 Hz, 2 H, Ar), 7.48 (m, 1 H,
Ar), 7.50 (d, J = 8.3 Hz, 2 H, Ar), 7.61 (d, J = 8.5 Hz, 2 H, Ar),
7.66 (d, J = 8.3 Hz, 2 H, Ar), 8.07 (d, J = 7.4 Hz, 2 H, Ar) ppm.
13C NMR (125.7 MHz, CDCl3, 26 °C): δ = 32.4 (CH2), 52.4 (CH3),
56.5 (CH), 76.0 (CH), 126.3 (2 CH), 127.1 (2 CH), 127.5 (2 CH),
127.6 (2 CH), 128.0 (2 CH), 128.5 (CH), 128.8 (2 CH), 130.9 (CH),
133.1 (C), 138.6 (C), 140.6 (C), 141.6 (C), 156.9 (C), 172.5 (C) ppm.
MS (EI, 70 eV): m/z (%) = 371 (33) [M]+, 312 (18) [M –
COOCH3]+, 266 (6) [M – COPh]+, 180 (78) [M – BzNCHCO2-
CH3]+, 105 (100) [COPh]+, 77 (56) [Ph]+. HRMS: calcd. for
C24H21NO3 371.1521; found 371.1523; calcd. for C22H18NO
312.1388; found 312.1386. C24H21NO3 (371.44): calcd. C 77.61, H
5.70, N 3.77; found C 77.43, H 5.98, N 3.66.
Procedure for the Scission/Oxidation/Alkylation/Cyclization Se-
quence Ϫ Synthesis of Methyl (4R*,6S*)-2,6-Diphenyl-5,6-dihydro-
4H-1,3-oxazine-4-carboxylate [(؎)-12] and its (4S*,6S*) Isomer
(؎)-13: Iodine (60 mg, 0.22 mmol) and (diacetoxyiodo)benzene
(DIB) (180 mg, 0.56 mmol) were added to a solution of serine de-
rivative 1 (50 mg, 0.22 mmol) in dry CH2Cl2 (12 mL). The reaction
mixture was stirred for 2 h at room temperature (26 °C) under vis-
ible light irradiation. Then it was cooled to 0 °C and styrene
(130 μL, 1.12 mmol) was injected followed by the dropwise ad-
dition of BF3·OEt2 (85 μL, 0.67 mmol). The reaction mixture was
allowed to warm to room temperature and stirred for 4 h. Then it
was poured into 10% aqueous Na2S2O3/saturated aqueous
NaHCO3 (1:1, 10 mL) and extracted with CH2Cl2. The organic
layer was dried with sodium sulfate, filtered and the solvents evapo-
rated under vacuum. The residue was purified by chromatography
on silica gel (hexanes/EtOAc, 90:10) to give products (Ϯ)-12
(30 mg, 58%) and (Ϯ)-13 (10 mg, 20%).
Compound (؎)-15: White solid, m.p. 117–118 °C (neat). IR
1
(CHCl ): ν = 3011, 1738, 1649 cm–1. H NMR (500 MHz, CDCl ,
˜
3
3
26 °C): δ = 2.26 (ddd, J = 5.7, 9.4, 14.0 Hz, 1 H, 5-Ha), 2.53 (ddd,
J = 3.8, 3.8, 14.0 Hz, 1 H, 5-Hb), 3.84 (s, 3 H, OMe), 4.50 (br. dd,
J = 4.0, 5.6 Hz, 1 H, 4-H), 5.53 (dd, J = 3.5, 9.5 Hz, 1 H, 6-H),
7.38 (dd, J = 7.4, 7.4 Hz, 1 H, Ar), 7.43 (dd, J = 7.4, 7.6 Hz, 2 H,
Ar), 7.44–7.48 (m, 4 H, Ar), 7.50 (dd, J = 7.4, 7.4 Hz, 1 H, Ar),
7.60 (d, J = 8.1 Hz, 2 H, Ar), 7.65 (d, J = 8.3 Hz, 2 H, Ar), 8.11 (d,
J = 7.5 Hz, 2 H, Ar) ppm. 13C NMR (125.7 MHz, CDCl3, 26 °C): δ
= 31.0 (CH2), 52.5 (CH3), 54.0 (CH), 73.8 (CH), 126.1 (2 CH),
127.1 (2 CH), 127.6 (4 CH), 127.6 (CH), 127.7 (2 CH), 128.1 (2
CH), 128.8 (2 CH), 131.0 (CH), 133.3 (C), 138.9 (C), 140.6 (C),
141.4 (C), 156.8 (C), 172.8 (C) ppm. MS (EI, 70 eV): m/z (%) =
371 (100) [M]+, 312 (33) [M – COOCH3]+, 266 (24) [M – COPh]+,
180 (17) [M – BzNCHCOOCH3]+, 105 (18) [COPh]+, 77 (6) [Ph]+.
HRMS: calcd. for C24H21NO3 371.1521; found 371.1519; calcd. for
C22H18NO 312.1388; found 312.1384. C24H21NO3 (371.44): calcd.
C 77.61, H 5.70, N 3.77; found C 77.61, H 5.98, N 3.70.
Compound (؎)-12: White solid, m.p. 74–75 °C (neat). IR (CHCl3):
ν = 3030, 1742, 1652, 1276 cm–1. 1H NMR (500 MHz, CDCl3,
˜
26 °C): δ = 2.12 (ddd, J = 11.6, 11.6, 13.6 Hz, 1 H, 5-Ha), 2.54
(ddd, J = 2.8, 4.8, 13.6 Hz, 1 H, 5-Hb), 3.80 (s, 3 H, OMe), 4.59
(dd, J = 4.8, 11.4 Hz, 1 H, 4-H), 5.32 (dd, J = 2.8, 11.6 Hz, 1 H,
6-H), 7.37–7.40 (m, 3 H, Ar), 7.41–7.43 (m, 4 H, Ar), 7.45 (dd, J
= 7.2, 8.8 Hz, 1 H, Ar), 8.03 (d, J = 7.1 Hz, 2 H, Ar) ppm. 13C
NMR (125.7 MHz, CDCl3, 26 °C): δ = 32.4 (CH2), 52.4 (CH3),
56.5 (CH), 76.2 (CH), 125.8 (2 CH), 127.6 (2 CH), 128.0 (2 CH),
128.5 (CH), 128.8 (2 CH), 130.9 (CH), 133.1 (C), 139.7 (C), 157.0
(C), 172.5 (C) ppm. MS (EI, 70 eV): m/z (%) = 295 (43) [M]+, 236
(72) [M – CO2Me]+, 130 (14) [M – H – CO2Me – COPh]+, 105
(100) [COPh]+, 77 (39) [Ph]+. HRMS: calcd. for C18H17NO3
295.1208; found 295.1212; calcd. for C16H14NO 236.1075; found
236.1076. C18H17NO3 (295.34): calcd. C 73.20, H 5.80, N 4.74;
found C 73.39, H 5.86, N 4.54.
Synthesis of Methyl (4R*,6S*)-6-(Naphthalen-2-yl)-2-phenyl-5,6-di-
hydro-4H-1,3-oxazine-4-carboxylate [(؎)-16] and Its (4S*,6S*) Iso-
mer (؎)-17: Obtained from serine derivative 1 according to the ge-
neral procedure with 2-vinylnaphthalene as the nucleophile and
TMSOTf (120 μL, 0.67 mmol) as the Lewis acid. After the usual
work-up and purification, the procedure yielded compounds (؎)-
16 (46%) and (؎)-17 (29%).
Compound (؎)-13: White solid, m.p. 63–64 °C (neat). IR (CHCl3):
ν = 2956, 1738, 1650, 1283 cm–1. 1H NMR (500 MHz, CDCl3,
˜
26 °C): δ = 2.19 (ddd, J = 5.7, 9.3, 14.8 Hz, 1 H, 5-Ha), 2.48 (ddd,
J = 3.8, 3.9, 14.0 Hz, 1 H, 5-Hb), 3.82 (s, 3 H, OMe), 4.44 (dd, J
= 4.2, 5.6 Hz, 1 H, 4-H), 5.46 (dd, J = 3.6, 9.3 Hz, 1 H, 6-H), 7.34–
7.45 (m, 7 H, Ar), 7.47 (dd, J = 7.2, 7.4 Hz, 1 H, Ar), 8.06 (d, J =
7.2 Hz, 2 H, Ar) ppm. 13C NMR (125.7 MHz, CDCl3, 26 °C): δ =
31.0 (CH2), 52.5 (CH3), 54.0 (CH), 73.8 (CH), 125.6 (2 CH), 127.6
(2 CH), 128.1 (2 CH), 128.3 (CH), 128.7 (2 CH), 131.0 (CH), 133.3
(C), 140.0 (C), 157.1 (C), 172.8 (C) ppm. MS (EI, 70 eV): m/z (%)
= 295 (19) [M]+, 236 (31) [M – CO2Me]+, 105 (100) [COPh]+, 77
(38) [Ph]+. HRMS: calcd. for C18H17NO3 295.1208; found
295.1216; calcd. for C16H14NO 236.1075; found 236.1079.
C18H17NO3 (295.34): calcd. C 73.20, H 5.80, N 4.74; found C
73.22, H 5.86, N 4.61.
Compound (؎)-16: White solid, m.p. 107–108 °C (neat). IR
1
(CHCl ): ν = 3013, 1739, 1652 cm–1. H NMR (500 MHz, CDCl ,
˜
3
3
26 °C): δ = 2.22 (ddd, J = 11.5, 11.5, 13.7 Hz, 1 H, 5-Ha), 2.61
(ddd, J = 2.8, 4.8, 13.8 Hz, 1 H, 5-Hb), 3.81 (s, 3 H, OMe), 4.64
(dd, J = 4.8, 11.5 Hz, 1 H, 4-H), 5.48 (dd, J = 2.8, 11.5 Hz, 1 H,
6-H), 7.39 (dd, J = 7.2, 7.8 Hz, 2 H, Ar), 7.46 (dd, J = 7.2, 7.5 Hz,
1 H, Ar), 7.51–7.53 (m, 3 H, Ar), 7.86–7.90 (m, 3 H, Ar), 7.91 (d,
J = 8.6 Hz, 1 H, Ar), 8.06 (d, J = 8.2 Hz, 2 H, Ar) ppm. 13C NMR
(125.7 MHz, CDCl3, 26 °C): δ = 32.3 (CH2), 52.4 (CH3), 56.6 (CH),
76.4 (CH), 123.5 (CH), 125.1 (CH), 126.3 (CH), 126.4 (CH), 127.6
(2 CH), 127.8 (CH), 128.1 (3 CH), 128.7 (CH), 130.9 (CH), 133.2
(2 C), 133.3 (C), 137.0 (C), 156.9 (C), 172.6 (C) ppm. MS (EI,
70 eV): m/z (%) = 345 (22) [M]+, 286 (19) [M – COOCH3]+, 105
(100) [COPh]+, 77 (36) [Ph]+. HRMS: calcd. for C22H19NO3
345.1365; found 345.1367; calcd. for C7H5O 105.0340; found
105.0344. C22H19NO3 (345.40): calcd. C 76.50, H 5.54, N 4.06;
found C 76.44, H 5.68, N 3.69.
Synthesis of Methyl (4R*,6S*)-6-(Biphenyl-4-yl)-2-phenyl-5,6-dihy-
dro-4H-1,3-oxazine-4-carboxylate [(؎)-14] and its (4S*,6S*) Isomer
(؎)-15: Obtained from serine derivative 1 according to the general
procedure with phenylstyrene as the nucleophile. After the usual
work-up and purification, the procedure yielded compounds (؎)-
14 (62%) and (؎)-15 (29%).
X-ray Analysis: C22H19NO3, Mr = 345.38. A single colourless prism
Compound (؎)-14: White solid, m.p. 126–127 °C (neat). IR crystal (0.50ϫ 0.48ϫ 0.21 mm3) from EtOAc/n-hexane coated with
(CHCl ): ν = 3018, 1742, 1649, 1488 cm–1. 1H NMR (500 MHz, dry perfluoropolyether was mounted on a glass fiber and fixed to
˜
3
394
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 391–397

Oxazine Derivatives of γ-Aryl-γ-(hydroxy)amines
the goniometer head in a stream of cold nitrogen [T = 173(2) K].
Data collection was performed with a Bruker–Nonius X8APEX-II
CCD diffractometer with monochromatic radiation [λ(Mo-Kα1) =
0.71073 Å], and ω and φ scans. Monoclinic, space group C2/c, a =
16.7250(5), b = 8.8469(3), c = 23.4755(7) Å, β = 94.6630(10)°, V =
3462.04(19) Å3, Z = 8, ρcalcd. = 1.325 gcm–3, F(000) = 1456, μ =
0.088 mm–1. Measured reflections 54040, of which 5256 were
unique (Rint = 0.0215). The asymmetric unit of the structure is
formed by one molecule of compound 16. Refined parameters 236,
final R1 = 0.0411, for reflections with IϾ2σ(I), wR2 = 0.1179 (all
data), GOF = 1.028. Max./min. residual electron density +0.211/
–0.165 eÅ–3.
(2 CH), 128.0 (2 CH), 129.3 (CH), 130.8 (CH), 133.4 (C), 141.3
(C), 141.5 (C), 157.5 (C), 172.9 (C) ppm. MS (EI, 70 eV):
m/z (%) = 307 (2) [M]+, 248 (20) [M – COOCH3]+, 202 (21) [M –
PhCO]+, 186 (24) [M – H – CH3 – PhCO]+, 116 (86) [M –
BzNCHCOOCH3]+, 105 (100) [PhCO]+, 77 (31) [Ph]+. HRMS:
calcd. for C19H17NO3 307.1208; found 307.1209; calcd. for
C17H14NO 248.1075; found 248.1067. C19H17NO3 (307.35): calcd.
C 74.25, H 5.58, N 4.56; found C 74.22, H 5.61, N 4.47.
Synthesis of Methyl 2,6,6-Triphenyl-5,6-dihydro-4H-1,3-oxazine-4-
carboxylate [(؎)-20] and Methyl 2-Benzamido-4,4-diphenylbut-3-en-
oate [(؎)-21]: Obtained from serine derivative 1 according to the
general procedure using 2,2-diphenylethene as the nucleophile and
BF3·OEt2 as the Lewis acid. After the usual work-up and purifica-
tion, the procedure yielded compounds (؎)-20 (59%) and (؎)-21
(11%).
Compound (؎)-17: White solid, m.p. 97–98 °C (neat). IR (CHCl3):
ν = 3013, 1737, 1649, 1438 cm–1. 1H NMR (500 MHz, CDCl3,
˜
26 °C): δ = 2.28 (ddd, J = 5.6, 9.3, 14.2 Hz, 1 H, 5-Ha), 2.54 (ddd,
J = 3.8, 3.8, 14.0 Hz, 1 H, 5-Hb), 3.83 (s, 3 H, OMe), 4.46 (dd, J
= 4.0, 5.6 Hz, 1 H, 4-H), 5.63 (dd, J = 3.5, 9.2 Hz, 1 H, 6-H), 7.41
(dd, J = 7.2, 7.7 Hz, 2 H, Ar), 7.46–7.53 (m, 4 H, Ar), 7.84–7.87
(m, 3 H, Ar), 7.90 (d, J = 8.5 Hz, 1 H, Ar), 8.08 (d, J = 7.1 Hz, 2
H, Ar) ppm. 13C NMR (125.7 MHz, CDCl3, 26 °C): δ = 31.0
(CH2), 52.5 (CH3), 54.0 (CH), 74.0 (CH), 123.3 (CH), 124.7 (CH),
126.3 (CH), 126.5 (CH), 127.6 (2 CH), 127.7 (CH), 128.0 (CH),
128.1 (2 CH), 128.7 (CH), 131.0 (CH), 133.1 (C), 133.2 (C), 133.4
(C), 137.3 (C), 157.1 (C), 172.9 (C) ppm. MS (EI, 70 eV): m/z (%)
= 345 (48) [M]+, 286 (10) [M – COOCH3]+, 240 (8) [M – COPh]+,
154 (52) [naphthyl-CH=CH2]+, 105 (100) [COPh]+, 77 (75) [Ph]+.
HRMS: calcd. for C22H19NO3 345.1365; found 345.1357; calcd. for
C20H16NO 286.1232; found 286.1220. C22H19NO3 (345.40): calcd.
C 76.50, H 5.54, N 4.06; found C 76.67, H 5.78, N 3.82.
Compound (؎)-20: Syrup. IR (CHCl ): ν = 3019, 1740, 1655,
˜
3
1484 cm–1. H NMR (500 MHz, CDCl3, 26 °C): δ = 2.64 (dd, J =
1
11.5, 13.7 Hz, 1 H, 5-Ha), 3.20 (dd, J = 4.7, 13.7 Hz, 1 H, 5-Hb),
3.81 (s, 3 H, OMe), 4.18 (dd, J = 4.6, 11.4 Hz, 1 H, 4-H), 7.30–
7.55 (m, 14 H, Ar), 8.23 (d, J = 7.2 Hz, 2 H, Ar) ppm. 13C NMR
(125.7 MHz, CDCl3, 26 °C): δ = 34.6 (CH2), 52.4 (CH3), 54.2 (CH),
82.0 (C), 125.3 (2 CH), 125.7 (2 CH), 127.7 (2 CH), 127.9 (CH),
128.0 (CH), 128.3 (2 CH), 128.5 (2 CH), 129.0 (2 CH), 131.2 (CH),
142.8 (C), 144.0 (C), 155.8 (C), 172.7 (C) ppm. MS (EI, 70 eV): m/z
(%) = 371 (6) [M]+, 312 (19) [M – COOCH3]+, 266 (66)
[M – COPh]+, 191 (64) [M – Ph2C=CH2]+, 180 (52) [Ph2C=CH2]+,
105 (100) [COPh]+, 77 (44) [Ph]+. HRMS: calcd. for C24H21NO3
371.1521; found 371.1515; calcd. for C7H5O 105.0340; found
105.0341. C24H21NO3 (371.44): calcd. C 77.61, H 5.70, N 3.77;
found C 77.56, H 5.74, N 3.62.
Synthesis of Methyl (4R*,4aR*,9bS*)-2-Phenyl-4,4a,5,9b-tetra-
hydroindeno[2,1-e][1,3]oxazine-4-carboxylate [(؎)-18] and its
(4S*,4aR*,9bS*) Isomer (؎)-19: Obtained from serine derivative 1
according to the general procedure using indene as the nucleophile
and BF3·OEt2 as the Lewis acid. After the usual work-up and puri-
fication, the procedure yielded compounds (؎)-18 (42%) and (؎)-
19 (31%).
Vinyl Glycine (؎)-21: White solid, m.p. 168–169 °C (neat). IR
(CHCl ): ν = 3439, 3020, 1740, 1665, 1510 cm–1. 1H NMR
˜
3
(500 MHz, CDCl3, 26 °C): δ = 3.73 (s, 3 H, OMe), 5.25 (dd, J =
6.7, 9.6 Hz, 1 H, 2-H), 5.98 (d, J = 9.6 Hz, 1 H, 3-H), 6.69 (d, J =
6.6 Hz, 1 H, NH), 7.14–7.23 (m, 5 H, Ar), 7.27–7.37 (m, 7 H, Ar),
7.42 (dd, J = 7.5, 7.6 Hz, 1 H, Ar), 7.66 (d, J = 7.2 Hz, 2 H,
Ar) ppm. 13C NMR (125.7 MHz, CDCl3, 26 °C): δ = 52.8 (CH3),
53.1 (CH), 121.7 (CH), 127.2 (2 CH), 127.6 (2 CH), 128.0 (CH),
128.2 (CH), 128.3 (2 CH), 128.5 (2 CH), 128.6 (2 CH), 129.8 (2
CH), 131.8 (CH), 133.8 (C), 138.5 (C), 141.3 (C), 147.8 (C), 166.5
(C), 171.8 (C) ppm. MS (EI, 70 eV): m/z (%) = 371 (11) [M]+, 339
(13) [M –CH3OH]+, 266 (86) [M – COPh]+, 191 (82) [M –
Ph2C=CH2]+, 105 (100) [COPh]+, 77 (59) [Ph]+. HRMS: calcd. for
C24H21NO3 371.1521; found 371.1522; calcd. for C17H16NO2
266.1181; found 266.1190; calcd. for C7H5O 105.0340; found
105.0340. C24H21NO3 (371.44): calcd. C 77.61, H 5.70, N 3.77;
found C 77.57, H 5.58, N 3.81.
Compound (؎)-18: White solid, m.p. 161–162 °C (neat). IR
1
(CHCl ): ν = 3013, 1732, 1650 cm–1. H NMR (500 MHz, CDCl ,
˜
3
3
26 °C): δ = 2.92 (dd, J = 8.0, 16.1 Hz, 1 H, 5-Ha), 3.04 (dd, J =
9.4, 16.1 Hz, 1 H, 5-Hb), 3.36 (m, 1 H, 4a-H), 3.86 (s, 3 H, OMe),
4.68 (d, J = 4.9 Hz, 1 H, 4-H), 5.68 (d, J = 6.2 Hz, 1 H, 9b-H),
7.24 (d, J = 7.1 Hz, 1 H, Ar), 7.28–7.34 (m, 4 H, Ar), 7.37 (dd, J
= 7.4, 7.4 Hz, 1 H, Ar), 7.57 (d, J = 6.7 Hz, 1 H, Ar), 7.88 (d, J =
7.1 Hz, 2 H, Ar) ppm. 13C NMR (125.7 MHz, CDCl3, 26 °C): δ =
31.9 (CH2), 39.1 (CH), 52.3 (CH3), 55.9 (CH), 80.7 (CH), 125.3
(CH), 125.6 (CH), 127.1 (CH), 127.5 (2 CH), 127.9 (2 CH), 129.9
(CH), 130.7 (CH), 133.3 (C), 140.8 (C), 144.0 (C), 158.4 (C), 172.4
(C) ppm. MS (EI, 70 eV): m/z (%) = 307 (6) [M]+, 276 (4) [M –
CH3O]+, 203 (7) [M + H – COPh]+, 202 (24) [M – COPh]+, 105
(100) [COPh]+, 77 (47) [Ph]+. HRMS: calcd. for C19H17NO3
307.1208; found 307.1197; calcd. for C12H13NO2 203.0946; found
203.0947. C19H17NO3 (307.35): calcd. C 74.25, H 5.58, N 4.56;
found C 74.37, H 5.71, N 4.48.
Synthesis of (1R,2S,3R)-3-(Formyloxy)-1-[(R)-2-methyl-6,6-di-
phenyl-5,6-dihydro-4H-1,3-oxazin-4-yl]butane-1,2,4-triyl Triacetate
(25) and (1R,2S,3R)-3-(Formyloxy)-1-[(S)-2-methyl-6,6-diphenyl-
5,6-dihydro-4H–1,3-oxazin-4-yl]butane-1,2,4-triyl Triacetate (26):
2,3,4,6-Tetraacetylated glucosamine 22 (200 mg, 0.58 mmol) under-
went the scission/oxidation/alkylation/cyclization procedure de-
scribed above to afford products 25 (32 mg, 11%) and 26 (158 mg,
54%) as colourless oils.
Compound (؎)-19: Syrup. IR (CHCl ): ν = 3020, 1740, 1664 cm–1.
˜
3
1H NMR (500 MHz, CDCl3, 26 °C): δ = 2.97 (m, 1 H, 4a-H), 3.03
(dd, J = 5.1, 15.9 Hz, 1 H, 5-Ha), 3.17 (dd, J = 6.9, 15.8 Hz, 1 H, Compound 25: White solid, decomposition on heating. [α]D = –3.6
5-Hb), 3.86 (s, 3 H, OMe), 4.10 (d, J = 6.2 Hz, 1 H, 4-H), 5.73 (d,
J = 6.4 Hz, 1 H, 9b-H), 7.28–7.34 (m, 3 H, Ar), 7.37 (dd, J = 7.2,
7.9 Hz, 2 H, Ar), 7.43 (dd, J = 7.2, 7.4 Hz, 1 H, Ar), 7.53 (d, J =
7.2 Hz, 1 H, Ar), 8.00 (d, J = 7.2 Hz, 2 H, Ar) ppm. 13C NMR
(c = 0.007, CHCl ). IR (CHCl ): ν = 3024, 1739, 1677 cm–1. 1H
˜
3 3
NMR (500 MHz, CDCl3 with TMS, 26 °C): δ = 1.94 (s, 3 H, Me),
2.02 (s, 3 H, Ac), 2.05 (m, 1 H, 5-Ha), 2.10 (br. s, 3 H, Ac), 2.11
(s, 3 H, Ac), 2.66 (dd, J = 4.1, 13.5 Hz, 1 H, 5-Hb), 3.17 (m, 1 H,
(125.7 MHz, CDCl3, 26 °C): δ = 34.8 (CH2), 37.4 (CH), 52.4 (CH3), 4-H), 4.14 (dd, J = 7.0, 12.4 Hz, 1 H, 4Ј-Ha), 4.33 (dd, J = 2.9,
57.0 (CH), 78.7 (CH), 124.9 (CH), 125.5 (CH), 127.2 (CH), 127.5 12.3 Hz, 1 H, 4Ј-Hb), 5.04 (dd, J = 3.8, 8.4 Hz, 1 H, 1Ј-H), 5.36
Eur. J. Org. Chem. 2012, 391–397
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
395

A. Boto, J. A. Gallardo, E. Álvarez
FULL PAPER
(dddd, J = 0.8, 2.8, 7.0, 7.0 Hz, 1 H, 3Ј-H), 5.68 (dd, J = 3.8,
2711.1(6) Å3, Z = 4, ρcalcd. = 1.288 gcm–3, F(000) = 1112, μ =
6.8 Hz, 1 H, 2Ј-H), 7.26–7.35 (m, 10 H, Ar), 7.99 (s, 1 H, 0.096 mm–1. Measured reflections 24978, of which 3059 were
CHO) ppm. 13C NMR (125.7 MHz): δC = 20.5 (CH3), 20.7 (CH3), unique (Rint = 0.0393). The asymmetric unit of the structure is
20.9 (CH3), 21.9 (CH3), 33.9 (CH2), 50.3 (CH), 62.1 (CH2), 68.9 formed by one molecule of 27. Because of a large standard uncer-
(CH), 69.4 (CH), 73.3 (CH), 81.5 (C), 125.4 (2 CH), 125.7 (2 CH), tainty on the Flack parameter, the Friedel pairs were averaged in
127.6 (CH), 127.8 (CH), 128.4 (2 CH), 128.8 (2 CH), 143.2 (C),
144.4 (C), 159.8 (C), 169.6 (C), 170.3 (C), 170.4 (C) ppm. MS (EI,
the refinement (MERG 4 command). Thereby the absolute config-
uration of the new chiral centres were assigned by reference to
70 eV): m/z (%) = 466 (14) [M + H – AcO]+, 250 (30) [N-(3,3- other unchanging chiral centres of known absolute configuration
diphenylallylidene)acetamide + H] +, 191 (100) [N-(3,3-diphenyl-
allylidene)acetamide – NHAc]+. HRMS: calcd. for C26H28NO7
466.1866; found 466.1851; calcd. for C17H16NO 250.1232; found
250.1231.
in the synthetic procedure. Refined parameters 350, final R1
0.0373, for reflections with IϾ2σ(I), wR2 = 0.1040 (all data), GOF
=
=
1.059. Max./min. residual electron density +0.380/
–0.247 eÅ–3.
CCDC-841914 (for 16) and -783576 (for 27) contain the crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Compound 26: White solid, decomposition on heating. [α]D = –4.1
(c = 0.17, CHCl ). IR (CHCl ): ν = 3024, 1733, 1679 cm–1. 1H
˜
3
3
NMR (500 MHz, CDCl3 with TMS, 26 °C): δ = 2.00 (s, 3 H, Me),
2.04 (s, 3 H, Ac), 2.06 (m, 1 H, 5-Ha), 2.10 (br. s, 6 H, Ac 2), 2.88
(dd, J = 2.6, 13.3 Hz, 1 H, 5-Hb), 3.11 (m, 1 H, 4-H), 4.15 (dd, J
= 5.4, 12.6 Hz, 1 H, 4Ј-Ha), 4.27 (dd, J = 2.7, 12.6 Hz, 1 H, 4Ј-
Hb), 5.08 (dd, J = 2.8, 8.5 Hz, 1 H, 1Ј-H), 5.28 (ddd, J = 2.6, 5.6,
7.8 Hz, 1 H, 3Ј-H), 5.54 (dd, J = 2.7, 8.0 Hz, 1 H, 2Ј-H), 7.23–7.28
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of new compounds 12–21, 25–27,
ORTEP representations of the X-ray structures of oxazine 16 and
amine 27.
(m, 4 H, Ar), 7.29–7.34 (m, 6 H, Ar), 7.96 (s, 1 H, CHO) ppm. 13
C
NMR (125.7 MHz, CDCl3, 26 °C): δ = 20.6 (2 CH3), 20.9 (CH3),
22.0 (CH3), 34.0 (CH2), 50.2 (CH), 61.7 (CH2), 68.2 (CH), 68.7
(CH), 72.6 (CH), 81.2 (C), 125.4 (2 CH), 125.6 (2 CH), 127.6 (CH),
127.8 (CH), 128.4 (2 CH), 128.8 (2 CH), 143.0 (C), 144.3 (C), 157.2
(C), 159.5 (C), 170.0 (C), 170.5 (C) ppm. MS (EI, 70 eV): m/z (%)
= 527 (Ͻ1), [M + 2H]+, 480 (4) [M – OCHO]+, 466 (15) [M –
AcO]+, 250 (31) [N-(3,3-diphenylallylidene)acetamide + H]+, 191
(100) [N-(3,3-diphenylallylidene)acetamide – NHAc]+. HRMS:
calcd. for C28H33NO9 527.2155; found 527.2136; calcd. for
C17H16NO 250.1232; found 250.1238.
Acknowledgments
This work was supported by the Plan Nacional de Investigación
Científica, Desarrollo e Innovación Tecnológica of the Ministerio
de Ciencia e Innovación (MICINN), Spain (Investigation Program
CTQ2009-07109). We also acknowledge financial support from
from FEDER funds (European Funds for Regional Development).
J. A. G. thanks the Consejo Superior de Investigaciones Científicas
(CSIC) for his Junta de Ampliación de Estudios (JAE) postdoc-
toral contract.
Ring-Opening of Oxazine 26 and Formation of (2R,3S,4R,5S)-5-
Acetamido-2-(formyloxy)-7,7-diphenylhept-6-ene-1,3,4-triyl Triace-
tate (27): Oxazine 26 (50 mg, 0.1 mmol) was dissolved in CHCl3
(2 mL) and heated at 60 °C for 1 h to afford amine 27 (50 mg,
Ͼ99%) as a crystalline white solid (m.p. 208–209 °C, from dryness):
[1] a) D. B. Ramachary, S. Jain, Org. Biomol. Chem. 2011, 9, 1277–
1300; b) D. Enders, C. Grondal, M. R. M. Hüttl, Angew. Chem.
2007, 119, 1590–1601; Angew. Chem. Int. Ed. 2007, 46, 1570–
1581; c) L. F. Tietze, G. Brasche, K. Gericke, Domino Reactions
in Organic Synthesis, Wiley-VCH, Weinheim, 2006; d) K. C.
Nicolaou, D. J. Edmons, P. G. Bulger, Angew. Chem. 2006, 118,
7292–7344; Angew. Chem. Int. Ed. 2006, 45, 7134–7186; e) H.
Pellissier, Tetrahedron 2006, 62, 1619–1665 (Part A); H. Pelliss-
ier, Tetrahedron 2006, 62, 2143–2173 (Part B), and references
cited therein.
[2] a) A. Boto, I. Romero-Estudillo, Org. Lett. 2011, 13, 3426–
3429; b) A. Boto, D. Hernández, R. Hernández, Eur. J. Org.
Chem. 2010, 6633–6642; c) A. Boto, D. Hernández, R.
Hernández, Eur. J. Org. Chem. 2010, 3847–3857; d) A. Boto,
R. Hernandez, C. Saavedra, Synlett 2010, 659–663; e) C. Saa-
vedra, R. Hernandez, A. Boto, E. Alvarez, J. Org. Chem. 2009,
74, 4655–4665; f) A. Boto, D. Hernández, R. Hernández, E.
Alvarez, Eur. J. Org. Chem. 2009, 3853–3857; g) A. Boto, D.
Hernández, R. Hernández, Tetrahedron Lett. 2008, 49, 455–
458; h) A. Boto, D. Hernández, R. Hernández, A. Montoya,
E. Suárez, Eur. J. Org. Chem. 2007, 325–334; i) A. Boto, D.
Hernández, R. Hernández, Org. Lett. 2007, 9, 1721–1724; j) A.
Boto, D. Hernández, R. Hernández, E. Álvarez, J. Org. Chem.
2007, 72, 9523–9532; k) A. Boto, J. A. Gallardo, D. Hernández,
R. Hernández, J. Org. Chem. 2007, 72, 7260–7269; l) for a re-
view on the modification of amino acids and carbohydrates by
radical chemistry, see: S. G. Hansen, T. Skrydstrup, Top. Curr.
Chem. 2006, 264, 135–162.
[α]D = –45.3 (c = 0.006, CHCl ). IR (CHCl ): ν = 3434, 3022, 1742,
˜
3
3
1679 cm–1. 1H NMR (500 MHz, CDCl3 with TMS, 26 °C): δ = 1.71
(s, 3 H, Ac), 1.88 (s, 3 H, Ac), 1.96 (s, 3 H, Ac), 2.01 (s, 3 H, Ac),
3.91 (dd, J = 3.2, 12.6 Hz, 1 H, 1-Ha), 3.99 (dd, J = 6.6, 12.3 Hz,
1 H, 1-Hb), 4.96 (ddd, J = 6.8, 9.2, 9.2 Hz, 1 H, CHN), 5.09 (m, 1
H, 2-H), 5.11 (dd, J = 4.4, 6.9 Hz, 1 H, 4-H), 5.26 (dd, J = 4.3,
6.5 Hz, 1 H, 3-H), 5.68 (d, J = 9.1 Hz, 1 H, 6-H), 5.80 (d, J =
9.1 Hz, 1 H, NH), 7.08–7.10 (m, 2 H, Ar), 7.15–7.21 (m, 5 H, Ar),
7.24 (dd, J = 7.6, 7.6 Hz, 1 H, Ar), 7.31 (dd, J = 7.6, 7.6 Hz, 2 H,
Ar), 7.80 (s, 1 H, CHO) ppm. 13C NMR (125.7 MHz, CDCl3,
26 °C): δ = 20.3 (CH3), 20.5 (CH3), 20.6 (CH3), 23.2 (CH3), 48.9
(CH), 61.5 (CH2), 68.9 (CH), 69.0 (CH), 72.9 (CH), 122.8 (CH),
127.6 (2 CH), 127.8 (CH), 128.0 (CH), 128.2 (2 CH), 128.4 (2 CH),
129.8 (2 CH), 138.2 (C), 141.8 (C), 146.8 (C), 159.5 (C), 169.0 (C),
169.6 (C), 170.3 (C), 170.4 (C) ppm. MS (EI, 70 eV): m/z (%) =
525 (Ͻ1) [M]+, 191 (100) [N-(3,3-diphenylallylidene)acetamide –
NHAc]+. HRMS: calcd. for C28H31NO9 525.1999; found 525.2004;
calcd. for C15H11 191.0861; found 191.0860.
X-ray Analysis: C28H31NO9, Mr = 525.54. A single colourless nee-
dle crystal (0.31ϫ 0.24ϫ 0.16 mm3) from EtOAc/n-hexane coated
with dry perfluoropolyether was mounted on a glass fiber and fixed
to the goniometer head in a stream of cold nitrogen [T = 173(2) K].
Data collection was performed with a Bruker–Nonius X8APEX-II
CCD diffractometer using monochromatic radiation [λ(Mo-Kα1) =
0.71073 Å] and ω and φ scans. Orthorhombic, space group P212121
(no. 19), a = 9.3895(13), b = 14.956(2), c = 19.305(2) Å, V =
[3] For reviews on other methods of coupling radical and ionic
reactions, see: a) E. Godineau, Y. Landais, Chem. Eur. J. 2009,
15, 3044–3055; b) J.-i. Yoshida, K. Kataoka, R. Horcajada, A.
Nagaki, Chem. Rev. 2008, 108, 2265–2299; c) J. P. Ebran, C. M.
Jensen, S. A. Johannesen, J. Karaffa, K. B. Lindsay, R. Taan-
396
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 391–397

Oxazine Derivatives of γ-Aryl-γ-(hydroxy)amines
ing, T. Skrydstrup, Org. Biomol. Chem. 2006, 4, 3553–3564; d)
I. Ryu, Chem. Soc. Rev. 2001, 30, 16–25; e) J. A. Murphy, Pure
Appl. Chem. 2000, 72, 1327–1334; f) J. Utley, Chem. Soc. Rev.
1997, 26, 157–167.
Dai, Tetrahedron 1993, 49, 3907–3918; b) for reviews on the
addition of nucleophiles to iminium ions, see: A. Yazici, S. G.
Pyne, Synthesis 2009, 339–368 (Part I) and A. Yazici, S. G.
Pyne, Synthesis 2009, 513–541 (Part 2); c) D. Ferraris, Tetrahe-
dron 2007, 63, 9581–9597; d) G. K. Friestad, A. K. Mathies,
Tetrahedron 2007, 63, 2541–2569; e) S. E. Schaus, A. Ting, Eur.
J. Org. Chem. 2007, 5797–5815; f) M. Petrini, E. Torregiani,
Synthesis 2007, 159–186; g) M. Petrini, Chem. Rev. 2005, 105,
3949–3977; h) J. Royer, M. Bonin, L. Micouin, Chem. Rev.
2004, 104, 2311–2352; i) B. E. Maryanoff, H. C. Zhang, J. H.
Cohen, I. J. Turchi, C. A. Maryanoff, Chem. Rev. 2004, 104,
1431–1628.
[4] a) L. Lazar, F. Fülop, “1,3-Oxazines and their Benzo Deriva-
tives” in Comprehensive Heterocyclic Chemistry (Eds.: A. R.
Katritzky, C. A. Ramsden, E. F. V. Scriven, R. J. K. Taylor), El-
sevier, Oxford, 2008, vol. 3, pp. 373–459; b) M. Sainsbury, “1,3-
Oxazines and their Benzo Derivatives” in Comprehensive Het-
erocyclic Chemistry II (Eds.: A. R. Katritzky, C. W. Rees,
E. F. V. Scriven), Pergamon Press, Oxford, 1996, pp. 301–348;
c) S. M. Lukyanov, Adv. Heterocycl. Chem. 1995, 64, 341–368;
d) for articles with a summary of the synthesis and applications
of 5,6-dihydro-4H-1,3-oxazines, see: I. Mohammadpoor-Bal-
tork, M. Moghadam, S. Tangestaninejad, V. Mirkhani, Z. Es-
kandari, Ultrason. Sonochem. 2010, 17, 857–862; e) P. Wipf,
G. B. Hayes, Tetrahedron 1998, 54, 6987–6998.
[5] For recent syntheses of oxazines, see: a) A. S. K. Hashmi,
A. M. Schuster, S. Litters, F. Rominger, M. Pernpointner,
Chem. Eur. J. 2011, 17, 5661–5667; b) A. S. K. Hashmi, A. M.
Schuster, M. Zimmer, F. Rominger, Chem. Eur. J. 2011, 17,
5511–5515; c) I. Mohammadpoor-Baltork, M. Moghadam, S.
Tangestaninejad, V. Mirkhani, Z. Eskandari, J. Heterocycl.
Chem. 2011, 48, 479–483; d) M. Sugiura, M. Kumahara, M.
Nakajima, Chem. Commun. 2009, 3585–3587; e) F. Shibahara,
A. Yoshida, T. Murai, Chem. Lett. 2008, 37, 646–647; f) J. E.
Joo, K. Y. Lee, V. T. Pham, W. H. Ham, Eur. J. Org. Chem.
2007, 1586–1593; g) for other syntheses, see: Y. Zhu, S. Huang,
J. Wan, L. Yan, Y. Pan, A. Wu, Org. Lett. 2006, 8, 2599–2602;
h) T. Murai, H. Sano, H. Kawai, H. Aso, F. Shibahara, J. Org.
Chem. 2005, 70, 8148–8153; i) O. V. Singh, D. J. Kampf, H.
Han, Tetrahedron Lett. 2004, 45, 7239–7242; j) M. A. Mitchell,
B. C. Benicewicz, Synthesis 1994, 675–677.
[11]
In the NOESY experiment of the major isomer 18, spatial in-
teractions between 9b-H (δH = 5.68 ppm) and 4-H (δH
=
4.68 ppm) were observed. The NOESY experiment for the
minor isomer 19 displayed spatial correlations between the
methoxy group protons and the 4a-H (δH = 2.97 ppm). In ad-
dition, 9a-H (δH = 5.68 ppm) showed a stronger correlation
with 5-Hb (δH = 3.36 ppm) than with 5-Ha (δH = 3.03 ppm)
whereas the opposite was true for 4-H (δH = 4.10 ppm; 4-H/5-
Ha stronger than 4-H/5-Hb), which suggests that 9a-H and 4-
H have a trans relationship. Thus, compound 18 was assigned
as 4,4a-cis/4a,9a-cis and compound 19 was assigned as 4,4a-
trans/4a,9a-cis.
The experimental coupling constants for compounds 18 and 19
were compared with theoretical values, which were calculated
for the minimum-energy conformations of all the possible dia-
stereomers. The calculations were carried out by using Maestro
9.2 (Schrödinger, LLC) and the OPLS and MMFF force fields,
which gave similar results. Thus, for the 4a,9b-cis and the
4a,9b-trans diastereomers, the theoretical coupling constants
(MMFF) are J4a,9b = 7.3 and 9.5 Hz, respectively. The values
for the 4a,9b-cis diastereomers match better the experimental
results (J4a,9b = 6.2–6.4 Hz); for these diastereomers, the theo-
retical coupling constants for the 4,4a-cis and 4,4a-trans dia-
stereomers are J4,4a = 4.5 and 11.5 Hz, respectively. Because
[12]
[6] a) S. Ihmaid, J. Al-Rawi, C. Bradley, M. J. Angove, M. N. Rob-
ertson, R. L. Clark, Bioorg. Med. Chem. 2011, 19, 3983–3994;
b) Y. Tabuchi, Y. Ando, H. Kanemura, I. Kawasaki, T. Ohishi,
M. Koida, R. Fukuyama, H. Nakamuta, S. Ohta, K. Nishide,
Y. Ohishi, Bioorg. Med. Chem. 2009, 17, 3959–3967.
compounds 18 and 19 display experimental values of J4,4a
=
4.9 and 6.5 Hz, compound 18 was assigned as the 4,4a-cis iso-
mer, and compound 19 as the 4,4a-trans isomer. These results
match the data obtained in the NOESY experiments (see
ref.[11]).
[7] a) C. M. Kim, J. H. Youn, Tetrahedron Lett. 1999, 40, 3581–
3582; b) L. Grigorieva, A. Jirgensons, Eur. J. Org. Chem. 2011,
2421–2425; c) T. S. Kim, Y. J. Lee, K. Lee, B. S. Jeong, H. Park,
S. Jew, Synlett 2009, 671–674; d) O. V. Singh, H. Han, Tetrahe-
dron Lett. 2007, 48, 2345–2348; e) O. V. Singh, D. J. Kampf, H.
Han, Tetrahedron Lett. 2004, 45, 7239–7242; f) Á. Balázs, Z.
Szakonyi, F. Fülöp, J. Heterocycl. Chem. 2007, 44, 403–406; g)
A. I. Meyers, N. Nazarenko, J. Org. Chem. 1978, 58, 175–176.
[8] For the extensive work by Meyers and others on the synthesis
and applications of oxazolines, see: a) D. Savoia, C. Trombini,
A. Umani-Ronchi, J. Org. Chem. 1978, 43, 2907–2910; b) T. A.
Nawid, A. I. Meyers, J. Org. Chem. 1974, 39, 2572–2574; c)
A. I. Meyers, E. M. Smith, M. S. Ao, J. Org. Chem. 1973, 38,
2129–2133; d) A. I. Meyers, E. M. Smith, A. F. Jurjevich, J.
Am. Chem. Soc. 1971, 93, 2314–2316; e) A. I. Meyers, A. Nab-
eya, H. W. Adickes, I. R. Politzer, J. Am. Chem. Soc. 1969, 91,
763–764; f) A. I. Meyers, A. Nabeya, H. W. Adickes, R. Ma-
lone, I. R. Politzer, J. Am. Chem. Soc. 1969, 91, 764–765.
[9] The C radical 2 reacts with iodine to give an unstable α-
iodoamine, which evolves to give acyliminium ion 3. This inter-
mediate is in equilibrium with N,O-acetal 4. A. Boto, R.
Hernández, Y. León, J. R. Murguía, A. Rodríguez-Afonso, Eur.
J. Org. Chem. 2005, 673–682.
[13] For studies on the mechanism and stereoselectivity of related
cyclization steps, see: a) V. T. Pham, J. E. Joo, K. Y. Lee, T. W.
Kim, Y. Mu, W. H. Ham, Tetrahedron 2010, 66, 2123–2131; b)
I. D. Gridnev, A. V. Shastin, E. S. Balenkova, Tetrahedron
1991, 47, 5577–5584; c) for conformational analysis of substi-
tuted 5,6-dihydro-4H-1,3-oxazines, see: A. R. Katritzky, I. Ghi-
viriga, K. Chen, D. O. Tymoshenko, A. A. A. Abdel-Fattah, J.
Chem. Soc. Perkin Trans. 2 2001, 530–537; d) A. R. Katritzky,
I. V. Shcherbakova, B. Mancheño, R. D. Tack, Magn. Reson.
Chem. 1993, 31, 615–620; e) G. Stájer, A. E. Szabó, S. Frim-
pong-Manso, G. Bernáth, P. Sohár, Tetrahedron 1990, 46,
6859–6868.
[14] For the synthesis and synthetic uses of allylamines, see: a) I. S.
Kim, O. P. Zee, Y. H. Jung, Org. Lett. 2006, 8, 4101–4104; b)
A. G. Jamieson, A. Sutherland, Org. Lett. 2007, 9, 1609–1611;
c) M. Barbazanges, C. Meyer, J. Cossy, Org. Lett. 2007, 9,
3245–3248; d) M. Takahashi, T. Maehara, T. Sengoku, N. Fu-
jita, K. Takabe, H. Yoda, Tetrahedron 2008, 64, 5254–5261; e)
M. D. Swift, A. Sutherland, Tetrahedron 2008, 64, 9521–9527
Received: August 31, 2011
[10] For the addition of alkenes to iminium ions to give oxazines,
see: a) A. R. Katritzky, I. V. Shcherbakova, R. D. Tack, X. Q.
Published Online: November 9, 2011
Eur. J. Org. Chem. 2012, 391–397
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
397