1,2-oxazines as building blocks for stereoselective synthesis: Preparation of oxygen-substituted 1,2-oxazines, either by alcohol addition or by epoxidation, and subsequent hydrogenation leading to 1,2-amino alcohols and pyrrolidines

Article abstract of DOI:10.1002/ejoc.201000425

Stereodefined oxygen-substituted 1, 2-oxazines were prepared by three different routes. The cycloaddition of enol ethers such as 1 with a-nitrosoalkenes generated in situ gave the heterocycles 3 and 4. Acid-catalysed additions of alcohols to the 6H-1, 2-oxazines 5 led to mixtures of the adducts 6 and the substitution products 7 with moderate chemoselectivity. Epoxidation of the 6H-1, 2-oxazines 5 proceeded more efficiently and furnished the corresponding epoxides 25 and 32 in reasonable to excellent yields. It was demonstrated that the resulting oxygen-substituted 1, 2-oxazines were suitable precursors for the preparation of cyclic or acyclic primary and secondary amines in racemic or enantiopure form. Hydrogenation of the 3-phenyl-substituted 1, 2-oxazines 3 and 25a and of (6S)- and (6R)-32 preferentially furnished the 1, 2amino alcohols 15, rac-29 and (2S)- and (2R)-29. On the other hand, reduction of the 3-ethoxycarbonyl-substituted 1, 2-oxazines 4, 6d and 20 led to the formation of the N-protected proline esters 21-24 in moderate yields. It was also found that the 5-methyl-6H-1, 2-oxazine 10 was a good precursor for the propargylic ether 11, which allowed a Pauson-Khand reaction leading to the tricyclic compounds 13 and 14. Hydrogen peroxide converted 10 into a hydroperoxide intermediate, which was further transformed into the l, 2-oxazin-6-one 28b. Overall, the results demonstrate the remarkable potential of suitably substituted 1, 2-oxazine derivatives for the stereoselective synthesis of amines.

Full text of DOI:10.1002/ejoc.201000425

FULL PAPER
DOI: 10.1002/ejoc.201000425
1,2-Oxazines as Building Blocks for Stereoselective Synthesis: Preparation of
Oxygen-Substituted 1,2-Oxazines, either by Alcohol Addition or by
Epoxidation, and Subsequent Hydrogenation Leading to 1,2-Amino Alcohols
and Pyrrolidines
Reinhold Zimmer,[a] Monika Buchholz,[a,b] Markus Collas,[c,d] Jörg Angermann,[c]
Kai Homann,[e] and Hans-Ulrich Reissig*[a]
Keywords: N,O Heterocycles / Epoxidation / Hydrogenation / Amino alcohols / 1,2-Oxazines / Proline esters
Stereodefined oxygen-substituted 1,2-oxazines were pre- and of (6S)- and (6R)-32 preferentially furnished the 1,2-
pared by three different routes. The cycloaddition of enol
ethers such as 1 with α-nitrosoalkenes generated in situ gave
the heterocycles 3 and 4. Acid-catalysed additions of alcohols
to the 6H-1,2-oxazines 5 led to mixtures of the adducts 6 and
the substitution products 7 with moderate chemoselectivity.
Epoxidation of the 6H-1,2-oxazines 5 proceeded more ef-
ficiently and furnished the corresponding epoxides 25 and 32
in reasonable to excellent yields. It was demonstrated that
the resulting oxygen-substituted 1,2-oxazines were suitable
precursors for the preparation of cyclic or acyclic primary and
amino alcohols 15, rac-29 and (2S)- and (2R)-29. On the other
hand, reduction of the 3-ethoxycarbonyl-substituted 1,2-ox-
azines 4, 6d and 20 led to the formation of the N-protected
proline esters 21–24 in moderate yields. It was also found that
the 5-methyl-6H-1,2-oxazine 10 was a good precursor for the
propargylic ether 11, which allowed a Pauson–Khand reac-
tion leading to the tricyclic compounds 13 and 14. Hydrogen
peroxide converted 10 into a hydroperoxide intermediate,
which was further transformed into the 1,2-oxazin-6-one 28b.
Overall, the results demonstrate the remarkable potential of
secondary amines in racemic or enantiopure form. Hydro- suitably substituted 1,2-oxazine derivatives for the stereose-
genation of the 3-phenyl-substituted 1,2-oxazines 3 and 25a
lective synthesis of amines.
their potential biological activities – as specific glycosidase
inhibitors, for example – and hence as lead compounds for
novel drugs.[4] Consequently, a wide variety of methods to
enable the efficient and stereoselective synthesis of 1,2-oxaz-
ine derivatives, in particular of the polyhydroxylated tetra-
hydro-2H-1,2-oxazines A (Figure 1), have been developed.[5]
In contrast with the various syntheses and applications of
oxygen-substituted 1,2-oxazines, the related 5,6-dihydro-
4H-1,2-oxazines B have gained less attention.[6] To the best
of our knowledge, there is only one report, from our group,
systematically dealing with the cis-dihydroxylation of the
easily accessible 6H-1,2-oxazines.[7] Here we describe the
synthesis of stereodefined oxygen-substituted dihydro-4H-
1,2-oxazines (type B), mainly through the employment of
6H-1,2-oxazines as ideal precursors,[8] and their subsequent
transformations into synthetically useful amino alcohols
and pyrrolidine derivatives.
Introduction
Since the first systematic studies in the 1970s, the synthe-
sis of 1,2-oxazine derivatives and their subsequent transfor-
mations into a variety of acyclic and cyclic nitrogen-con-
taining compounds have been the subjects of constantly in-
creasing attention.[1] This ongoing interest is also due to the
occurrence of the 1,2-oxazine skeleton in natural products,
such as trichodermamides A–C or penicillazine.[2] Polyhy-
droxylated 1,2-oxazines are particularly useful precursors in
the synthesis of oxygen-substituted heterocycles of different
ring sizes.[1d,3] In this context, polyhydroxylated pyrrolidine
and piperidine derivatives are of great interest because of
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
Fax: +49-30-838-55367
E-mail: hans.reissig@chemie.fu-berlin.de
[b] Hochschule Fresenius,
Limburger Strasse 2, 65510 Idstein, Germany
[c] Institut für Organische Chemie, Technische Universität
Dresden,
01061 Dresden, Germany
[d] Hochschule Lausitz, Fachbereich Bio-, Chemie- und
Verfahrenstechnik,
01958 Senftenberg, Germany
[e] Institut für Organische Chemie, Technische Universität
Darmstadt,
64287 Darmstadt, Germany
Figure 1. Substitution patterns of the tetrahydro-2H-1,2-oxazines
A and the dihydro-4H-1,2-oxazines B.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000425.
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Synthesis of Oxygen-Substituted 1,2-Oxazines
Table 1. Addition reactions of alcohols R2OH to 6H-1,2-oxazines.
One straightforward synthesis of oxygen-substituted 1,2-
oxazines would seem to be the direct approach, through
hetero-Diels–Alder reactions between enediol derivatives
and α-nitrosoalkenes, generated in turn from the corre-
sponding α-haloketoximes. Despite this obvious means of
access, only a few examples have been reported, with the
use of symmetrical 1,2-bis-O-substituted olefins such as 1,2-
bis(trimethylsiloxy)ethene.[9] An alternative good dienophile
candidate in such cycloadditions would be 1-acetoxy-2-
(benzyloxy)ethene (1).[10] Treatment of the oxime 2a with 1
in excess (cis/trans = 70:30) under typical reaction condi-
tions exclusively furnished 5-acetoxy-6-benzyloxy-4H-1,2-
oxazine (3) in good yield (Scheme 1). The observed excel-
lent trans selectivity was expected and consistent with pre-
vious results demonstrating that E-configured alkenes gen-
erally react more rapidly than the corresponding Z-config-
ured alkenes with α-nitrosoalkenes generated in situ.[11] The
reaction between the pyruvate oxime 2b and the olefin 1
afforded the corresponding 4H-1,2-oxazine 4 in excellent
yield but with lower trans/cis selectivity. This result shows
that the α-nitrosoalkene derived from 2b is significantly
more reactive than that generated from 2a, as also already
observed in previous studies with 2b as a heterodiene pre-
cursor.[11] Nevertheless, this direct route to oxygen-func-
tionalized 1,2-oxazines suffers from the restriction that no
substituent can be installed at C–4.
Entry[a]
5
R1
R2
6
% Yield[b]
7 or 5 % Yield
1
2
3
4
5
5a Ph
5a Ph
5a Ph
5b CO2Et Et
5a Ph Me
Me
6a 73
7a
7b
7c
5b
13
27
46
CH2CϵCH 6b 62
Bn 6c 19 (34:66)
6d 57 (13:87)
17
6a 44 (43:57)[c]
[c]
[a] Entries 1–4: Method A; Entry 5: Method B. [b] cis/trans ratio
given in brackets. [c] Calculated yield; mixture of 5a and trans-6a.
The 5,6-dihydro-4H-1,2-oxazines 6 were obtained either
as single trans diastereomers (Entries 1 and 2) or predomi-
nantly with trans configurations (Entries 3 and 4). Taking
into account that the addition of R2OH to 5 is a reversible
process, we also changed the reaction conditions. When the
reaction of 5b in ethanol was performed at high pressure
(6–13 kbar) and with prolonged reaction times (1–7 d), bet-
ter product to precursor ratios (up to 87:13) could be
achieved but the yields were significantly lower.[14] Finally,
an attempt to add methanol to 5a under basic conditions
(Method B) resulted in incomplete conversion and only an
inseparable mixture of 5a and 6a (ca. 1:1) was obtained
(Entry 5).
An interesting intramolecular version of the alkoxy ex-
change reaction by Method A was observed with the easily
accessible 6H-1,2-oxazine 8[15] (Scheme 2). Treatment of 8
with a catalytic amount of sulfuric acid in dichloromethane
at room temperature furnished the bicyclic product 9 in
74% yield.
Scheme 1. Synthesis of the oxygen-substituted 1,2-oxazines 3 and
4 through hetero-Diels–Alder reactions.
We next focused our efforts on a two-step route to oxy-
gen-functionalized 1,2-oxazines. Encouraged by our pre-
viously published synthetic applications of the 6H-1,2-
oxazines 5,[12] we chose these heterocycles as reliable start-
ing materials for addition reactions to the C-4,C-5 double
bond. We first examined additions of alcohols to the double
bonds of compounds 5 (Table 1). The heterocycles 5a and
5b were each treated with catalytic amounts of sulfuric acid
Scheme 2. Intramolecular acetal formation leading to the bicyclic
6H-1,2-oxazine derivative 9.
When the 5-methyl-6H-1,2-oxazine 10[8a] (Scheme 3) was
in various alcohols R2OH at room temperature (Table 1, treated with a catalytic amount of sulfuric acid in propargyl
Entries 1–4). In general, mixtures of the desired addition alcohol (Method A), we could not achieve the addition of
products 6a–6d and the transacetalization products 7a–7c the alcohol to the C=C double bond but we did observe a
were formed, and in some cases the mixtures could be sepa- clean transacetalization, forming the 6-propargyloxy-substi-
rated by fractional distillation (6a/7a) or by chromatog- tuted 1,2-oxazine 11 in excellent yield. This reaction out-
raphy (6b/7b). In all products 6a–6d the 6-ethoxy group had come is clearly due to the 5-methyl group, which hampers
been replaced by the 6-OR2 group, which indicates that the the 1,4-addition of the alcohol. Compound 11, bearing
exchange at the 6-position is faster than the addition of the CϵC and C=C units, is an interesting candidate for further
alcohol to the C,C-double bond.[13] The isolation of the 6H- synthetic manipulation such as the Pauson–Khand reac-
1,2-oxazines 7 also indicates that the exchange at the 6-posi- tion.[16] The addition of Co2(CO)8 to the triple bond in 11
tion is faster than the addition of the corresponding alcohol cleanly furnished the expected cobalt complex 12 in high
to the C,C-double bond.
yield. A subsequent Pauson–Khand reaction was carried
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1,2-Oxazines as Building Blocks for Stereoselective Synthesis
out by treatment of 12 with trimethylamine N-oxide at
0 °C[16e] and afforded the expected tricyclic heterocycle 13
as a single diastereomer together with compound 14, both
in low yields. The formation of 14 probably occurs during
workup with dilute HCl solution through addition of water
to the α,β-unsaturated precursor 13. We do not have unam-
biguous proof of the given relative configurations of 13 and
14, but the depicted structures should be most likely, due
to the considerably higher strain of alternative isomers.
Scheme 4. Palladium-catalysed hydrogenations of 3-phenyl- and 3-
ethoxycarbonyl-substituted 4H-1,2-oxazines.
We then examined the reductive ring-contraction of the
trans-enriched ethoxycarbonyl-substituted 4H-1,2-oxazines
4, 6d and 20 (Scheme 4). Hydrogenation of these com-
pounds in the presence of Raney nickel and Boc anhydride
exclusively produced the hydroxyproline derivatives 21–24
in moderate to good yields, but with low diastereoselectiv-
ity. The low stereocontrol is not surprising in view of related
previous results.[7a,17b,17e] Like the bis(siloxy)-substituted
1,2-oxazine 16 the 3-ethoxycarbonyl-substituted analogue
20 also underwent a partial desilylation leading to the pro-
line esters 21 and 22, both in a cis/trans ratio close to 2:1.
It should be mentioned that the hydrogenation of the 4H-
1,2-oxazine 4 was also carried out under high-pressure con-
ditions (50 bar), but the yield and the cis/trans ratio were
very similar to those observed under atmospheric pres-
sure.[14]
Scheme 3. Formation of the 6H-1,2-oxazine 11 by transacetaliza-
tion and subsequent Pauson–Khand reaction.
Hydrogenations of Oxygen-Substituted 1,2-Oxazines
The most commonly employed subsequent transforma-
tions of 1,2-oxazines involve palladium- and nickel-cata-
lysed hydrogenations, leading to acyclic and cyclic nitrogen-
containing products. The outcome of these reactions
strongly depends on the substitution pattern of the sub-
strates.[17] In order to address the role of the C-5 oxygen
substituent, the ring cleavage was examined with the 3-
phenyl-substituted 1,2-oxazines 3 and 16 (Scheme 4),[9a] as
well as with the 3-ethoxycarbonyl-substituted compounds
4, 6d and 20. Treatment of 3 with hydrogen in the presence
of palladium on charcoal and subsequent acetylation fur-
nished the ring-opened product 15 in low yield (31%). Sub-
sequent acetylation to afford the N,O-bisacetylated product
was necessary because the primary hydrogenated product
Epoxidations of 6H-1,2-Oxazines
In our search for alternative procedures suitable for func-
was obtained as a mixture of N- and O-monoacetylated 1,2- tionalization of the C=C bond of 6H-1,2-oxazines we exam-
amino alcohols as a result of a partial O-to-N acetyl shift. ined epoxidation methods. The results are compiled in
In contrast, we were not able to convert the 3-phenyl-5,6- Table 2. Because the double bond in a 6H-1,2-oxazine is
bis(trimethylsiloxy)-substituted 4H-1,2-oxazine 16 com- moderately electron-deficient we first applied a typical
pletely into the corresponding 1,2-amino alcohol. The hy- epoxidation protocol by treating the 3-phenyl-substituted
drogenation of this compound in the presence of Boc anhy- precursor 5a with hydrogen peroxide and aqueous NaOH
dride led to a mixture of the O-silylated pyrrolidine 17, its (8 ) in a methanol/THF mixture (3:1) at 0 °C. This pro-
desilylated derivative 18 as main component and the amino cedure gave the epoxide 25a and the methanol adduct 26 as
alcohol 19 as by-product (7%). The obtained products a ca. 1:1 mixture in moderate yield (Entry 1, Method A).
could easily be separated by column chromatography on To overcome the competing alcohol addition, we modified
alumina.
the conditions and avoided the use of methanol as solvent.
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When the epoxidation was performed with tert-butyl hydro- verted into γ-amino acids or into γ-keto carboxylic acids. It
peroxide and DBU in dichloromethane[18] the reaction pro- has already demonstrated with 28b that the outcomes of
ceeded chemoselectively and the desired epoxides 25a–25d palladium-catalysed hydrogenation of this compound
could be obtained in moderate to good yields (Entries 2–5, strongly depend on the solvent.[17c]
Method B). The best results for the epoxidation of the 3-
aryl-substituted 6H-1,2-oxazines 5a and 5c were obtained
by a protocol developed by Yadav and Kapoor with tert-
butyl hydroperoxide in the presence of KF on alumina in
acetonitrile (Entries 6 and 8).[19] In contrast, the 3-ethoxy-
carbonyl- or 3-trifluoromethyl-substituted 1,2-oxazines 5b
and 5d did not undergo epoxidation when exposed to the
conditions of Method C, leading either to no reaction or to
complete decomposition (Entries 7 and 9). Finally,
Method C was also suitable for the epoxidation of the 6H-
1,2-oxazine 5e with a (diethoxy)methyl group at C-3 (En-
Scheme 5. Synthesis of the 6H-1,2-oxazin-6-ones 28.
try 10). It should be noted that very high (here exclusive)
trans selectivity of the addition reaction was again ob-
served. The axially orientated 6-alkoxy groups in 1,2-oxaz-
ines such as 5 strongly steer the incoming reagent to the
opposite face of the heterocyclic core, as also observed in
several previously studied addition reactions.[5d,6b,7b,20]
Hydrogenations of Epoxides
The hydrogenation of the epoxide 25a (Scheme 6) pro-
ceeded cleanly and resulted in regioselective formation of
the 1,2-amino alcohol 29 in excellent yield. The outcome of
this reduction could be confirmed by conversion of 29 into
compound 30 in 49% yield on treatment with diphosgene.
The NMR spectroscopic data for 30 are in agreement with
an oxazolidin-2-one structure and not with a conceivable
Table 2. Epoxidation of the 6H-1,2-oxazines 5.
six-membered heterocycle derived from
alcohol.
a 1,3-amino
Entry
5
R
Method 25
% Yield
1
2
3
4
5
6
7
8
9
5a
5a
5b
5c
5d
5a
5b
5c
5d
5e
Ph
Ph
A
B
B
B
B
C
C
C
C
C
25a
39[a]
71
25a
25b
25c
25d
25a
25b
25c
25d
25e
CO2Et
3-CF3C6H4
CF3
48[b]
67
24
91
0
Ph
CO2Et
3-CF3C6H4
CF3
70
[c]
10
CH(OEt)2
52[d]
[a] Mixture of 25a/26 54:46. [b] Crude product. [c] Decomposition.
[d] In addition, 5e (19%) was recovered.
Remarkably, the reaction outcome was completely
changed when we applied hydrogen peroxide as in
Method A, but without NaOH (8 ). Instead of the epox-
ides 25 we obtained the 6-hydroperoxy-substituted 6H-1,2-
Scheme 6. Catalytic hydrogenation of the epoxides 25a and 25c.
When the epoxide 25c (Scheme 6) was subjected to the
oxazines 27a and 27b (Scheme 5) as the only products and catalytic hydrogenation protocol, we were able to isolate the
in good yields. When the reaction of 10 was performed in trans-configured 5-hydroxy-substituted 1,2-oxazine deriva-
the presence of dilute NaOH solution (2) a better yield tive 31 as a single diastereomer in moderate yield. Currently
was obtained for 27b. The hydroperoxide intermediates 27 it is not clear why the change from 25a to 25c (Ph vs. the
underwent subsequent dehydration on treatment with tri- more electron-deficient m-CF3-C6H4) considerably slowed
methylsilyl chloride and hexamethyldisilazene in dichloro- down the reduction steps. Nevertheless, the isolation of a
methane at room temperature, furnishing the 6H-1,2-ox- primary reduction product such as 31 provides additional
azin-6-ones 28a and 28b in 54–79% yields. Overall, oxi- evidence for the proposed mechanistic pathway involving a
dation of 1,2-oxazines at C-6 has thus been achieved. 6H- regioselective ring-opening of the epoxide moiety (see be-
1,2-Oxazin-6-ones are versatile compounds that can be con- low).
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1,2-Oxazines as Building Blocks for Stereoselective Synthesis
A plausible mechanism for the formation of 1,2-amino ation protocol (Method C) described above. The reactions
alcohols is illustrated in Scheme 7. The first step probably again proceeded with excellent degrees of diastereoselectiv-
involves the regioselective reduction of the epoxide unit of ity, providing the expected epoxides (6S)-32 and (6R)-32 as
25a to provide compound C.[21] Subsequent reductive cleav- single diastereomers and in very good yields. Unlike in the
age of the N–O bond followed by the reduction of the C=N case of Method C, epoxidations of (6S)-5f or (6R)-5f by
bond leads to the intermediate D. Ring closure of D and Method B afforded the expected products only in moderate
subsequent water elimination to give the cyclic imine E, fol- yields (32–42%).
lowed by reduction of the C=N unit and finally by re-
Subsequent catalytic hydrogenation of the epoxides (6S)-
ductive cleavage of the benzylic bond of the pyrrolidine F, 32 and (6R)-32 with palladium on charcoal led to the ex-
furnish the isolated 1,2-amino alcohol 29.
pected 1,2-amino alcohols (S)-29 and (R)-29 (Scheme 9) in
moderate yields but with excellent enantiomeric excesses
(Ն94%).[23] The levels of conversion in these hydrogena-
tions were high, but the yields suffered from inefficient puri-
fication caused by difficulties in completely removing liber-
ated menthol from the products. This problem could be
solved by converting the crude amino alcohols directly into
their N-Boc-protected derivatives. Under these conditions
the hydrogenation of (6S)-32 and (6R)-32 provided (2S)-33
and (2R)-33, respectively, in good overall yields. The mea-
sured optical rotation of (2S)-33 is almost identical to the
already known value, thus confirming the high optical pu-
rity of the compound.[26]
Scheme 7. Plausible mechanism for the conversion of the epoxide
25a into the 1,2-amino alcohol 29.
Synthesis of Enantiopure Compounds
The easily accessible enantiopure 6-menthyloxy-substi-
tuted 6H-1,2-oxazines (6S)-5f and (6R)-5f[22] (Scheme 8)
also served as suitable substrates for the optimized epoxid-
Scheme 9. Reductive ring opening of enantiopure 1,2-oxazines 32.
Reductive cleavage of epoxy-1,2-oxazines is just one op-
tion for use of these polyfunctionalized heterocycles. Ring
opening by attack of nucleophiles followed by transforma-
tions of the oxime ether and acetal groups would certainly
lead to more complex compounds, either in racemic or in
enantioenriched form.
Conclusions
We have presented three different approaches for the syn-
thesis of stereodefined oxygen-substituted 1,2-oxazines:
Scheme 8. Epoxidation of the enantiopure 6-menthyloxy-substi-
tuted 6H-1,2-oxazines 5f.
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18.4 Hz, 1 H, 4-H), 4.69, 4.88 (2ϫd, J = 11.7 Hz, 1 H each,
CH2Ph), 5.12–5.21 (m, 2 H, 5-H, 6-H), 7.27–7.34, 7.37–7.44 (2ϫm,
8 H, Ph), 7.69–7.74 (m, 2 H, Ph) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 21.0 (q, CH3), 23.0 (t, C-4), 63.2 (d, C-5), 69.6 (t,
CH2Ph), 92.8 (d, C-6), 125.4, 128.0, 128.1, 128.5, 128.6, 130.0,
135.2, 136.7 (6ϫd, 2ϫs, Ph), 154.2 (s, C-3), 170.3 (s, C=O) ppm.
Additional signals for cis-3: 1H NMR (300 MHz, CDCl3): δ = 2.12
(s, 3 H, CH3), 5.31–5.32 (m, 2 H, 5-H, 6-H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 20.9 (q, CH3), 65.3 (d, C-5), 69.5 (t,
CH2Ph), 92.9 (d, C-6), 125.6, 127.9, 128.4, 130.1, 137.0 (4ϫd, s,
a) direct synthesis through cycloadditions between α-ni-
trosoalkenes and appropriate electron-rich olefins such as
1, b) acid-catalysed additions of various alcohols to the 6H-
1,2-oxazines 5, which often led to mixtures of the addition
products 6 and the substitution products 7 with moderate
chemoselectivities, and c) the efficient epoxidation of the
6H-1,2-oxazines 5 which afforded the epoxides 25 in moder-
ate to excellent yields. Reactions of 5-methyl-substituted
6H-1,2-oxazine 10 often resulted in different outcomes,
leading to products such as 11, 13 or 28. Furthermore, we Ph), 155.3 (s, C-3), 170.2 (s, C=O) ppm. cis/trans-3: IR (neat): ν =
˜
3085–2880 (=C–H, C–H), 1740 (C=O), 1610 (C=N) cm–1.
C19H19NO4 (325.4): calcd. C 70.14, H 5.89, N 4.31; found C 69.79,
H 6.01, N 4.60.
have successfully demonstrated that oxygen-substituted 1,2-
oxazines such as 3, 4, 6, 16, 20, 25 and 32 are useful key
compounds that can be converted into 1,2-amino alcohols
and hydroxyproline derivatives. The developed epoxidation/
ring-cleavage sequence leading to 1,2-amino alcohols was
Ethyl 5-Acetoxy-6-(benzyloxy)-5,6-dihydro-4H-1,2-oxazine-3-carb-
oxylate (4): A mixture of the oxime 2b (0.630 g, 3.00 mmol), the
successfully expanded to the synthesis of optically pure sub- alkene 1 (3.26 g, 17.0 mmol, cis/trans = 70:30), and Na2CO3
(1.91 g, 18.0 mmol) in MeOtBu (60 mL) was stirred for 6 d as de-
scribed in GP 1. The resulting crude product was purified by col-
umn chromatography (alumina, hexane/EtOAc, 4:1) to give the 5-
acetoxy-4H-1,2-oxazine 4 (0.887 g, 92%, cis/trans = 30:70) as a
strates such as (6S)- and (6R)-32, hence smoothly allowing
the preparation of enantiopure 1,2-amino alcohols.
1
colourless oil. trans-4: H NMR (300 MHz, CDCl3): δ = 1.35 (t, J
Experimental Section
= 7 Hz, 3 H, CH3), 2.05 (s, 3 H, CH3), 2.66–2.68 (m, 2 H, 4-H),
4.32–4.39 (m, 2 H, CH2O), 4.66, 4.85 (2ϫd, J = 11.7 Hz, 1 H each,
CH2Ph), 5.11–5.14 (m, 1 H, 5-H), 5.18 (d, J = 2.4 Hz, 1 H, 6-H),
7.30–7.39 (m, 5 H, Ph) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
14.1 (q, CH3), 20.8 (q, CH3), 21.9 (t, C-4), 62.2 (t, CH2O), 61.9 (d,
C-5), 70.1 (t, CH2Ph), 93.2 (d, C-6), 128.1, 128.2, 128.5, 136.1
(3ϫd, s, Ph), 149.3 (s, C-3), 162.8, 169.9 (2ϫs, C=O) ppm. Ad-
ditional signals for cis-4: 1H NMR (300 MHz, CDCl3): δ = 1.41 (t,
J = 7 Hz, 3 H, CH3), 2.09 (s, 3 H, CH3), 2.62, 2.93 (2ϫdd, J =
7.0, 18.4 Hz, 1 H each, 4-H), 4.67, 4.87 (2ϫd, J = 11.7 Hz, 2 H
each, CH2Ph), 4.94–5.01 (m, 1 H, 5-H), 5.32 (d, J = 2.8 Hz, 1 H,
6-H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 20.7 (q, CH3), 23.2
(t, C-4), 62.3 (t, CH2O), 64.0 (d, C-5), 70.0 (t, CH2Ph), 93.4 (d, C-
6), 127.9, 128.4, 136.4 (2ϫd, s, Ph), 150.1 (s, C-3), 162.2 (s,
General: Unless otherwise stated all reactions were performed un-
der argon in flame-dried flasks with addition of the components
by syringe. All solvents were dried by standard procedures. 1H and
13C NMR spectra were recorded with Bruker instruments (AC 500,
AC 300, WH 270, AC 250) in CDCl3 or C6D6. The chemical shifts
are given relative to the TMS or to the CDCl3 signal (δH
=
7.27 ppm, δC = 77.0 ppm). Higher-order NMR spectra were ap-
proximately interpreted as first-order spectra if possible. Missing
signals of minor isomers were either hidden by signals of major
isomers or could not be unambiguously identified due to low inten-
sity. IR spectra were measured with a Nicolet 5 SXC FT-IR spec-
trometer. The MS and HRMS spectra were recorded with a Varian
MAT 711 instrument. Neutral aluminium oxide (activity III,
Fluka/Merck) or silica gel (0.040–0.063 mm, Fluka) were used for
column chromatography. Nucleosil 50-5 (Macherey–Nagel) was
used for HPLC. Melting points (uncorrected) were measured with
a Thermovar melting point microscope from Reichert. Optical ro-
tations were determined with a Perkin–Elmer 241 polarimeter. The
starting materials 1,[10] 2a and 2b,[24] 5a–d,[8c] 5e,[12b] 5f,[22] 10[8a]
and 16[9a] were prepared by literature procedures. All other chemi-
cals were commercially available and were used as received.
C=O) ppm. cis/trans-4: IR (neat): ν = 3065–2880 (=C–H, C–H),
˜
1745, 1720 (C=O), 1605 (C=N) cm–1. C16H19NO6 (321.3): calcd. C
59.81, H 5.96, N 4.36; found C 60.33, H 6.04, N 4.52.
Treatment of 6H-1,2-Oxazines with Alcohol in the Presence of Sul-
furic Acid. General Procedure 2 (GP 2): Concd. H2SO4 (1 drop/
mmol of 5) was added to a solution of the 6H-1,2-oxazine 5 in the
corresponding alcohol (5 mL/mmol of 5) and the mixture was
stirred at room temp. for the time indicated in the individual experi-
ment. The solution was then neutralized with solid NaHCO3, the
alcohol was removed in vacuo, and the residue was dissolved in
tBuOMe and filtered. The crude product was purified either by
kugelrohr distillation or by column chromatography.
Hetero Diels–Alder Reaction. General Procedure 1 (GP 1): Freshly
ground Na2CO3 (6 equiv.) was added to a solution of 1-acetoxy-2-
(benzyloxy)ethene (1, 5.3–5.7 equiv.) and the corresponding α-halo
ketoxime 2 (1 equiv.) in MeOtBu (20 mL/mmol 1). After the system
had been stirred at room temp. for the time indicated under the
individual reaction, the suspension was filtered through a pad of
Celite to remove inorganic salts. The resulting filtrate was concen-
trated in vacuo and the residue was purified by column chromatog-
raphy.
trans-5,6-Dimethoxy-3-phenyl-5,6-dihydro-4H-1,2-oxazine (6a): The
6H-1,2-oxazine 5a (0.406 g, 2.00 mmol) dissolved in MeOH
(10 mL) was treated with concd. H2SO4 for 4 h at room temp. as
described in GP 2. The resulting crude product was purified by
kugelrohr distillation: the first fraction (110 °C/0.02 mbar) gave a
5-Acetoxy-6-(benzyloxy)-3-phenyl-5,6-dihydro-4H-1,2-oxazine (3): mixture of 6a and 7a (2:1, 0.128 g) and the second fraction (120 °C/
A mixture of the oxime 2a (0.680 g, 4.01 mmol), the alkene 1 0.01 mbar) gave pure 6a (0.246 g, 56%) as a colourless oil, which
(4.97 g, 21.0 mmol, cis/trans 70:30) and Na2CO3 (2.54 g, slowly crystallized (m.p. 53–55 °C). Calculated yields: 73% (6a) and
=
24.0 mmol) in MeOtBu (80 mL) was stirred for 8 d as described in
GP 1. The resulting crude product was purified by column
chromatography (alumina, hexane/EtOAc, 4:1) to give the 5-ace-
toxy-4H-1,2-oxazine 3 (0.940 g, 72%, cis/trans = 10:90) as a colour-
less oil. trans-3: 1H NMR (300 MHz, CDCl3): δ = 2.07 (s, 3 H,
CH3), 2.64 (dd, J = 1.0, 18.4 Hz, 1 H, 4-H), 2.97 (dd, J = 5.3,
13% (7a). 5,6-trans-Configured 4H-1,2-oxazine 6a: 1H NMR
(300 MHz, CDCl3): δ = 2.60 (dd, J = 2.5, 18 Hz, 1 H, 4-Heq), 2.77
(dd, J = 5, 18 Hz, 1 H, 4-Hax), 3.45, 3.51 (2ϫs, 3 H each, OCH3),
3.68 (mc, 1 H, 5-H), 4.98 (d, J = 2.5 Hz, 1 H, 6-H), 7.35–7.39, 7.67–
7.72 (2ϫm, 3 H, 2 H, Ph) ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 23.4 (t, C-4), 55.9, 57.1 (2ϫq, OCH3), 70.5 (d, C-5), 96.2 (d, C-
4116
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4111–4121

1,2-Oxazines as Building Blocks for Stereoselective Synthesis
6), 125.6, 128.2, 129.8, 135.8 (3ϫd, s, Ph), 155.0 (s, C-3) ppm. IR
C-4) ppm. IR (ATR): ν = 3060–2850 (=C–H, C–H), 1710 (C=O),
˜
(neat):
ν =
˜
3200–2720 (=C–H, C–H), 1575 (C=N) cm–1. 1650 (C=C), 1555 (C=N) cm–1 . HRMS (ESI): calcd. for
C12H15NO3 (221.3): calcd. C 65.14, H 6.83, N 6.33; found C 65.09,
H 6.84, N 6.31. Additional spectroscopic data for 6-methoxy-3-
phenyl-6H-1,2-oxazine (7a): 1H NMR (300 MHz, CDCl3): δ = 3.48
(s, 3 H, OCH3), 5.49 (d, J = 4.5 Hz, 1 H, 6-H), 6.39 (dd, J = 4.5,
10 Hz, 1 H, 5-H), 6.58 (d, J = 10 Hz, 1 H, 4-H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 55.8 (q, OCH3), 93.2 (d, C-6), 116.3 (d,
C-4), 126.1, 125.6, 128.6, 130.1, 133.9 (4ϫd, s, Ph, C-5), 154.3 (s,
C-3) ppm.
C15H14NO3 [M]+: 256.0974; found 256.0965.
2a-Hydroxy-7b-methyl-5-phenyl-2a,3,7a,7b-tetrahydro-2H,4aH-1,7-
dioxa-6-azacyclopenta[cd]inden-4-one (14): 1H NMR (CDCl3,
400 MHz): δ = 1.31 (s, 3 H, CH3), 1.98 (s, 1 H, OH), 2.90, 3.13
(dd, d, J = 1.6, 17.6 Hz, J = 17.6 Hz, 1 H each, 3-H), 3.67 (d, J =
1.6 Hz, 1 H, 4a-H), 4.10, 4.35 (AB system, JAB = 9.4 Hz, 1 H each,
2-H), 4.88 (s, 1 H, 7a-H), 7.38–7.53, 7.77–7.82 (2ϫm, 3 H, 2 H,
Ph) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 17.0 (q, CH3), 53.4
(t, C-3), 55.8 (d, C-4a), 56.7 (s, C-7b), 77.4 (t, C-2), 78.4 (s, C-2a),
108.3 (d, C-7a), 127.0, 128.7, 131.2, 133.3 (3ϫd, s, Ph), 168.8 (s,
5-Methyl-3-phenyl-6-(prop-2-yn-1-oxy)-6H-1,2-oxazine (11): The
6H-1,2-oxazine 10 (0.406 g, 2.00 mmol) dissolved in propargyl
alcohol (10 mL) was treated with concd. H2SO4 for 3 h at room
temp. as described in GP 2. Purification by column chromatog-
raphy (alumina, hexane/EtOAc, 4:1) afforded 11 (0.420 g, 93%) as
a colourless oil. 1H NMR (300 MHz, CDCl3): δ = 2.09 (d, J =
1.4 Hz, 3 H, CH3), 2.48 (t, J = 2 Hz, 1 H, ϵCH), 4.30, 4.48 (AB
part of ABX system, JAB = 15.4, JAX = JBX = 2 Hz, 2 H, 1 H each,
OCH2), 5.65 (s, 1 H, 6-H), 6.36 (q, J = 1.4 Hz, 1 H, 4-H), 7.36–
7.47, 7.64–7.75 (2ϫm, 3 H, 2 H, Ph) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 18.8 (q, CH3), 54.6 (t, OCH2), 75.2, 78.7 (d, s, CϵCH),
93.5 (d, C-6), 112.1 (d, C-4), 126.1, 128.5, 129.8, 133.7 (3ϫd, s,
C-5), 207.5 (s, C-4) ppm. IR (ATR): ν = 3060–2860 (=C–H, C–H),
˜
1730 (C=O), 1670 (C=C), 1570 (C=N) cm–1. HRMS (ESI): calcd.
for C15H16NO4 [M + Na]+: 276.0899; found 276.0925.
Hydrogenation of 1,2-Oxazines with Palladium on Charcoal. Gene-
ral Procedure 3 (GP 3): A suspension of Pd/C (10%, 0.100–0.300 g/
mmol of 1,2-oxazine) in MeOH or in a mixture (1:1) of MeOH/
EtOAc (10 mL/mmol of 1,2-oxazine) was saturated with H2. The
corresponding 1,2-oxazine was added and the mixture was stirred
at room temp. under H2 at atmospheric pressure for the time indi-
cated in the individual experiment. The suspension was then fil-
tered through a pad of Celite with elution with EtOAc. The filtrate
was concentrated in vacuo and the crude product was purified
either by filtration or by kugelrohr distillation.
Ph), 137.3 (s, C-5), 154.1 (s, C-3) ppm. IR (neat): ν = 3120–2780
˜
(ϵC–H, =C–H, C–H), 2115 (CϵC), 1660 (C=C), 1580
(C=N) cm–1. C14H13NO2 (227.3): calcd. C 73.99, H 5.77, N 6.16;
found C 73.83, H 5.84, N 5.64.
2-Acetoxy-(4-phenylbutyl)acetamide (15): The 1,2-oxazine 3
(0.325 g, 1.00 mmol, cis/trans = 10:90) was treated with Pd/C (10%,
0.100 g) in MeOH (40 mL) under H2 for 3 d. After workup as de-
scribed in GP 3, the crude product was dissolved in CH2Cl2 (5 mL),
acetic acid anhydride (200 µL, 2.10 mmol) and pyridine (0.25 mL,
3.10 mmol) were added, and the mixture was stirred under reflux
for an additional 3 h. The solution was then cooled to room temp.
and washed with HCl solution (2 ), and the organic phase was
dried (Na2SO4). Removal of the solvent in vacuo and purification
by column chromatography (alumina, EtOAc) afforded 15 (0.077 g,
Treatment of 11 with Octacarbonyldicobalt: The 1,2-oxazine 11
(0.227 g, 1.00 mmol) was dissolved in a diethyl ether/pentane mix-
ture (3 mL/3 mL). After addition of Co2(CO)8 (0.342 g,
1.00 mmol), the solution was stirred for 15 h at room temp. It was
then filtered through neutral alumina (hexane/EtOAc, 9:1) and the
filtrate was concentrated to a third of the volume. After the solu-
tion had been kept at –10 °C, the resulting crystals were separated
and dried in vacuo (0.01 mbar) to give 12 (0.428 g, 83%) as red-
brown crystals, m.p. 90–91 °C. 1H NMR (CDCl3, 60 MHz): δ =
2.00 (mc, 3 H, CH3), 4.50–6.35 (m, 5 H, 4-H, 6-H, ϵCH, OCH2),
1
31%) as a colourless oil. H NMR (300 MHz, CDCl3): δ = 1.76–
7.45 (m , 5 H, Ph) ppm. IR (KBr): ν = 3050–2840 (ϵC–H, =C–H,
˜
c
2.00 (m, 2 H, 3-H), 1.98, 2.07 (2ϫs, 3 H each, CH3), 2.59–2.72 (m,
2 H, 4-H), 3.44–3.48 (m, 2 H, 1-H), 4.90–4.98 (m, 1 H, 2-H), 5.76
(brs, 1 H, NH), 7.15–7.22, 7.26–7.34 (2ϫm, 5 H, Ph) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 21.0, 23.0 (2ϫq, CH3), 33.3, 35.4
(2ϫt, C-3, C-4), 42.8 (t, C-1), 72.8 (d, C-2), 126.0, 128.3, 128.4,
C–H), 2055, 2030, 1995 (CϵO), 1655 (C=C), 1560 (C=N) cm–1.
MS (EI, 70 eV): m/z (%) = 457 (7) [M – 2CO]+, 429 (11) [M –
3CO]+, 401 (1) [M – 4CO]+, 373 (15) [M – 5CO]+, 355 (18) [M –
6CO]+,315(100)[M–6CO–NO]+,143(33)[Co(CO)3]+,115(15)[Co-
(CO)2]+, 87 (24) [Co(CO)]+, 77 (30) [Ph]+, 59 (60), 51 (22)
[C4H3]+. C20H13Co2NO8 (513.2): calcd. C 46.81, H 2.55, N 2.73;
found C 46.72, H 2.58, N 2.70.
140.8 (3ϫd, s, Ph), 170.2, 171.1 (2ϫs, C=O) ppm. IR (neat): ν =
˜
3410 (N–H), 3030–2865 (C–H), 1700, 1640 (C=O) cm– 1
.
C14H18NO3 (248.3): calcd. C 67.72, H 7.31, N 5.64; found C 67.21,
H 7.88, N 5.98.
Pauson–Khand Reaction of 12: Me3NO (0.316 g, 4.21 mmol) was
added in one portion at 0 °C to a solution of the 1,2-oxazine 12
(0.216 g, 0.421 mmol) in CH2Cl2 (5 mL). The solution was stirred
at this temperature for 18 h and then treated with HCl solution
(10%, 1 mL). The separated organic phase was washed with brine
(2ϫ 2 mL) and dried (Na2SO4). After removal of the solvent under
reduced pressure, the residue was purified by preparative TLC (hex-
ane/EtOAc, 4:1) to afford the tricyclic heterocycles 13 (0.017 g,
16%) as a colourless oil and 14 (0.018 g, 16%) as a colourless solid,
m.p. 136–139 °C (dec.).
Hydrogenation of 1,2-Oxazines with Raney nickel. General Pro-
cedure 4 (GP 4): Raney nickel (suspension in H2O; 0.200 g/mmol
of 1,2-oxazine) was washed several times with ethanol and finally
suspended in dry ethanol or ethanol/EtOAc (20–60 mL/mmol of
1,2-oxazine). This suspension was saturated with H2 for 30 min at
room temp. The corresponding 1,2-oxazine dissolved in ethanol (or
in ethanol/EtOAc) and Boc2O dissolved in EtOAc were added and
the mixture was stirred at room temp. under H2 at atmosphere
pressure for the time indicated in the individual experiment. The
suspension was then filtered through a pad of Celite by elution
with EtOAc. The filtrate was concentrated in vacuo and the crude
product was purified by column chromatography.
7b-Methyl-5-phenyl-7a,7b-dihydro-2H,4aH-1,7-dioxa-6-azacyclo-
penta[cd]inden-4-one (13): 1H NMR (CDCl3, 250 MHz): δ = 1.15
(s, 3 H, CH3), 3.79 (s, 1 H, 4a-H), 4.84, 4.92 (AB system, JAB
=
14.6 Hz, 1 H each, 2-H), 5.09 (s, 1 H, 7a-H), 6.19 (s, 1 H, 3-H),
7.35–7.55, 7.93–8.02 (2 ϫ m, 3 H, 2 H, Ph) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 20.8 (q, CH3), 53.9 (d, C-4a), 54.6 (s, C-
7b), 65.3 (t, C-2), 100.7 (d, C-7a), 126.5 (d, C-3), 127.3, 128.5,
128.7, 130.5 (3ϫd, s, Ph), 156.4 (s, C-5), 181.5 (s, C-2a), 199.9 (s,
1-tert-Butyl 2-Ethyl 4-(Trimethylsiloxy)pyrrolidine-1,2-dicarboxyl-
ate (21) and 1-tert-Butyl 2-Ethyl 4-Hydroxypyrrolidine-1,2-dicarb-
oxylate (22): The 1,2-oxazine 20 (0.451 g, 1.26 mmol, trans/cis
Ͼ95:5) was treated with Raney nickel (0.250 g) and Boc2O (0.413 g,
1.89 mmol) in ethanol/EtOAc (10 mL/4 mL) under H2 for 5 d as
Eur. J. Org. Chem. 2010, 4111–4121
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4117

H.-U. Reissig et al.
FULL PAPER
described in GP 4, followed by workup and purification by column
chromatography (alumina, hexane/EtOAc, 8:1) to give 21 (0.086 g,
22%, cis/trans = 65:35) and 22 (0.067 g, 22%, cis/trans = 65:35) as
colourless oils.
t-4,t-5-Epoxy-r-6-ethoxy-3-phenyl-5,6-dihydro-4H-1,2-oxazine
(25a): The 6H-1,2-oxazine 5a (0.812 g, 4.00 mmol), dissolved in a
MeOH/THF mixture (80 mL), was treated with NaOH solution
(8 , 40 mL) and H2O2 solution (30 %, 20 mL) as described in
GP 5. Workup and purification by recrystallization (Et2O) gave a
56:44 mixture of 25a and 26 (39%).
Pyrrolidine 21 (two rotamers): 1H NMR (250 MHz, CDCl3): δ =
0.09, 0.11 (2ϫs, 9 H, SiMe3), 1.25–1.30 (m, 3 H, CH3), 1.44–1.51
[m, 9 H, C(CH3)3], 2.00–2.35 (m, 2 H, 3-H), 3.27–3.39, 3.61–3.71
(2ϫm, 1 H each, 5-H), 4.14–4.39 (m, 4 H, OCH2, 2-H, 4-H) ppm.
13C NMR (62.9 MHz, CDCl3): δ = –0.3, –0.2 (2ϫq, SiMe3), 14.0,
14.1 (2ϫq, CH3), 28.2, 28.3 [2ϫq, C(CH3)3], 38.5,* 38.6,* 39.3,
39.6 (4ϫt, C-3), 53.6, 54.2, 54.4,* 54.3* (4ϫt, C-5), 57.3,* 57.7,
57.9 (3ϫd, C-2), 60.7 (t, OCH2), 69.1, 69.2, 69.9,* 70.0* (4ϫd, C-
4), 79.9 [s, C(CH3)3], 153.7 (s, C=O), 173.1, 172.3 (2 ϫ s,
C=O) ppm. Signals of the minor rotamer are marked with *. IR
The 6H-1,2-oxazine 5a (0.609 g, 3.00 mmol), dissolved in CH2Cl2
(15 mL), was treated with tBuOOH (6  in decane, 5.0 mL,
30.0 mmol) and DBU (547 mg, 3.60 mmol) as described in GP 6.
Workup and purification by chromatography (alumina, hexane/
EtOAc, 4:1) gave 25a (0.469 g, 71%) as a colourless solid.
The 6H-1,2-oxazine 5a (0.609 g, 3.00 mmol), dissolved in MeCN
(9 mL), was treated with tBuOOH (6  in decane, 1.00 mL,
6.00 mmol) and KF·Al2O3 (0.720 g, 4.50 mmol KF) for 17 h at
room temp. as described in GP 7. After workup and purification
by chromatography (alumina, hexane/EtOAc, 6:1) 25a (0.600 g,
91 %) was obtained as a colourless solid, m.p. 110–112 °C. 1H
NMR (CDCl3, 300 MHz): δ = 1.24 (t, J = 7 Hz, 3 H, Me), AB
(neat): ν = 2980–2900 (C–H), 1750, 1705 (C=O) cm– 1
.
˜
C15H29NO5Si (311.5): calcd. C 54.35, H 8.82, N 4.23; found C
54.29, H 8.51, N 4.38.
Pyrrolidine 22 (two rotamers): 1H NMR (250 MHz, CDCl3): δ =
1.15–1.26 (m, 3 H, CH3), 1.34–1.38 [m, 9 H, C(CH3)3], 1.97–2.34
(m, 2 H, 3-H), 3.14–3.62 (m, 3 H, 5-H, OH), 4.00–4.40 (m, 4 H,
OCH2, 2-H, 4-H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 13.9,
14.0 (2ϫq, CH3), 28.15, 28.24 [2ϫq, C(CH3)3], 37.6,* 38.3,* 38.5,
39.0 (4ϫt, C-3), 54.3, 55.2, 55.7* (3ϫt, C-5), 57.5,* 57.7, 57.9
(3ϫd, C-2), 60.9, 61.5, 61.7* (3ϫt, OCH2), 69.1, 69.2,* 70.0, 71.0*
(4ϫd, C-4), 80.1, 80.3 [2ϫs, C(CH3)3], 153.6, 153.9, 154.3 (3ϫs,
C=O), 173.0, 174.8 (2ϫs, C=O) ppm. Signals of the minor rotamer
part of ABX3 system (δA = 3.69, δB = 3.96, JAX = JBX = 7, JAB
=
9.5 Hz, 2 H, OCH2), 3.83 (s, 2 H, 4-H, 5-H), 5.42 (s, 1 H, 6-H),
1
7.38–7.49, 7.73–7.83 (2ϫm, 3 H, 2 H, Ph) ppm. H NMR (C6D6,
200 MHz): δ = 0.98 (t, J = 7 Hz, 3 H, Me), AB part of ABX3
system (δA = 3.23, δB = 3.30, JAX = JBX = 1.2, JAB = 4.6 Hz, 2 H,
4-H, 5-H), 3.19–3.34, 3.70–3.85 (2ϫm, 1 H each, OCH2), 5.03 (d,
J = 1.2 Hz, 1 H, 6-H), 6.97–7.06, 7.54–7.59 (2 ϫ m, 3 H, 2 H,
Ph) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 14.9 (q, Me), 41.2 (d,
C-4), 55.5 (d, C-5), 64.8 (t, OCH2), 93.6 (d, C-6), 126.2, 128.7,
are marked with *. IR (neat): ν = 3445 (O–H), 2980–2935 (C–H),
˜
130.4, 133.5 (3 ϫ d, s, Ph), 158.3 (s, C-3) ppm. IR (Nujol): ν =
˜
1750, 1700 (C=O) cm–1. The spectroscopic data are in agreement
with those given in ref.[25]
3250–2550 (=C–H, C–H), 1560 (C=N) cm–1. C20H27NO3 (329.4):
calcd. C 72.92, H 8.26, N 4.25; found C 72.93, H 8.27, N 4.39.
Epoxidation of 1,2-Oxazines with Hydrogen Peroxide. General Pro-
cedure 5 (GP 5): NaOH solution (8 , 10 mL/mmol 5) and H2O2
solution (30%, 5 mL/mmol 5) were added dropwise at 0 °C to a
vigorously stirred solution of the appropriate 6H-1,2-oxazine 5 in
a 3:1 mixture of MeOH and THF (20 mL/mmol 5). The mixture
was stirred at 0 °C for 2.5 h and diluted with H2O (50 mL/mmol
5). The solution was then carefully quenched with aqueous sodium
hydrogen sulfite (40%, 10 mL/mmol 5) to destroy excess H2O2. The
aqueous phase was separated and extracted with CH2Cl2
(3ϫ40 mL/mmol 5), and the combined organic extracts were dried
(Na2SO4). The crude product was purified as described in the indi-
vidual experiment.
trans-6-Ethoxy-5-methoxy-3-phenyl-5,6-dihydro-4H-1,2-oxazine
(26): 1H NMR (CDCl3, 200 MHz): δ = 1.20 (t, J = 7 Hz, 3 H, Me),
2.61 (dd, J = 2.3, 18 Hz, 1 H, 4-Heq), 2.80 (dd, J = 5.2, 18 Hz, 1
H, 4-Hax), 3.47 (s, 3 H, OMe), 3.64–3.74, 3.89–4.03 (2ϫm, 2 H, 1
H, 5-H, OCH2), 5.09 (d, J = 2.8 Hz, 1 H, 6-H), 7.37–7.43, 7.68–
7.74 (2ϫm, 3 H, 2 H, Ph) ppm. 13C NMR (CDCl3, 50.3 MHz): δ
= 15.0 (q, Me), 23.5 (t, C-4), 57.0 (q, OMe), 63.9 (t, OCH2), 70.7
(d, C-5), 94.9 (d, C-6), 125.4, 128.4, 129.9, 135.7 (3ϫd, s, Ph),
154.8 (s, C-3) ppm.
6-Hydroperoxy-3-phenyl-6H-1,2-oxazine (27a): H2O2 (30% in H2O,
10 mL) was added to a solution of the 6H-1,2-oxazine 5a (0.406 g,
2.00 mmol) dissolved in MeOH/THF (15 mL/5 mL) and the mix-
ture was stirred for 5 h at 0 °C. It was then slowly poured into
aqueous sodium hydrogen sulfite solution (40 %) and saturated
aqueous NaHCO3 solution (20 mL each) and the mixture was
stirred for an additional 0.5 h at room temp. The aqueous layer
was extracted with diethyl ether (3ϫ 20 mL) and dried (MgSO4).
Purification by recrystallization (CH2Cl2/hexane) gave 27a (0.224 g,
59 %) as a colourless solid, m.p. 116–117.5 °C (dec.). 1H NMR
([D6]acetone, 300 MHz): δ = 3.05 (s, 1 H, OOH), 6.12 (mc, 1 H, 6-
H), 6.50 (dd, J = 5, 10 Hz, 1 H, 5-H), 6.91 (dd, J = 0.5, 10 Hz, 1
H, 4-H), 7.44–7.49, 7.74–7.80 (2ϫm, 3 H, 2 H, Ph) ppm. 13C NMR
([D6]acetone, 75.5 MHz): δ = 96.6 (d, C-6), 119.1 (d, C-4), 123.8,
126.7, 129.6, 130.8, 134.7 (4ϫd, s, Ph, C-5), 154.2 (s, C-3) ppm.
Epoxidation of 1,2-Oxazines with tert-Butyl Hydroperoxide. General
Procedure 6 (GP 6): tert-Butyl hydroperoxide (1.2–10 equiv.) and
DBU (1.2 equiv.) were added to a solution of the 6H-1,2-oxazine 5
(1 equiv.) in CH2Cl2 (3–5 mL/mmol 5) and the mixture was stirred
at room temp. for 2 d. It was then diluted with CH2Cl2 (3–5 mL/
mmol 5), aqueous sodium hydrogen sulfite solution (40%, 3–5 mL/
mmol 5) was added, and the mixture was stirred for an additional
1 h at room temp. The organic layer was washed with H2O and
brine (1ϫ10 mL each/mmol 5) and dried (Na2SO4). The crude
product was purified as described in the individual experiment.
Epoxidation of 1,2-Oxazines with tert-Butyl Hydroperoxide and
KF·Al2O3. General Procedure 7 (GP 7): tert-Butyl hydroperoxide
(2 equiv.) and the corresponding 1,2-oxazine 5 (1 equiv.), dissolved
in MeCN (0.5 mL/mmol 5), were added to a suspension of
KF·Al2O3 (1.5 mmol KF/mmol 5) in MeCN (3 mL/mmol 5). The
mixture was stirred for the time indicated in the individual experi-
ment at room temp. The suspension was then filtered through Ce-
lite with elution with EtOAc and the filtrate was concentrated in
vacuo. The crude product was purified as described in the individ-
ual experiment.
IR (KBr): ν = 3120 (O–H), 3080–2700 (=C–H, C–H), 1645 (C=C),
˜
1535 (C=N) cm–1. C10H9NO3 (191.2): calcd. C 62.82, H 4.75, N
7.33; found C 62.57, H 4.67, N 7.22.
3-Phenyl-6H-1,2-oxazin-6-one (28a): TMSCl (1 mL) was added to
a suspension of the 6H-1,2-oxazine 27a (0.147 g, 0.770 mmol) in
HMDS (10 mL) and the system was stirred for 1 d at room temp.
The solvent was then removed under reduced pressure and the resi-
due was purified by recrystallization to afford the 1,2-oxazin-6-one
4118
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4111–4121

1,2-Oxazines as Building Blocks for Stereoselective Synthesis
28a (0.072 g, 54 %) as colourless crystals, m.p. 152–153 °C. 1H
NMR ([D6]acetone, 300 MHz): δ = 6.96 (d, J = 10 Hz, 1 H, 5-H),
7.52–7.63, 7.87–7.93 (2ϫm, 3 H, 2 H, Ph), 7.91 (d, J = 10 Hz, 1
H, 4-H) ppm. 13C NMR ([D6]acetone, 75.5 MHz): δ = 126.2, 127.6,
130.0, 131.9, 132.6, 133.4 (4ϫd, s, d, Ph, C-4, C-5), 154.7 (s, C-3),
room temp. as described in GP 7. Workup and purification by
chromatography (alumina, hexane/EtOAc, 8:1) gave (4S,5S,6S)-32
(0.056 g, 94%) as colourless crystals, m.p. 146–147 °C, [α]2D5 = –16.0
(c = 0.10, CHCl3). 1H NMR (CDCl3, 300 MHz): δ = 0.76–1.70 [m,
16 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H, 5Ј-CH3, CH(CH3)2], 2.09 [mc, 1 H,
CH(CH3)2], 2.21–2.28 (m, 1 H, 2Ј-H), 3.57 (dt, J = 4.5, 10.5 Hz, 1
163.1 (s, C-6) ppm. IR (KBr): ν = 3080–2900 (=C–H, C–H), 1745
˜
(C=O), 1620 (C=C), 1520 (C=N) cm–1. C10H7NO2 (173.2): calcd. H, 1Ј-H), 3.83 (s, 2 H, 4-H, 5-H), 5.44 (s, 1 H, 6-H), 7.41–7.51,
C 69.36, H 4.01, N 8.09; found C 69.34, H 4.04, N 8.19.
7.68–7.77 (2 ϫ m, 3 H, 2 H, Ph) ppm. 13C NMR (CDCl3,
75.5 MHz): δ = 16.3, 21.1 [2ϫq, CH(CH3)2], 22.1 (q, 5Ј-CH3), 23.2
(t, C-3Ј), 25.7 [d, CH(CH3)2], 31.6 (d, C-5Ј), 34.2 (t, C-4Ј), 42.4 (t,
C-6Ј), 41.6 (d, C-4), 48.6 (d, C-2Ј), 55.5 (d, C-5), 80.9 (d, C-1Ј),
94.9 (d, C-6), 126.4, 128.8, 130.4, 133.7 (3ϫd, s, Ph), 158.2 (s, C-
1-Amino-4-phenylbutan-2-ol (29): The 1,2-oxazine 25a (0.327 g,
1.49 mmol) was treated with Pd/C (10%, 0.150 g) in MeOH/EtOAc
(15 mL) under H2 for 20 h as described in GP 3, followed by
workup and purification by filtration (alumina, hexane/EtOAc, 2:1)
3) ppm. IR (KBr): ν = 3050–2800 (=C–H, C–H), 1620 (C=N) cm–1.
˜
1
to give 29 (0.236 g, 96%) as a colourless oil. H NMR (300 MHz,
C20H27NO3 (329.4): calcd. C 72.92, H 8.26, N 4.25; found C 72.45,
H 7.78, N 4.29.
CDCl3): δ = 1.62–1.78 (m, 2 H, CH2), 2.52–2.85 (m, 4 H, CH2),
2.89 (brs, 3 H, OH, NH2), 3.51–3.58 (m, 1 H, 2-H), 7.14–7.29 (m,
5 H, Ph) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 31.9, 36.3 (2ϫt,
C-3, C-4), 47.3 (t, C-1), 71.1 (d, C-2), 125.7, 128.28, 128.30, 141.9
(3ϫd, s, Ph) ppm. Complete characterization was performed after
the following protection step.
(4R,5R,6R)-6-[(1ЈR,2ЈS,5ЈR)-2Ј-Isopropyl-5Ј-methylcyclohexyl-
oxy]-4,5-epoxy-3-phenyl-5,6-dihydro-4H-1,2-oxazine [(6R)-32]: The
6H-1,2-oxazine (6R)-5f (0.846 g, 2.70 mmol), dissolved in MeCN
(12 mL), was treated with tBuOOH (6  in decane, 0.90 mL,
5.40 mmol) and KF·Al2O3 (0.646 g, 4.05 mmol KF) for 24 h at
room temp. as described in GP 7. Workup and purification by
chromatography (alumina, hexane/EtOAc, 8:1) gave (4R,5R,6R)-32
(0.756 g, 85%) as colourless crystals, m.p. 141–143 °C, [α]2D8 = –42.4
(c = 0.50, CHCl3). 1H NMR (CDCl3, 300 MHz): δ = 0.71–1.74 [m,
16 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H, 5Ј-CH3, CH(CH3)2], 2.06 [mc, 1 H,
CH(CH3)2], 2.09–2.20 (m, 1 H, 2Ј-H), 3.72 (dt, J = 4, 10.5 Hz, 1
H, 1Ј-H), 3.77 (dd, J = 1, 4.5 Hz, 1 H, 5-H), 3.81 (d, J = 4.5 Hz,
1 H, 4-H), 5.58 (d, J = 1 Hz, 1 H, 6-H), 7.41–7.54, 7.63–7.76
(2ϫm, 3 H, 2 H, Ph) ppm. 13C NMR (CDCl3, 75.5 MHz): δ =
15.9, 21.0 [2ϫq, CH(CH3)2], 22.3 (q, 5Ј-CH3), 22.8 (t, C-3Ј), 25.2
[d, CH(CH3)2], 31.3 (d, C-5Ј), 34.3 (t, C-4Ј), 40.2 (t, C-6Ј), 41.3 (d,
C-4), 47.9 (d, C-2Ј), 56.2 (d, C-5), 76.6 (d, C-1Ј), 93.7 (d, C-6),
126.1, 128.8, 130.4, 133.8 (3ϫd, s, Ph), 158.3 (s, C-3) ppm. IR
5-(2-Phenylethyl)oxazolidin-2-one (30): Aqueous NaOH solution
(50 %, 5 mL) and diphosgene (324 µL, 2.67 mmol) were slowly
added at –20 °C to a solution of the amino alcohol 29 (0.230 g,
1.39 mmol) in CH2Cl2 (5 mL) and the mixture was stirred for 1.5 h
at room temp. For the subsequent hydrolysis of excess diphosgene,
water (5 mL) was added. After separation of the phases, the aque-
ous phase was extracted with CH2Cl2 (3ϫ 5 mL) and the combined
organic phases were dried (Na2SO4), and concentrated in vacuo.
The resulting residue was purified by column chromatography
(SiO2, hexane/EtOAc, 1:2, then EtOAc/MeOH, 1:1) to yield 30
(0.130 g, 49 %) as colourless crystals, m.p. 82–84 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.89–1.96, 2.08–2.16 (2 ϫm, 1 H each,
CH2), 2.69–2.75, 2.80–2.86 (2ϫm, 1 H each, CH2Ph), 3.20–3.23,
3.56–3.66 (2ϫm, 1 H each, NCH2), 4.56–4.62 (m, 1 H, OCH), 6.06
(brs, 1 H, NH), 7.15–7.32 (m, 5 H, Ph) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 31.9 (t, CH2Ph), 36.6 (t, CH2), 45.8 (t, NCH2), 76.0
(d, OCH), 126.2, 128.4, 128.5, 140.4 (3 ϫ d, s, Ph), 160.0 (s,
(KBr):
ν =
˜
3050–2800 (=C–H, C–H), 1630 (C=N) cm–1.
C20H27NO3 (329.4): calcd. C 72.92, H 8.26, N 4.25; found C 72.93,
H 8.27, N 4.39.
C=O) ppm. IR (KBr): ν = 3290 (N–H), 3090–2860 (=C–H, C–H),
˜
tert-Butyl (2S)-(2-Hydroxy-4-phenylbutyl)carbamate (33): The 1,2-
oxazine (6S)-32 (0.151 g, 0.458 mmol) was treated with Pd/C (10%,
0.080 g) in MeOH/EtOAc (10 mL/4 mL) under H2 for 1 d as de-
scribed in GP 3, followed by workup and removal of the liberated
menthol by sublimation (50 °C, 0.05 mbar). The crude (2S)-29
(0.088 g) was directly dissolved in CH2Cl2 (4.5 mL), and Hünig
base (162 µL, 0.916 mmol) and Boc2O (0.111 g, 0.505 mmol) were
subsequently introduced into the reaction mixture. After 3 h at
room temp., the mixture was diluted with EtOAc (5 mL), washed
with satd. aq. NH4Cl solution, water and brine (3 mL each) and
dried (MgSO4), and the solvent was removed under reduced pres-
sure. The crude product was purified by column chromatography
(silica gel, hexane/EtOAc, 2:1) to afford (2S)-33 (0.100 g, 82%) as
a colourless oil, [α]2D3 = –8.8 (c = 0.63, CH2Cl2); ref.[26]: [α]2D5 = –8.86
(c = 0.56, CH2Cl2). The spectroscopic data agree with the data
given in the literature.[26]
1720 (C=O) cm–1. C11H13NO2 (191.2): calcd. C 69.09, H 6.87, N
7.32; found C 69.70, H 7.01, N 7.15.
6-Ethoxy-5-hydroxy-3-(3-trifluoromethylphenyl)-5,6-dihydro-4H-
1,2-oxazine (31): The 1,2-oxazine 25c (0.458 g, 1.59 mmol) was
treated with Pd/C (10%, 0.160 g) in MeOH (15 mL) under H2 for
20 h as described in GP 3, followed by workup and purification by
column chromatography (alumina, hexane/EtOAc, 4:1) to give 31
1
(0.155 g, 34%) as a brownish resin. H NMR (CDCl3, 300 MHz):
δ = 1.21 (t, J = 7 Hz, 3 H, Me), 2.27 (dd, J = 2.3, 18 Hz, 1 H, 4-
Heq), 2.36 (s, 1 H, OH), 2.89 (dd, J = 5.2, 18 Hz, 1 H, 4-Hax), 3.64–
3.74, 3.87–3.98 (2ϫm, 1 H each, OCH2), 4.12 (mc, 1 H, 5-H), 4.99
(d, J = 3 Hz, 1 H, 6-H), 7.52 (t, J = 7.8 Hz, 1 H, Ar), 7.66, 7.88
(2ϫd, J = 7.8 Hz each, 2 H, Ar), 7.97 (s, 1 H, Ar) ppm. 13C NMR
(CDCl3, 75.5 MHz): δ = 14.9 (q, Me), 26.7 (t, C-4), 61.6 (d, C-5),
64.4 (t, OCH2), 97.5 (d, C-6), 123.9 (q, 1JC,F = 274 Hz, CF3), 122.3,
126.4 (2ϫdq, 3JC,F = 3.8 Hz each, Ar), 128.6 (q, 4JC,F = 1 Hz, Ar),
tert-Butyl (2R)-(2-Hydroxy-4-phenylbutyl)carbamate (33): The 1,2-
oxazine (6R)-32 (0.115 g, 0.348 mmol) was treated with Pd/C (10%,
0.061 g) in MeOH/EtOAc (8 mL/3 mL) under H2 for 1 d as de-
scribed in GP 3, followed by workup and removal of the liberated
menthol by sublimation (50 °C, 0.05 mbar). The crude (2R)-29
(0.053 g) was directly dissolved in CH2Cl2 (4 mL), and Hünig base
(123 µL, 0.696 mmol) and Boc2O (0.084 g, 0.384 mmol) were sub-
sequently introduced into the reaction mixture. After 3 h at room
temp., the mixture was diluted with EtOAc (4 mL), washed with
satd. aq. NH4Cl solution, water and brine (3 mL each) and dried
2
129.1 (d, Ar), 131.0 (q, JC,F = 33 Hz, Ar), 136.2 (s, Ar), 154.4 (s,
C-3) ppm. IR (neat): ν = 3400 (O–H), 3040–2930 (=C–H, C–H),
˜
1600 (C=N), 1170, 1130 (C–F) cm–1. C13H14F3NO3 (289.3): calcd.
C 53.97, H 4.89, N 4.84; found C 54.32, H 5.11, N 4.96.
(4S,5S,6S)-6-[(1ЈR,2ЈS,5ЈR)-2Ј-Isopropyl-5Ј-methylcyclohexyloxy]-
4,5-epoxy-3-phenyl-5,6-dihydro-4H-1,2-oxazine [(6S)-32]: The 6H-
1,2-oxazine (6S)-5f (0.057 g, 0.18 mmol), dissolved in MeCN
(1 mL), was treated with tBuOOH (6  in decane, 59 µL,
0.36 mmol) and KF·Al2O3 (0.043 g, 0.27 mmol KF) for 22 h at
Eur. J. Org. Chem. 2010, 4111–4121
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4119

H.-U. Reissig et al.
FULL PAPER
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The replacement of the 6-alkoxy group obviously proceeds via
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(MgSO4), and the solvent was removed under reduced pressure.
The crude product was purified by column chromatography (silica
gel, hexane/EtOAc, 3:1) to afford (2R)-33 (0.050 g, 55%) as a
colourless oil, [α]2D3 = +8.6 (c = 0.64, CH2Cl2).
Supporting Information (see also the footnote on the first page of
this article): Procedures for the synthesis of 6b–d, 9, 17, 18, 23, 24,
25b–e, 27b, 28b, (2R)-29 and (2S)-29.
Acknowledgments
We are most grateful for generous support of this work by the
Deutsche Forschungsgemeinschaft (DFG) (Graduiertenkolleg
“Struktur-Eigenschafts-Beziehungen
bei
Heterocyclen”
at
TU Dresden), the Fonds der Chemischen Industrie and Bayer
Schering Pharma AG. We thank Regina Czerwonka, Ute Hain
(TU Dresden), Luise Schefzig, Daniel M. Ziemens and Robby
Klemme (FU Berlin) for their experimental help.
[6]
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Received: March 30, 2010
Published Online: June 10, 2010
Eur. J. Org. Chem. 2010, 4111–4121
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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