Highly stereoselective and flexible synthesis of 6-alkoxy-5,6-dihydro-4h-1,2-oxazines by conjugate addition of organolithium compounds to 6h-1,2-oxazines followed by trapping with electrophiles

Article abstract of DOI:10.1055/s-2002-33107

Conjugate additions of reactive organolithium compounds such as phenyllithium, n-butyllithium, tert-butyllithium, and 2-propenyllithium to 6H-1,2-oxazines 1, 24, and 25 followed by trapping of the intermediates with electrophiles gave a variety of highly substituted 6-alkoxy-5,6-dihydro-4H-1,2-oxazines 2-15 and 27-30 generally in very good yields. Most interestingly, this reaction sequence proceeds with high stereocontrol producing in large excess or exclusively the trans, trans-diastereomers. Using benzaldehyde as the electrophile, only compound 8, which is one of eight possible diastereomers, was formed. Methyllithium or lithiated methoxyallene as the nucleophilic component provide expected addition products 17 and 19, but formation of bis-1,2-oxazines 18 and 20 seems to be inevitable with these less reactive organolithium compounds.

Full text of DOI:10.1055/s-2002-33107

1412
PAPER
Highly Stereoselective and Flexible Synthesis of 6-Alkoxy-5,6-dihydro-4H-1,2-
oxazines by Conjugate Addition of Organolithium Compounds to 6H-1,2-
Oxazines Followed by Trapping with Electrophiles
Synthesis of
Oxazine
D
o
erivatives nika Buchholz, Hans-Ulrich Reissig*
Freie Universität Berlin, Institut für Chemie - Organische Chemie, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 19 March 2002
Abstract: Conjugate additions of reactive organolithium com-
pounds such as phenyllithium, n-butyllithium, tert-butyllithium,
and 2-propenyllithium to 6H-1,2-oxazines 1, 24, and 25 followed
by trapping of the intermediates with electrophiles gave a variety of
highly substituted 6-alkoxy-5,6-dihydro-4H-1,2-oxazines 2 15 and
27 30 generally in very good yields. Most interestingly, this reac-
tion sequence proceeds with high stereocontrol producing in large
Scheme 1
excess or exclusively the trans,trans-diastereomers. Using benzal-
dehyde as the electrophile, only compound 8, which is one of eight
possible diastereomers, was formed. Methyllithium or lithiated
this precursor at –78 °C (Scheme 2) followed by quench-
methoxyallene as the nucleophilic component provide expected ad-
dition products 17 and 19, but formation of bis-1,2-oxazines 18 and
20 seems to be inevitable with these less reactive organolithium
compounds.
ing the mixture with water provided the expected addition
product 2 as pure trans-diastereomer in excellent yield
(Table 1, entry 1). When the solution of intermediate, 4-
lithiated 1,2-oxazine was treated with methyl iodide, the
resulting adduct 3 was again formed as single isomer. In
accordance with our former results and confirmed by
NMR spectroscopy the configuration of 3 was assigned to
be 4,5-trans, 5,6-trans (Table 1, entry 2).
Key Words: asymmetric synthesis, conjugate addition, organolith-
ium compounds, 1,2-oxazines, alkylation
6
For systematic investigations of reductive conversions1
of 6-alkoxy-5,6-dihydro-4H-1,2-oxazines B into highly
substituted pyrrolidine derivatives C, we required the pre-
cursor heterocycles B with a variety of different substitu-
ents at C-4 and C-5. For this purpose, addition reactions to
the C C double bond of the , -unsaturated oxime ether
moiety incorporated in 6H-1,2-oxazines A seem to be
7
most suitable. Thus, dihydroxylations,5
epoxida-
tions,8 10 addition of oxygen or nitrogen nucleophiles8
as well as 1,3-dipolar cycloadditions11 have successfully
been performed. In this report, we extend our earlier de-
scribed method12 which employs conjugate addition of or-
ganolithium compounds to A and trapping of the
intermediate 4-lithiated 1,2-oxazine by electrophiles
(Scheme 1). Whereas in our preliminary publication only
protons (or deuterons) and reactive alkyl halides were
used as electrophilic components, we now expand our ex-
periments to a variety of electrophiles. In addition, we
10
Scheme 2
Similar results were obtained when dimethyl disulfide, an
present results illustrating the effect of the attacking orga- electrophilic fluorine reagent, oxygen and an azo ester
nolithium compound and also that of different substitu- were employed as electrophiles (Table 1, entries 3 to 6).
ents R2 at C-3 of precursor A on the outcome of this In all cases only the trans,trans-diastereomers of 4–7
reaction sequence.
were detected. These transformations thus allowed
straightforward syntheses of 1,2-oxazines with heteroat-
oms at C-4. Although hydroxylation with molecular oxy-
gen provided compound 6 in 40% yield only we did not
attempt to improve the oxygenation process by use of al-
ternative electrophilic reagents. The reaction with benzal-
dehyde as electrophile is remarkable (Table 1, entry 7)
since out of eight possible diastereomers, only one was
isolated in excellent yield. The configuration of 8 has un-
ambiguously been determined by an X-ray analysis13 and
Standard 6H-1,2-oxazine 1 is easily accessible by hetero
Diels–Alder reaction involving a highly reactive -nitro-
sostyrene as intermediate.10 Addition of phenyllithium to
Synthesis 2002, No. 10, 30 07 2002. Article Identifier:
1437-210X,E;2002,0,10,1412,1422,ftx,en;T02802SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Stereoselective and Flexible Synthesis of 6-Alkoxy-5,6-dihydro-4H-1,2-oxazines
1413
lent yield but slightly diminished diastereoselectivity
(dr = 92: 8, Table 1, entry 9). We assume that the minor
diastereomer is formed by subsequent isomerization of
the primarily formed trans,trans-isomer and thus is likely
to have 4,5-cis, 5,6-trans configuration.
Table 1 Synthesis of Substituted 3-Phenyl-5,6-dihydro-4H-1,2-ox-
azines 2 15
En- R
try
ElX
Prod- El
uct
Yield dr
(%)
1
2
3
4
5
6
Ph
H2O
2
3
4
5
6
7
H
89
70
73
73
40
95:5
95:5
95:5
95:5
95:5
95:5
For an anticipated synthesis of the endothelin antagonist
ABT-627,16 we required a 1,2-benzodioxol-5-yl substitu-
ent at C-5 of a 1,2-oxazine. Thus, we also studied the
model reaction of 1 with 1,2-benzodioxol-5-yllithium fol-
lowed by trapping with Mander´s reagent. Under opti-
mized conditions (30 equivalents of the acylating agent,
low temperature) we obtained the desired adduct 11 in
67% yield and a diastereomeric ratio of 87:13 (Table 1,
entry 10). The large excess of acylating agent traps the un-
reacted aryllithium species and thus prevents a subsequent
deprotonation of product 11. Using less electrophile and
warming up to room temperature led to formation of 11 in
35% and of N-acylated compound 16 (Scheme 2) in 20%
yield. The diacylated product is probably formed by
deprotonation of 11 by the excess of the aryllithium spe-
cies during warm-up and reaction with a second equiva-
lent of ethyl cyanoformate.
Ph
Ph
Ph
Ph
Ph
MeI
Me
SMe
F
MeSSMe
FN(SO2Ph)2
O2
OH
BocN=NBoc
BocN NH- 66
Boc
7
8
9
Ph
Ph
Ph
PhCHO
8
9
PhCHOH 86
95:5
95:5
ClCO2Bn
NCCO2Et
CO2Bn
34
86
67
10 CO2Et
11 CO2Et
92:8
10 1,2-Benzo- NCCO2Et
dioxol-5-yl
87:13
11 tert-Bu
12 n-Bu
NCCO2Et
12 CO2Et
73
44
82
83
95:5
95:5
95:5
95:5
We also investigated the conjugate addition reactions of
other organolithium compounds. In our preliminary
report12 we could show that n-butyllithium and sec-butyl-
lithium are very suitable nucleophilic components where-
as methyllithium gave an adduct only in disappointingly
low yield. Not surprisingly, we could introduce a tert-bu-
tyl group without difficulties by use of tert-butyllithium as
organolithium component (Table 1, entry 11). Also, the
known addition of n-butyllithium to 1 could be supple-
mented by an experiment where the intermediate was
trapped with the electrophilic fluorine reagent. The ex-
pected trans,trans-configurated 1,2-oxazine 13 was ob-
tained in moderate yield (Table 1, entry 12). An apt
nucleophile is 2-propenyllithium which allowed synthesis
of the new 1,2-oxazines 14 and 15 in good yield and with
the anticipated high trans,trans-selectivity (Table 1, en-
tries 13 and 14). Thus, these rather reactive organolithium
compounds behave as expected.
FN(SO2Ph)2
13
14
15
F
13 2-Propenyl EtOH
14 2-Propenyl
H
its formation can be explained by a chair-like transition
state D as illustrated in the Figure. This high selectivity
was unexpected since a related reaction of a lithiated 6-
bis(trimethylsilyl)amino substituted 1,2-oxazine with
benzaldehyde provided a 1:1 mixture of diastereomers
differing in the configuration of the exocyclic stereogenic
centre.14
In contrast, less nucleophilic species such as methyllithi-
um or lithiated methoxyallene17 provided the desired con-
jugate addition products 17 and 19, but these were
inevitably accompanied by bis-1,2-oxazines 18 and 20,
respectively, in approximately 20% yield (Scheme 3). We
explain this observation by relatively slow addition of less
reactive organolithium species to 1, and therefore the in-
termediate 4-lithiated 1,2-oxazines add to a second mole-
cule of precursor 1 to furnish the bisadducts. Even large
excesses of methyllithium or lithiated methoxyallene and
inverse addition (i.e. slow addition of 1 to the excess of the
organolithium compound) did not prevent formation of
these byproducts. Nevertheless, we could demonstrate
with these experiments that weakly nucleophilic organo-
lithium compounds may also be added to 1,2-oxazines
such as 1. The configurational relation between the stereo-
genic centres C-4 and C-5 , which connect the two 1,2-ox-
azine rings, could so far not been determined, however,
Figure
The introduction of a 4-alkoxycarbonyl substituent is
complicated by the possible isomerization of the products
by deprotonation/protonation (or tautomers via the enam-
ine structure) due to the high CH-acidity at C-4 of the re-
sulting products. Addition of phenyllithium to 1 and
trapping with benzyl chloroformate furnished the expect-
ed trans,trans-configurated adduct 9 although in low yield
(Table 1, entry 8). The efficiency could be drastically im-
proved using Mander’s reagent,15 ethyl cyanoformate,
which afforded tetrasubstituted 1,2-oxazine 10 in excel-
Synthesis 2002, No. 10, 1412–1422 ISSN 0039-7881 © Thieme Stuttgart · New York

1414
M. Buchholz, H.-U. Reissig
PAPER
Scheme 3
only one diastereomer of the sixteen possible isomers was 26 in small amounts. These two compounds could easily
detected. Bis-1,2-oxazines 18 and 20 are thus formed un- be separated by column chromatography.
der control of five stereogenic centres.
With these two new 1,2-oxazines in hand, we could inves-
Low chemoselectivity is an obvious limitation of our ap- tigate their behaviour towards organolithium compounds.
proach to highly substituted 5,6-dihydro-4H-1,2-oxazines The additions of phenyllithium to 1,2-oxazine 24 proceed-
B by addition of organolithium compounds to A. This se- ed with high diastereoselectivity affording 27 as trans-
quence does not allow the synthesis of heterocycles B isomer whereas 28 was formed in lower yield and pre-
bearing substituents at C-3 prone to react with organolith- dominating trans,trans-selectivity (Scheme 5). For 28, we
iums compounds. Thus, the desirable preparation of B again assume subsequent isomerization diminishing the
with 3-alkoxycarbonyl groups, whose reduction would initial diastereoselectivity of the addition process
3
lead to highly substituted proline derivatives,1 is not (Table 2, entries 1 and 2).
possible by this route. An attempt to add phenyllithium to
ester 21 resulted in formation of addition products to the
carbonyl group. Therefore, we converted the ethoxycar-
bonyl group of 21 into functionalities, which are unreac-
tive towards organolithium compounds. The preparation
of acetals 24 and 25, which are excellent candidates for
this purpose is described in Scheme 4. Reduction of 21
with diisobutylaluminum hydride provides aldehyde 22 in
very good yield, which can be further reduced to the alco-
hol 23. Acetalization of 23 occurs without event giving
1,2-oxazine 24 with reasonable overall efficiency. In con-
trast, conversion of aldehyde 22 into its acetal 25 was ac-
companied by formation of the conjugate addition product
Scheme 5
Scheme 4 Reaction Conditions: (i) DIBAL-H, THF, –50 °C, 2 h (ii) DIBAL-H, THF, –50 °C 1 h (iii) HC(OEt)3, H+, EtOH, r.t., 2 d (iv) 2-
methoxypropene, H+, THF, r.t., 2 h.
Synthesis 2002, No. 10, 1412–1422 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Stereoselective and Flexible Synthesis of 6-Alkoxy-5,6-dihydro-4H-1,2-oxazines
1415
Table 2 Synthesis of Substituted 5,6-Dihydro-4H-1,2-oxazines 27 30
Entry
1,2-Oxazine
R
ElX
Product
27
El
Yield (%)
dr
95:5
1
2
3
4
24
24
25
25
Ph
H2O
H
71
27
79a
58
Ph
NCCO2Et
28
CO2Et
87:13
95:5
2-propenyl
n-Bu
29
FN(SO2Ph)2
30
F
50:50
a Compound 31 was isolated as side product (7 %).
Addition of 2-propenyllithium to acetal 25 followed by
trapping with allyl bromide furnished the expected tetra-
substituted 1,2-oxazine 29 in good yield and high diaste-
reoselectivity (Table 2, entry 3). However, for the first
time a small amount of the corresponding 1,2-addition
product 31 could be isolated, whose configuration was not
determined. Addition of n-butyllithium and subsequent
electrophilic fluorination provided 30 in moderate yield
and, rather surprisingly, completely without diastereose-
lectivity (Table 2, entry 4). We have no explanation so far
for this exceptional, but reproducible behaviour.
All reactions were performed under argon atmosphere in flame-
dried flasks by adding the components via syringes. All solvents
were dried using standard procedures. IR spectra were measured
with Perkin Elmer FT-IR spectrometer Nicolet 5 SXC. 1H and 13
C
NMR spectra were recorded on Bruker instruments (AC 500, WH
270, AC 250) in CDCl3 soln. The chemical shifts are given in rela-
tive to the TMS or to the CDCl3 signal ( H = 7.27, C =77.0). Higher
order NMR spectra were approximately interpreted as first-order
spectra if possible. Missing signals of minor isomers are hidden by
signals of major isomers, or they could not be unambiguously iden-
tified due to low intensity. The MS and HRMS spectra were record-
ed with a Varian MAT 771, MAT 112 S or Hewlett Packard HP
5890 (series II) instrument and an HP 5972 A MS-selective detector
or HP 5965 B IR-detector. Neutral alumina (activity III, Fluka/Mer-
ck) was used for column chromatography. Melting points (uncor-
rected) were measured with an Thermovar melting point
microscope from Reichert. Starting materials 1, 21,10 1,2-benzo-
dioxol-5-lithium20 and 2-propenyllithium21 were prepared by litera-
ture procedures. All other chemicals were commercially available
and were used as received.
In this report, we could demonstrate that the earlier
described12 conjugate addition of organolithium com-
pounds to 6H-1,2-oxazines A is a reaction with broad ap-
plicability.18 Different organolithium compounds can be
used and several groups R2 turned out to be suitable C-3
substituents at the 1,2-oxazine. The addition step always
occurs with very high trans-selectivity with respect to the
6-ethoxy group. Only for weaker nucleophilic organolith-
ium compounds such as methyllithium or lithiated meth-
oxyallene the conjugate addition is complicated by the
inevitable formation of bis-1,2-oxazines such as 18 and
20.
Substituted 3-Phenyl-5,6-dihydro-4H-1,2-oxazines 2–16; Gen-
eral Procedure
To a soln of the corresponding organolithium compound (2.2 equiv)
in THF (10 mL/mmol of 1,2-oxazine), was added a soln of an
6H-1,2-oxazine (1 equiv) in THF (10 mL/mmol of 1,2-oxazine)
at –78 °C over a period of 15 min. Then the electrophilic component
was added, the mixture was stirred at –78 °C (time as indicated in
Tables 1 and 2) and allowed to warm up to r.t. After addition of sat.
aq NH4Cl soln (10 mL/mmol of 1,2-oxazine) the mixture was ex-
tracted with Et2O (2 20 mL/mmol of 1,2-oxazine), the combined
extracts were dried (Na2SO4) and the solvent removed in vacuo. The
crude product was purified by column chromatography (hexane–
EtOAc). Yields, IR and NMR data are given in Table 3, Table 4,
Table 5, Table 6, Table 7, Table 8 and Table 9.
The primary conjugate addition products can be trapped
with electrophiles in a highly stereoselective fashion. This
allows introduction of alkyl, hydroxyalkyl and alkoxycar-
bonyl groups at C-4 of the 1,2-oxazine. Also, sulfur, oxy-
gen and nitrogen could be installed as heteroatoms at C-4
by employing the appropriate electrophiles. Future reports
will deal with subsequent reactions of the highly substitut-
ed 1,2-oxazines presented here as well as with the exten-
sion of the described conjugate addition to
enantiomerically pure 6H-1,2-oxazines.19
Table 3 Synthesis of Substituted 3-Phenyl-5,6-dihydro-4H-1,2-oxazines 2 16 (General Procedure)
1 [g (mmol)]
0.610 (3.00)
0.305 (1.50)
0.310 (1.52)
0.310 (1.52)
0.314 (1.54)
RLi [mL (mmol)]
PhLi 3.30 (6.60)
PhLi 2.00 (3.70)
PhLi 1.65 (3.30)
PhLi 1.65 (3.30)
PhLi 1.65 (3.30)
ElX
(mmol)
Time
-
Yield [g (%)]
2 0.746a (89)
3 0.312b (70)
4 0.359a (73)
5 0.330b (73)
6 0.183b (40)
7 0.168d (66)
dr
H2O
1.50 mL (94.0)
0.28 mL (4.50)
0.40 mL (4.50)
1.42 g (4.50)
95:5
95:5
95:5
95:5
95:5
95:5
MeI
2 h
MeSSMe
FN(SO2Ph)2
70 min
45 min
1 h
c
O2
0.102 (0.500) PhLi 0.55 (1.10)
BocN=NBoc
0.345 g (1.50)
2 h
Synthesis 2002, No. 10, 1412–1422 ISSN 0039-7881 © Thieme Stuttgart · New York

1416
M. Buchholz, H.-U. Reissig
PAPER
Table 3 Synthesis of Substituted 3-Phenyl-5,6-dihydro-4H-1,2-oxazines 2 16 (General Procedure) (continued)
1 [g (mmol)]
RLi [mL (mmol)]
ElX
(mmol)
Time
2.5 h
2 h
Yield [g (%)]
8 0.167e (86)
9 0.219b (34)
10 0.317e (86)
11 0.267b (67)
dr
0.102 (0.500) PhLi [0.74 (1.50)]
PhCHO
ClCO2Bn
NCCO2Et
NCCO2Et
0.30 mL (3.00)
0.65 mL (4.50)
2.95 mL (30.0)
2.90 mL (30.0)
95:5
95:5
0.315 (1.54)
0.211 (1.04)
0.216 (1.05)
PhLi [1.65 (3.30)]
PhLi [1.30 (2.60)]
2 h
92:8
1,3-Benzodioxol-5-yllithium
2 h
87:13
[465 mg (2.31)], [5-Bromo-1,3-benzodiox-
ol, 3.1 mL (4.65), t-BuLi]
0.610 (3.00)
1,3-Benzodioxol-5-yllithium
[1.33 g (6.60)], [5-Bromo-1,3-benzodioxol,
8.8 mL (13.0), t-BuLi]
NCCO2Et
1.0 mL (10.0)
1 h
11 0.411b (35)
16 0.276 (20)
87:13
95:5
0.208 (1.02)
0.616 (3.03)
t-BuLi [1.8 (2.2)]
n-BuLi [2.75 (6.6)]
NCCO2Et
0.30 mL (3.00)
2.84 g (9.00)
0.5 mL (8.6)
1 h
12 0.150b (44)
13 0.525f (62)
14 0.074d (82)
95:5
95:5
95:5
FN(SO2Ph)2
45 min
-
0.075 (0.368) 2-Propenyllithium [98 mg (0.81)], [2-Bro- EtOH
mopropene, 1.1 mL (1.62), t-BuLi]
0.203 (1.00)
2-Propenyllithium [0.264 mg (2.20)], [2- Allylbromide
0.25 mL (2.9)
2 h
15 0.238g (83)
95:5
Bromopropene, 2.60 mL (3.96), t-BuLi]
a Purified by chromatography hexane–EtOAc, 9:1.
b Purified by chromatography hexane–EtOAc, 15:1.
c Anhyd O2 gas was bubbled through the soln.
d Purified by chromatography hexane–EtOAc, 8:1.
e Purified by chromatography hexane–EtOAc, 10:1.
f Purified by chromatography hexane–EtOAc, 30:1.
g Purified by chromatography hexane–EtOAc, 20:1.
Table 4 Analytical Data for 5,6-Dihydro-4H-1,2-oxazines 2–15 and 5,6-Dihydro-2H-1,2-oxazine 16
Prod- Mp
uct
IRa (cm–1)
MS (EI, 80 eV)b
2
3
4
5
6
7
89–90 °C
3040–2875 (CH), 1605 (C=N), 1590, 1570,
1105, 895
281 (M+, 4), 236 (M+ OEt, 10), 220 (14), 207 (21), 148 (5), 120 (10),
117 (9), 104 (C8H8 , 100)
+
56–58 °C
oil
3150–2900 (CH), 1600 (C=N), 1450, 1105,
965, 890, 765, 700
-
3090–2870 (CH), 1600 (C=N), 1110, 890, 700 327 (M+, 1), 280 (M+ SMe, 4), 253 (21), 236 (21), 206 (100), 150
(C9H10S+, 91), 135 (12), 120 (14), 105 (19), 91 (12), 77 (11)
77–78 °C
97–99 °C
oil
3060–2880 (CH), 1605 (C=N), 1590, 1110,
1025, 885
299 (M+, 1), 279 (M+ HF, 1) 255 (M+ C2H4O, 13), 238 (17), 122
(C8H7F+, 100)
3490 (OH), 3060–2885 (CH), 1605 (C=N),
1090, 1050, 1035, 890, 690
297 (M+, 1), 253 (M+ C2H4O, 5), 236 (5), 206 (6), 148 (82), 120
(C8H10N+, 100)
3390 (NH), 3065–2930 (CH), 1760, 1720
(C=O), 1605 (C=N), 1395, 1370, 1155
511 (M+, 2), 455 (M+ C4H8, 15), 411 (M+ Boc, 24), 399 (M+
C8H16, 27), 355 (49), 309 (42), 236 (57), 207 (36), 178 (74), 148 (77),
+
57 (C4H9 , 100)
8
9
oil
oil
3395 (OH), 3060–2925 (CH), 1600 (C=N),
1090, 900, 700
-
3060–2930 (CH), 1740 (C=O), 1595 (C=N),
1495, 1445
415 (M+, 2), 371 (M+ – C2H4O, 57), 260 (24), 236 (23), 206 (44), 183
(43), 105 (31), 91 (100)
10 68–75 °C
3060–2880 (CH), 1725 (C=O), 1600 (C=N),
1245, 1115, 1035, 905
-
11 118–120 °C
3075–2930 (CH), 1730 (C=O), 1600 (C=N),
1505, 1230, 1035, 895
415 (M+, 0.5), 371 (M+ C2H4O, 32), 260 (20), 236 (19), 206 (34), 183
(66), 154 (20), 105 (58), 91 (100)
Synthesis 2002, No. 10, 1412–1422 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Stereoselective and Flexible Synthesis of 6-Alkoxy-5,6-dihydro-4H-1,2-oxazines
1417
Table 4 Analytical Data for 5,6-Dihydro-4H-1,2-oxazines 2–15 and 5,6-Dihydro-2H-1,2-oxazine 16 (continued)
Prod- Mp
uct
IRa (cm–1)
MS (EI, 80 eV)b
-
12 78–80 °C
3060–2875 (CH), 1725 (C=O), 1595 (C=N),
1250, 1105, 900
13 69–72 °C
14 44–46 °C
15 oil
3070–2870 (CH), 1590 (C=N), 1120, 890, 695 279 (M+, 5), 235 (M+ C2H4O, 75), 218 (35), 178 (C10H9FNO+, 100),
104 (C7H6N+, 29)
3085–2905 (CH), 1650 (C=C), 1605, 1570
(C=N), 1105, 900, 885
-
-
-
3075–2915 (CH), 1640 (C=C), 1590, 1565
(C=N), 1445, 1105, 900
16 107–110 °C
3060–2905 (CH), 1725 (C=O), 1630 (C=C),
1490, 1235, 1040
a Oils as films, crystals as KBr pellets.
b Compound 2 showed satisfactory HRMS data. Compound 3–16, showed satisfactory elemental analysis.
Table 5 1H-NMR Data for 5,6-Dihydro-4H-1,2-oxazines 2–15 and 5,6-Dihydro-2H-1,2-oxazine 16 (250or 270 MHz,
CDCl3/TMS)
Prod- , J (Hz)
uct
2
3
4
5
6
7.85–7.69 (m, 2 H, Ph), 7.45–7.18 (m, 8 H, Ph), 5.07 (d, J = 2.9, 1 H, 6-H), 3.94, 3.65 (2 qd, J = 7.1, 9.7, 1 H each, OCH2), 3.37 (td, J
= 2.9, 8.1, 1 H, 5-H), 3.12 (dd, J = 8.1, 18.1, 1 H, 4-Hax), 2.69 (dd, J = 2.9, 18.1, 1 H, 4-Heq), 1.21 (t, J = 7.1, 3 H, CH3)
7.63–7.60, 7.42–7.36 (2 m, 2 H each, Ph), 7.33–7.24 (m, 6 H, Ph), 5.02 (d, J = 3.6, 1 H, 6-H), 4.00–3.90, 3.64–3.54 (2 m, 1 H each,
OCH2), 3.12 (t, J = 3.6, 1 H, 5-H), 2.96 (dq, J = 3.6, 7.4, 1 H, 4-H), 1.28 (d, J = 7.4, 3 H, CH3), 1.19 (t, J = 7.0, 3 H, CH3)
7.70–7.67 (m, 2 H, Ph), 7.43–7.28 (m, 8 H, Ph), 4.90 (d, J = 5.9, 1 H, 6-H), 4.05–3.93 (m, 1 H, OCH2), 3.78 (d, J = 3.7, 1 H, 4-H), 3.69–
3.60 (m, 2 H, OCH2, 5-H), 2.00 (s, 3 H, SCH3), 1.19 (t, J = 7.0, 3 H, CH3)
7.86–7.83 (m, 2 H, Ph), 7.45–7.20 (m, 8 H, Ph), 5.26 (dd, J = 2.4, 2JHF = 43.4, 1 H, 4-H), 5.25 (d, J = 2.0, 1 H, 6-H), 3.98–3.87 (m, 1 H,
OCH2), 3.76–3.61 (m, 3 H, OCH2, 5-H), 1.23 (t, J = 7.1, 3 H, CH3)
7.95–7.93 (m, 2 H, Ph), 7.43–7.21 (m, 8 H, Ph), 5.37 (s, 1 H, 6-H), 4.35 (d, J = 11.8, 1 H, 4-H), 4.07 (d, J = 11.8, 1 H, OH), 4.01–3.92,
3.75–3.68 (2 m, 1 H each, OCH2), 3.63 (s, 1 H, 5-H), 1.26 (t, J = 7.4, 3 H, CH3)
7a 7.67 (dd, J = 1.8, 7.8, 2 H, Ph), 7.35 (d, J = 7.6, 2 H, Ph), 7.07–6.90 (m, 6 H, Ph), 6.21 (br s, 1 H, NH), 5.43 (br s, 1 H, 4-H), 4.92 (d, J
= 4.2, 1 H, 6-H), 3.76, 3.36 (2 qd, J = 7.1, 9.9, 1 H each, OCH2), 3.64 (br s, 1 H, 5-H), 1.24, 1.16 [2 s, 9 H each, C(CH3)3], 0.99 (t, J
= 6.9, 3 H, CH3)
8
7.65 (dd, J = 2.9, 6.6, 2 H, o-Ph), 7.45 (mc, 3 H, Ph), 7.40–7.24 (m, 5 H, Ph), 7.20 (mc, 3 H, Ph), 6.90–6.86 (m, 2 H, Ph), 5.25 (d, J = 9.7,
1 H, OH), 5.06 (dd, J = 4.1, 9.7, 1 H, CHOH), 5.01 (d, J = 1.5, 1 H, 6-H), 4.41, 3.76 (2 qd, J = 7.1, 9.8, 2 1 H, OCH2), 3.22 (d, J =
4.1, 1 H, 4-H), 3.14 (s, 1 H, 5-H), 1.39 (t, J = 7.1, 3 H, CH3)
9
10
11
7.64–7.61, 7.42–7.16, 7.01–6.98 (3 m, 15 H, Ph), 5.17 (d, J = 2.2, 1 H, 6-H), 5.15, 4.91 (2 d, J = 12.5, 1 H each, CH2Bn), 4.03 (t, J
= 2.2, 1 H, 5-H), 3.90–3.78 (m, 2 H, OCH2, 4-H), 3.57 (qd, J = 7.2, 9.2, 1 H, OCH2), 1.08 (t, J = 7.2, 3 H, CH3)
7.67–7.63 (m, 2 H, Ph), 7.41–7.24 (m, 8 H, Ph), 5.34a (d, J = 3.7, 0.08 H, 6-H), 5.18 (d, J = 2.0, 0.92 H, 6-H), 4.19–3.86 (m, 3 H, 5-H,
OCH2), 3.74 (d, J = 2.0, 1 H, 4-H), 3.65–3.55 (m, 1 H, OCH2), 1.17 (t, J = 7.0, 3 H, CH3), 1.08 (t, J = 7.0, 3 H, CH3)
7.64–7.61 (m, 2 H, Ph), 7.40–7.38 (m, 3 H, Ph), 6.79–6.75 (m, 3 H, Ar), 5.92 (s, 2 H, OCH2O), 5.26b (d, J = 3.4, 0.13 H, 6-H), 5.12 (d,
J = 2.6, 0.87 H, 6-H), 4.16–3.84 (m, 4 H, OCH2, 5-H), 3.67 (d, J = 1.7, 1 H, 4-H), 3.67–3.57 (m, 1 H, OCH2), 1.16 (t, J = 6.9, 3 H, CH3),
1.07 (t, J = 7.3, 3 H, CH3)
12
13
7.66–7.62 (m, 2 H, Ph), 7.40–7.37 (m, 3 H, Ph), 5.18 (d, J = 1.8, 1 H, 6-H), 4.13–3.80 (m, 3 H, OCH2), 3.61–3.51 (m, 1 H, OCH2), 3.49
(s, 1 H, 4-H), 2.49 (d, J = 1.8, 1 H, 5-H), 1.13 (t, J = 7.4, 3 H, CH3), 1.05 (t, J = 7.4, 3 H, CH3), 1.02 (s, 9 H, CH3)
7.84–7.80 (m, 2 H, Ph), 7.45–7.41 (m, 3 H, Ph), 5.07 (d, J = 2.2, 1 H, 6-H), 4.89 (dd, J = 2.0, 2JHF = 47.4, 1 H, 4-H), 3.92–3.79, 3.69–
3.57 (2 m, 1 H each, OCH2), 2.43 (ttd, J = 2.0, 7.1, 3JHF = 25.7, 1 H, 5-H), 1.43–1.23 (m, 6 H, CH2), 1.21, 0.91 (2 t, J = 7.1, 3 H each,
CH3)
14
7.74–7.71 (m, 2 H, Ph), 7.40–7.38 (m, 3 H, Ph), 5.02 (d, J = 2.9, 1 H, 6-H), 4.92, 4.84 (2 s, 1 H each, C=CH2), 3.94, 3.65 (2 qd, J =
7.1, 9.6, 2 1 H, OCH2), 2.89 (dd, J = 7.7, 17.5, 1 H, 4-H), 2.73–2.67 (m, 1 H, 5-H), 2.53 (dd, J = 3.7, 17.5, 1 H, 4-H), 1.82 (s, 3 H, CH3),
1.21 (t, J = 7.1, 3 H, CH3)
Synthesis 2002, No. 10, 1412–1422 ISSN 0039-7881 © Thieme Stuttgart · New York

1418
M. Buchholz, H.-U. Reissig
PAPER
Table 5 1H-NMR Data for 5,6-Dihydro-4H-1,2-oxazines 2–15 and 5,6-Dihydro-2H-1,2-oxazine 16 (250or 270 MHz,
CDCl3/TMS) (continued)
Prod- , J (Hz)
uct
15
16
7.67–7.63 (m, 2 H, Ph), 7.17–7.11 (m, 3 H, Ph), 5.70–5.54 (m, 1 H, CH2CH=CH2), 5.03 (br s, 1 H, CH2CH=CH2), 4.98–4.97 (m, 1 H,
CH2CH=CH2), 4.94 (br s, 1 H, CH2=CCH3), 4.88 (d, J = 3.7, 1 H, 6-H), 4.85 (mc, 1 H, CH2=CCH3), 3.92, 3.38 (2 dq, J = 7.0, 9.6, 1 H
each, OCH2), 2.88 (mc, 1 H, 5-H), 2.73–2.54 (m, 2 H, 4-H, CH2CH=CH2), 2.36–2.28 (m, 1 H, CH2CH=CH2), 1.69 (s, 3 H, CH3), 1.04 (t,
J = 7.0, 3 H, CH3)
7.43–7.26 (m, 5 H, Ph), 6.84–6.71 (m, 3 H, Ar), 5.92 (s, 2 H, OCH2O), 5.04 (s, 1 H, 6-H), 4.01–3.91 (m, 3 H, OCH2), 3.84 (s, 1 H, 5-H),
3.77–3.63 (m, 3 H, OCH2), 1.19, 0.94, 0.71 (3 t, J = 7.1, 1 H each, CH3)
a Toluene-d8, 500 MHz, 373 K.
b Minor isomer; missing signals are hidden by signals of the major isomer.
Table 6 13C-NMR Data for 5,6-Dihydro-4H-1,2-oxazines 2–15 and 5,6-Dihydro-2H-1,2-oxazine 16 (62.9 or 67.9 MHz CDCl3/TMS)
Prod- , J (Hz)
uct
2
3
4
5
6
156.5 (s, C=N), 140.5, 135.6 (2 s, Ph), 129.8, 128.7, 128.5, 127.6, 127.2, 125.5 (6 d, Ph), 98.6 (d, C-6), 63.8 (t, OCH2), 39.2 (d, C-
5), 24.2 (t, C-4), 15.0 (q, CH3)
162.3 (s, C=N), 141.1, 135.2 (2 s, Ph), 129.4, 128.8, 128.5, 127.7, 127.2, 126.6 (6 d, Ph), 99.8 (d, C-6), 64.2 (t, OCH2), 48.2 (d, C-
5), 32.5 (d, C-4), 19.5, 15.1 (2 q, CH3)
159.2 (s, C=N), 139.8, 134.3 (2 s, Ph), 129.8, 128.9, 128.4, 127.7, 127.6, 126.7 (6 d, Ph), 100.3 (d, C-6), 65.0 (t, OCH2), 50.4 (d, C-
5), 42.8 (d, C-4), 14.9 (q, CH3), 14.6 (q, SCH3)
161.6 (s, C=N), 133.1, 127.6 (2 s, Ph), 130.2, 129.1, 128.6, 128.0, 127.9, 126.5 (6 d, Ph), 97.8 (d, C-6), 79.2 (dd, 1JCF = 186, C-4),
64.3 (t, OCH2), 47.6 (dd, 2JCF = 20, C-5), 14.8 (q, CH3)
166.9 (s, C=N), 146.9, 136.4 (2 s, Ph), 130.0, 128.9, 128.6, 127.7, 126.4 (5 d, Ph), 98.0 (d, C-6), 64.4 (t, OCH2), 60.6 (d, C-4), 47.1
(d, C-5), 14.9 (q, CH3)
7a 154.7 (s, C=N), 139.8, 135.3 (2 s, Ph), 129.8, 129.0, 128.8, 128.7, 127.6, 127.2 (6 d, Ph), 99.9 (d, C-6), 81.8, 80.5 [2 s, C(CH3)3],
64.9 (t, OCH2), 53.7 (br d, C-4), 47.8 (d, C-5), 28.4 [q, C(CH3)3], 15.1 (q, CH3)
8
159.9 (s, C=N), 141.9, 141.2, 135.2 (3 s, Ph), 129.7, 129.0, 128.7, 128.4, 127.32, 127.27, 127.2, 127.0, 125.7 (9 d, Ph), 95.2 (d, C-6),
72.3 (d, CHOH), 64.1 (t, OCH2), 43.6 (d, C-4), 39.1 (d, C-5), 14.7 (q, CH3)
9
169.4 (s, C=O), 153.0 (s, C=N), 138.2, 136.0, 135.1 (3 s, Ph), 129.5, 128.9, 128.8, 128.4, 128.3, 128.0, 127.7, 127.6, 127.2 (9 d, Ph),
97.6 (d, C-6), 67.1 (t, Bn), 63.4 (t, OCH2), 42.3, 40.2 (2 d, C-5, C-4), 14.7 (q, CH3)
10
11
12
13
14
15
169.5 (s, C=O), 153.4 (s, C=N), 138.5, 136.2 (2 s, Ph), 129.4, 129.1, 128.9, 128.4, 127.6, 125.9 (6 d, Ph), 97.6 (d, 6-H), 63.5, 61.4 (2
t, OCH2), 42.4, 40.5 (2 d, C-4, C-5), 14.9, 13.7 (2 q, CH3)
169.5 (s, C=O), 153.3 (s, C=N), 148.1, 146.9, 136.1, 132.2 (4 s, Ar), 129.5, 128.4, 125.9, 121.0, 108.5, 108.1 (6 d, Ar), 101.1 (t,
OCH2O), 97.6 (d, C-6), 63.5, 61.5 (2 t, OCH2), 42.1, 40.9 (2 d, C-4, C-5), 14.9, 13.7 (2 q, CH3)
170.8 (s, C=O), 154.9 (s, C=N), 136.5 (s, Ph), 129.3, 128.4, 125.9 (3 d, Ph), 95.6 (d, C-6), 63.0, 61.2 (2 t, OCH2), 46.6 (d, C-4), 36.0
(d, C-5), 32.0 [s, C(CH3)3], 27.9 [q, C(CH3)3], 14.9, 13.7 (2 q, CH3)
153.8 (s, C=N), 133.6 (s, Ph), 130.0, 128.5, 126.3 (3 d, Ph), 97.7 (d, C-6), 78.7 (dd, 1JCF = 184, C-4), 64.2 (t, OCH2), 40.3 (dd, 2JCF
17.0, C-5), 28.9, 22.5 (2 t, CH2), 27.8 (dt, 3JCF = 7.3, 5-CH2), 14.7, 13.8 (2 q, CH3)
=
156.2 (s, C=N), 143.3 (s, C=CH2), 135.7 (s, Ph), 129.6, 128.4, 125.4 (3 d, Ph), 112.6 (t, C=CH2), 97.8 (d, C-6), 63.8 (t, OCH2), 40.0 (d,
C-5), 22.9 (t, C-4), 21.4, 15.0 (2 q, CH3)
160.8 (s, C=N), 144.0 (s, CH2=CCH3), 135.2 (s, Ph), 134.7 (d, CH2CH=CH2), 129.5, 128.6, 126.5 (3 d, Ph), 118.1 (t, CH2CH=CH2),
113.2 (t, CH2=CCH3), 99.3 (d, C-6), 64.4 (t, OCH2), 44.2 (d, C-5), 35.5 (t, CH2CH=CH2), 35.1 (d, C-4), 21.4 (q, CH2=CCH3), 15.1 (q,
CH3)
16
166.9 (s, C=O), 153.6 (s, C=N), 147.7, 146.7, 143.6, 135.9, 133.3 (5 s, Ph, C=O), 128.5, 128.1, 127.6 (3 d, Ph), 121.7 (d, Ar), 113.9
(s, C-4), 108.7, 108.1 (2 d, Ar), 105.3 (d, C-6), 100.9 (t, OCH2O), 66.2, 62.6, 60.1 (3 t, OCH2), 46.6 (d, C-5), 14.7, 13.5, 13.2 (3 q,
CH3)
a Toluene-d8, 125.8 MHz, 373 K.
Synthesis 2002, No. 10, 1412–1422 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Stereoselective and Flexible Synthesis of 6-Alkoxy-5,6-dihydro-4H-1,2-oxazines
1419
Addition of Methyllithium to 1
2.58 (dd, J = 6.6, 18.4 Hz, 1 H, 4 -H), 2.16 (dd, J = 2.9, 18.4 Hz, 1
H, 4-H), 1.28, 1.18 (2 t, J = 7.0 Hz, 3 H each, CH3).
According to the general procedure, a soln of 1 (107 mg, 0.526
mmol) in THF (20 mL) was slowly added to a soln of MeLi (10 mL
of 1.6 M soln in Et2O, 16 mmol) in THF (10 mL) at –78 °C over a
period of 4 h. After stirring for additional 1 h, H2O was added and
the mixture was allowed to warm up to r.t. Purification by chroma-
tography (hexane EtOAc, 15:1) provided 1722 (31 mg, 27%) as co-
lourless oil and 18 (22 mg, 20%) as colourless crystals (mp 123–
125 °C).
13C NMR (67.9 MHz, CDCl3): = 197.8 (s, C=C=CH2), 163.6,
155.8 (2 s, C=N), 136.0, 135.0, 133.4 (3 s, C=C=CH2, Ph),
129.7, 129.3, 128.6, 127.9, 126.4, 125.2 (6 d, Ph), 99.5 (d, C-6 ),
96.8 (d, C-6), 93.4 (t, = CH2), 65.4, 64.0 (2 t, OCH2), 56.3 (q,
OCH3), 42.9, 35.0, 34.9 (3 d, C-4, C-5, C-5 ), 22.0 (t, C-4 ), 15.2,
15.0 (2 q, CH3).
MS (EI, 80 eV): m/z (%) = 476 (M+, <1), 461 (M+ CH3, 12), 288
(25), 238 (26), 224 (46), 210 (70), 198 (73), 184 (100), 160 (58),
143 (54), 130 (31), 117 (43), 103 (45), 91 (50), 77 (48).
6,6 -Diethoxy-5-methyl-3,3 -diphenyl-5,5 ,6,6 -tetrahydro-
4H,4 H-4,5 -bi-1,2-oxazine (18)
HRMS (EI, 80 eV): m/z [M+
CH3] calcd for C27H29N2O5,
IR (film): 3055–2910 (CH), 1595, 1565 (C=N), 1110, 905, 890,
865, 695 cm–1.
461.2076; found, 461.2057.
1H NMR (270 MHz, CDCl3): = 7.47–7.43 (m, 2 H, Ph), 7.29–7.24
(m, 2 H, Ph), 7.19–7.14 (m, 6 H, Ph), 5.11 (d, J = 2.9 Hz, 1 H, 6 -
H), 4.73 (d, J = 3.7 Hz, 1 H, 6-H), 4.04, 3.86 (2 qd, J = 7.1, 9.6
Hz, 1 H each, OCH2), 3.69–3.53 (m, 2 H, OCH2), 2.82–2.74 (m, 1
H, 5 -H), 2.65 (br d, J = 9.6 Hz, 1 H, 4-H), 2.57–2.64 (m, 2 H, 4 -H,
5-H), 2.12 (dd, J = 2.2, 18.4 Hz, 1 H, 4-H), 1.25, 1.16 (2 t, J = 7.0
Hz, 3 H each, CH3), 1.08 (d, J = 7.4 Hz, 3 H, CH3).
13C NMR (67.9 MHz, CDCl3): = 160.9, 155.6 (2 s, C=N), 137.0,
135.0 (2 s, Ph), 129.5, 129.4, 128.7, 128.0, 126.2, 125.2 (8 d,
Ph), 102.1, 96.9 (2 d, C-6, C-6 ), 64.8, 64.0 (2 t, OCH2), 37.6,
34.6, 32.5 (3 d, C-5, C-5 , C-4), 22.1 (t, C-4 ), 17.6, 15.2, 15.0 (3
q, CH3).
6-Ethoxy-6H-1,2-oxazine-3-carbaldehyde (22)
A soln of 21 (100 mg, 0.502 mmol) in THF (5 mL) was stirred with
DIBAL-H (0.75 mL of 1.5 M soln in toluene, 1.13 mmol) at –50 °C
for 2 h. After addition of EtOH (0.75 mL) the mixture was allowed
to warm up to r.t. A soln of sodium/potassium tartrate was added
and the mixture was stirred for 1 h. After dilution with Et2O (10 mL)
the phases were separated, the organic phase was washed with H2O,
sat. aq NaHCO3 soln, brine and was dried (Na2SO4). The solvent
was removed in vacuo. Purification by kugelrohr distillation (0.5
mbar, 60 °C) afforded 22 (66 mg, 85%) as a colourless liquid.
IR (film): 2980–2890 (CH), 1710 (C=O), 1640 (C=C), 1550 (C=N),
1250, 1100, 1000, 840, 770 cm–1.
1H NMR (270 MHz, CDCl3): = 9.60 (s, 1 H, CHO), 6.59 (d,
J = 10.3 Hz, 1 H, 4-H), 6.27 (dd, J = 3.7, 10.3 Hz, 1 H, 5-H), 5.71
(d, J = 3.7 Hz, 1 H, 6-H), 3.99, 3.70 (2 qd, J = 7.1, 9.6 Hz, 1 H
each, OCH2), 1.20 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (67.9 MHz, CDCl3): = 188.4 (d, CHO), 153.6 (s, C=N),
125.2 (d, C-5), 111.9 (d, C-4), 93.9 (d, C-6), 64.7 (t, OCH2), 14.9 (q,
CH3).
Anal. Calcd for C25H30N2O4 (422.5): C, 71.07; H, 7.16; N, 6.63.
Found: C, 71.14; H, 7.23; N, 6.43.
Addition of Lithiated Methoxyallene to 1
Lithiated methoxyallene was prepared by addition of n-BuLi (2 mL
of a 2.5 M soln in hexane, 5.0 mmol) to a soln of methoxyallene
(0.84 g, 6.0 mmol) in THF (10 mL) at –40 °C and stirred for 15 min.
According to the general procedure, a soln of 1 (100 mg, 0.492
mmol) in THF (10 mL) was slowly added to the soln of lithated
methoxyallene at –78 °C over a period of 4 h. After stirring for fur-
ther 1 h, EtOH (1 mL) was added and the reaction mixture was al-
lowed to warm up to r.t. Purification by chromatography (hexane
EtOAc, 15:1) provided 19 (60 mg, 45%) as colourless crystals (mp
90–93 °C) and 20 (21 mg, 18%) as yellow oil.
MS (EI, 80 eV): m/z (%) = 155 (M+, 15), 110 (M+ C2H5O, 100),
98 (20), 82 (98), 55 (68), 41 (61), 39 (55), 29 (79).
HRMS (EI, 80 eV): m/z calcd for C7H9NO3, 155.0582; found,
155.0573.
(6-Ethoxy-6H-1,2-oxazin-3-yl)methanol (23)23
A soln of 22 (160 mg, 1.03 mmol) in THF (10 mL) was stirred with
DIBAL-H (1.35 mL of 1.5 M soln in toluene, 2.00 mmol) at –50 °C
for 1 h. After addition of EtOH (1.35 mL) the mixture was allowed
to warm up to r.t. A soln of sodium/potassium tartrate was added
and the mixture was stirred for 1 h. After dilution with Et2O (10 mL)
the phases were separated, the organic phase was washed with H2O,
sat. aq NaHCO3 soln, brine and was dried (Na2SO4). The solvent
was removed in vacuo. Purification by kugelrohr distillation (0.02
mbar, 100 °C) afforded 23 (125 mg, 77%) as colourless liquid.
6-Ethoxy-5-(1-methoxy-1,2-propadienyl)-3-phenyl-5,6-dihy-
dro-4H-1,2-oxazine (19)
IR (KBr): 3065–2900 (CH), 1960 (C=C=C), 1570 (C=N), 1105,
885 cm–1.
1H NMR (250 MHz, CDCl3): = 7.68–7.64 (m, 2 H, Ph), 7.39–7.36
(m, 3 H, Ph), 5.47, 5.43 (2 dd, J = 2.9, 7.4 Hz, 1 H each, =CH2),
5.24 (d, J = 2.2 Hz, 1 H, 6-H), 3.92, 3.67 (2 d, J = 7.2, 9.6 Hz, 1
H each, OCH2), 3.43 (s, 3 H, OCH3), 2.98–2.91 (m, 1 H, 5-H), 2.83
(dd, J = 7.7, 17.3 Hz, 1 H, 4-H), 2.47 (dd, J = 1.5, 17.7 Hz, 1 H, 4-
H), 1.20 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (62.9 MHz, CDCl3): = 198.0 (s, C=C=CH2), 155.4 (s,
C=N), 136.2, 133.8 (2 s, C=C=CH2, Ph), 129.3, 128.3, 125.4 (3
d, Ph), 95.5 (t, C=C=CH2), 93.1 (d, C-6), 63.8 (t, OCH2), 56.3 (q,
OCH3), 35.4 (d, C-5), 20.9 (t, C-4), 15.0 (q, CH3).
IR (film): 3380 (OH), 2980–2900 (CH), 1650 (C=C), 1565 (C=N),
1090, 1000, 900 cm–1.
1H NMR (250 MHz, CDCl3): = 6.25–6.13 (m, 2 H, 4-H, 5-H),
5.44 (dd, J = 1.4, 3.0 Hz, 1 H, 6-H), 4.33, 4.25 (2 d, J = 14.0 Hz,
1 H each, OCH2), 3.91–3.79, 3.63–3.51 (2 m, 1 H each, OCH2),
2.98 (br s, 1 H, OH), 1.13 (t, J = 7.4 Hz, 3 H, CH3).
Anal. Calcd for C16H19NO3 (273.3): C, 70.32; H, 7.01; N, 5.12.
Found: C, 70.29; H, 6.97; N, 5.07.
13C NMR (62.9 MHz, CDCl3): = 155.0 (s, C-3), 126.3 (d, C-5),
115.6 (d, C-4), 92.0 (d, C-6), 64.0, 62.2 (2 t, OCH2), 14.9 (q, CH3).
6,6 -Diethoxy-5-(1-methoxy-1,2-propadienyl)-3,3 -diphenyl-
5,5 ,6,6 -tetrahydro-4H,4 H-4,5 -bi-1,2-oxazine (20)
Anal. Calcd for C7H11NO3 (157.2): C, 53.48; H, 7.05; N, 8.91.
Found: C, 53.46; H, 7.05; N, 8.40.
1H NMR (250 MHz, CDCl3): = 7.53–7.11 (m, 10 H, Ph), 5.54,
5.45 (2 dd, J = 2.4, 7.9 Hz, 1 H each, =CH2), 5.10 (d, J = 2.9 Hz,
1 H, 6-H), 5.04 (d, J = 4.4 Hz, 1 H, 6 -H), 4.09–4.00, 3.94–3.82 (2
m, 1 H each, OCH2), 3.77–3.54 (m, 2 H, OCH2), 3.40 (s, 3 H,
OCH3), 3.15–3.12 (m, 2 H, 4-H, 5 -H), 2.89–2.78 (m, 1 H, 5-H),
6-Ethoxy-3-[(1-methoxy-1-methylethoxy)methyl]-6H-1,2-ox-
azine (24)
A soln of 23 (93 mg, 0.592 mmol), 2-methoxypropene (0.10 mL,
0.88 mmol) and a crystal of camphorsulfonic acid in anhyd THF (5
Synthesis 2002, No. 10, 1412–1422 ISSN 0039-7881 © Thieme Stuttgart · New York

1420
M. Buchholz, H.-U. Reissig
PAPER
mL) was stirred for 2 h at r.t. After addition of Na2CO3 and filtra-
tion, the solvent was removed in vacuo. Purification by chromatog-
raphy (n-hexane EtOAc, 9:1) afforded 24 (101 mg, 74%) as
colourless oil.
25
IR (film): 2980–2880 (CH), 1645 (C=C), 1570 (C=N), 1340, 1090,
1060, 1000 cm–1.
1H NMR (270 MHz, CDCl3): = 6.36 (d, J = 10.3 Hz, 1 H, 4-H),
6.28 (dd, J = 3.7, 10.3 Hz, 1 H, 5-H), 5.54 (d, J = 3.7 Hz, 1 H, 6-H),
4.97 (s, 1 H, 3-CH), 4.00–3.46 (m, 6 H, OCH2), 1.27–1.18 (m, 9 H,
CH3).
13C NMR (67.9 MHz, CDCl3): = 154.2 (s, C=N), 126.1 (d, C-5),
114.3 (d, C-4), 100.7 (d, C-6), 92.3 (d, 3-CH), 63.7, 63.0, 62.5 (3
t, OCH2), 14.9 (q, CH3).
IR (film): 3070–2830 (CH), 1650 (C=C), 1380, 1215, 1090, 900,
860 cm–1.
1H NMR (270 MHz, CDCl3): = 6.29–6.28 (m, 2 H, 4-H, 5-H),
5.53–5.52 (m, 1 H, 6-H), 4.20 (s, 2 H, CH2O), 3.95, 3.65 (2 qd,
J = 7.1 Hz, 2 H each, OCH2), 3.22 (s, 3 H, OCH3), 1.37 (s, 6 H,
C(CH3)2OCH3], 1.21 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (67.9 MHz, CDCl3): = 154.1 (s, C=N), 125.7 (d, C-5),
116.2 (d, C-4), 100.8 [s, C(CH3)2OCH3], 92.0 (d, C-6), 63.8, 60.7 (2
t, OCH2), 48.7 (q, OCH3), 24.4 [q, C(CH3)2OCH3], 15.0 (q, CH3).
MS (EI, 80 eV): m/z (%) = 229 (M+, 1), 184 (M+ C2H5O, 100),
139 (95), 128 (25), 110 (50), 103 [CH(OCHCH3)2 , 100], 97 (61),
82 (95), 75 (100), 47 (100).
+
Anal. Calcd for C11H19NO4 (229.3): C, 57.63; H, 8.35; N, 6.11.
Found: C, 57.18; H, 7.86; N, 5.80.
HRMS (EI, 80 eV): m/z calcd for C11H19NO4, 229.1314; found:
229.1342.
26
3-(Diethoxy)methyl-6-ethoxy-6H-1,2-oxazine (25)
A soln of 22 (78 mg, 0.502 mmol), triethyl orthoformate (1 mL) and
a crystal of camphorsulfonic acid in anhyd EtOH (5 mL) was stirred
for 2 d at r.t. After addition of NaHCO3 and filtration, the solvent
was removed in vacuo. Purification by chromatography (hexane
EtOAc, 10:1) afforded 25 (78 mg, 68%) and 26 (18 mg, 13%) as co-
lourless liquids.
1H NMR (270 MHz, CDCl3): = 4.94 (d, J = 2.9 Hz, 1 H, 6-H),
4.73 (s, 1 H, 3-CH), 3.92–3.42 (m, 9 H, OCH2, 5-H), 2.33 (d, J = 3.7
Hz, 2 H, 4-H), 1.23–1.13 (m, 12 H, CH3).
13C NMR (62.9 MHz, CDCl3): = 156.4 (s, C=N), 102.5 (d, 3-CH),
96.1 (d, C-6), 68.2 (d, C-5), 64.4, 63.7, 62.9 (3 t, OCH2), 21.3 (t,
C-4), 14.9 (q, CH3).
MS (EI, 80 eV): m/z (%) = 275 (M+, 1), 230 (M+ C2H5O, 84), 103
(100), 75 (100), 59 (58), 47 (C2H7O+,100).
Table 7 Synthesis of Substituted 5,6-Dihydro-4H-1,2-oxazines 27 31 (General Procedure)
1,2-Oxazine
[g (mmol)]
RLi [mL (mmol)]
ElX [mL
(mmol)]
Time
-
Yielda
dr
IRb (cm–1)
[g (%)] h
24
PhLi
1.10 (2.20)
H2O
0.30 (19.0)
27
95:5
3090–2830 (CH), 1605 (C=N), 1380,
1105, 890, 700
0.229 (1.00)
0.217c (71)
24
PhLi
NCCO2Et
0.30 (3.00)
2 hd
2 h
28
87:13
3065–2830 (CH), 1735 (C=O), 1605
(C=N), 1210, 1110, 1035, 900
0.202 (0.882) 1.00 (2.00)
0.090e (27)
25
2-Propenyllithium [277 mg Allyl bromide
(2.29) 2-Bromo-propene,
2.75 mL (4.13) t-BuLi]
29
95:5
95:5
3075–2875 (CH), 1640 (C=C), 1620
(C=N), 1110, 1065
2975–2880 (CH), 1645 (C=C), 1110,
1075, 1015
0.239 (1.04)
0.27 (3.13)
0.256f (79)
31
0.019 (7)
25
n-BuLi
0.90 (2.20)
FN(SO2Ph)2
0.946 g (3.00)
45 min
30
50:50
2975–2875 (CH), 1610 (C=N), 1180,
1110, 1065, 920
0.229 (1.00)
0.179g (58)
a All products were oils.
b As films.
c,f,g Purified by chromatography hexane EtOAc, c 15:1, f 20:1, g 7:1.
d Before warming up to r.t. 0.3 mL of EtOH was added.
e Purified by HPLC.
h Compounds 27–30 showed satisfactory elemental analysis.
Table 8 1H-NMR Data of 5,6-Dihydro-4H-1,2-oxazines 27–30 and 5,6-Dihydro-2H-1,2-oxazine 31 (250 or 270 MHz,
CDCl3/TMS)
Product , J (Hz)
27
7.33–7.21 (m, 5 H, Ph), 4.95 (d, J = 2.9, 1 H, 6-H), 4.09 (s, 2 H, CH2O), 3.86, 3.58 (2 qd, J = 7.0, 9.7, 1 H, OCH2), 3.25–3.20 (m,
1 H, 5-H), 3.20 (s, 3 H, OCH3), 2.74 (dd, J = 8.1, 18.6, 1 H, 4-Hax), 2.40 (dd, J = 2.6, 18.6, 1 H, 4-Heq), 1.35 (s, 6 H, CH3), 1.18 (t, J
= 7.0, 3 H, CH3)
28
7.35–7.22 (m, 5 H, Ph), 5.09 (d, J = 2.2, 1 H, 6-H), 4.48, 4.22 (2 d, J = 11.8, 1 H each, OCH2), 4.30–4.07 (m, 1 H, OCH2), 3.87 (t,
(major) J = 2.2, 1 H, 5-H), 3.86–3.74, 3.58–3.47 (2 m, 1 H each, OCH2), 3.51 (d, J = 2.2, 1 H, 4-H), 3.15 (s, 3 H, OCH3), 1.31, 1.30 (2 s,
3 H each, CH3), 1.28, 1.11 (2 t, J = 7.4, 3 H each, CH3)
Synthesis 2002, No. 10, 1412–1422 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Stereoselective and Flexible Synthesis of 6-Alkoxy-5,6-dihydro-4H-1,2-oxazines
1421
Table 8 1H-NMR Data of 5,6-Dihydro-4H-1,2-oxazines 27–30 and 5,6-Dihydro-2H-1,2-oxazine 31 (250 or 270 MHz,
CDCl3/TMS) (continued)
Product , J (Hz)
28
7.31–7.18 (m, 5 H, Ph), 5.12 (d, J = 3.7, 1 H, 6-H), 4.44, 4.20 (2 d, J = 11.8, 1 H each, OCH2), 3.96–3.84 (m, 2 H, OCH2, 5-H), 3.78
(minor) (q, J = 7.4, 2 H, OCH2), 3.68–3.56 (m, 1 H, OCH2), 3.51–3.45 (m, 1 H, 4-H), 3.16 (s, 3 H, OCH3), 1.32, 1.30 (2 s, 3 H each, CH3),
1.19 (t, J = 7.0, 3 H, CH3), 0.90 (t, J = 7.4, 3 H, CH3)
29a
5.72 (dddd, J = 6.1, 8.2, 10.4, 16.8, 1 H, CH=CH2), 5.12–5.07 (m, 2 H, CH=CH2), 4.88 [s, 1 H, CH(OEt)2], 4.86, 4.82 (2 mc, 1 H
each, C=CH2), 4.84 (d, J = 3.4, 1 H, 6-H), 3.91, 3.74, 3.69 (3 qd, J = 7.1, 9.5, 1 H each, OCH2), 3.59–3.51 (m, 3 H, OCH2), 2.75–
2.70, 2.60–2.54 (2 m, 1 H each, CH2CH=CH2), 2.62 (t, J = 3.4, 1 H, 5-H), 2.48 (td, J = 3.4, 10.0, 1 H, 4-H), 1.73 (s, 3 H, CH3),
1.238, 1.235, 1.21 (3 t, J = 7.1, 3 H each, CH3)
30a
5.18 (dd, J = 4.8, 2JHF = 48.2, 1 H, 4-H), 5.05 [s, 1 H, CH(OEt)2], 4.88 (dd, J = 3.7, 4JHF = 7.4, 1 H, 6-H), 3.99, 3.80 (2 qd, J = 7.1,
9.6, 1 H each, OCH2), 3.72–3.52 (m, 4 H, OCH2), 2.01–1.83 (m, 1 H, 5-H), 1.60–1.31 (m, 6 H, CH2), 1.28–1.22 (m, 9 H, CH3), 0.91
(t, J = 7.0, 3 H, CH3)
30b
31
5.07 [s, 1 H, CH(OEt)2], 4.99 (d, J = 1.5, 1 H, 6-H), 4.62 (dd, J = 1.5, 2JHF = 47.1, 1 H, 4-H), 3.89–3.76 (m, 2 H, OCH2), 3.67–3.53
(m, 4 H, OCH2), 2.39–2.23 (m, 1 H, 5-H), 1.45–1.30 (m, 6 H, CH2), 1.28–1.17 (m, 9 H, CH3), 0.90 (t, J = 7.0, 3 H, CH3)
6.49 (d, J = 10.0, 1 H, 4-H), 5.95 (s, 1 H, NH), 5.88 (dd, J = 2.5, 10.0, 1 H, 5-H), 5.10–5.09 (m, 2 H, C=CH2), 4.82 (d, J = 2.5, 1 H,
6-H), 4.36 [s, 1 H, CH(OEt)2], 3.93–3.71, 3.63–3.45 (2 m, 3 H, OCH2), 1.92 (s, 3 H, CH3), 1.24, 1.20 (2 t, J = 7.4, 3 H each, CH3),
1.22 (t, J = 7.1, 3 H, CH3)
a 500 MHz.
Table 9 13C-NMR Data of 5,6-Dihydro-4H-1,2-oxazines 27–30 and 5,6-Dihydro-2H-1,2-oxazine 31 (62.9 or 67.9 MHz CDCl3/TMS)
Prod- , J (Hz)
uct
27
158.2 (s, C=N), 140.5 (s, Ph), 128.6, 127.6, 127.1 (3 d, Ph), 100.7 [s, C(CH3)2OCH3], 98.7 (d, C-6), 63.7, 62.9 (2 t, OCH2), 48.7 (q,
OCH3), 38.6 (d, C-5), 24.3 [q, C(CH3)2OCH3], 23.5 (t, C-4), 14.9 (q, CH3)
28
169.6 (s, C=O), 154.2 (s, C=N), 138.3 (s, Ph), 128.6, 127.6, 127.4 (3 d, Ph), 100.7 (s, COCH3), 98.1 (d, C-6), 63.3, 62.4, 61.4 (3 t,
OCH2), 48.7 (q, OCH3), 41.4 (d, C-5), 37.9 (d, C-4), 24.3, 24.2 (2 q, CH3), 14.8, 14.0 (2 q, CH3)
29 a 159.3 (s, C=N), 143.6 (s, C=CH2), 135.8 (d, CH=CH2), 117.8 (t, CH=CH2), 112.7 (t, C=CH2), 103.5 [d, CH(OEt)2], 99.6 (d, C-6), 64.2,
63.4, 63.0 (3 t, OCH2), 42.8 (d, C-5), 34.8 (t, CH2CH=CH2), 31.8 (d, C-4), 21.4, 15.1, 15.0, 14.9 (4 q, CH3)
30a 152.3 (sd, 2JCF = 14.7, C=N), 101.3 (dd, 3JCF = 2.4, C-6), 100.6 [d, CH(OEt)2], 78.4 (dd, 1JCF = 179.4, C-4), 65.6, 63.4, 62.2 (3 t, OCH2),
38.6 (dd, 2JCF = 18.3, C-5), 28.6, 22.7 (2 t, CH2), 23.8 (td, 3JCF = 6.1, 5-CH2), 15.0, 14.95, 14.91, 13.8 (4 q, CH3)
30b 153.4 (sd, 2JCF = 15.9, C=N), 101.0 [d, CH(OEt)2], 97.9 (d, C-6), 76.0 (dd, 1JCF = 183.1, C-4), 64.3, 63.4, 62.2 (3 t, OCH2), 39.5 (dd,
2JCF = 17.1, C-5), 28.8, 22.5 (2 t, CH2), 27.3 (td, 3JCF = 7.3, 5-CH2), 15.0, 14.90, 14.86, 13.7 (4 q, CH3)
31
144.5 (s, C=CH2), 132.5 (d, C-4), 124.0 (d, C-5), 115.9 (t, C=CH2), 104.4 [d, CH(OEt)2], 94.0 (d, C-6), 66.7, 65.4, 63.8 (3 t, OCH2),
65.3 (s, C-3), 20.4, 15.2 (2 q, CH3)
a 125.8 MHz.
(6) Zimmer, R.; Angermann, J.; Hain, U.; Hiller, F.; Reissig, H.-
U. Synthesis 1997, 1467.
(7) Zimmer, R.; Homann, K.; Angermann, J.; Reissig, H.-U.
Synthesis 1999, 1223.
(8) Homann, K. Dissertation; Technische Hochschule:
Darmstadt, 1994.
Acknowledgement
Generous support by the Deutsche Forschungsgemeinschaft (Gra-
duiertenkolleg ‘Struktur-Eigenschafts-Beziehungen bei Heterocyc-
len’), Fonds der Chemischen Industrie and Schering AG is most
gratefully acknowledged.
(9) Angermann, J. Dissertation; Technische Universität:
Dresden, 1997.
(10) Homann, K.; Angermann, J.; Collas, M.; Zimmer, R.;
Reissig, H.-U. J. Prakt. Chem. 1998, 340, 649.
(11) Schmidt, E. Dissertation; Technische Universität: Dresden,
2001.
(12) Zimmer, R.; Hiller, F.; Reissig, H.-U. Heterocycles 1999,
50, 393.
(13) Hartl, H.; Brüdgam, I.; Reissig, H.-U.; Buchholz, M. Z.
Kristallogr. 2001, 216, 591.
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Synthesis 2002, No. 10, 1412–1422 ISSN 0039-7881 © Thieme Stuttgart · New York

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M. Buchholz, H.-U. Reissig
PAPER
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Synthesis 2002, No. 10, 1412–1422 ISSN 0039-7881 © Thieme Stuttgart · New York