The first catalytic inverse-electron demand hetero-Diels-Alder reaction of nitroso alkenes using pyrrolidine as an organocatalyst

Article abstract of DOI:10.1039/b316518c

The first catalytic inverse-electron demand hetero-Diels-Alder reaction of nitroso alkenes has been developed. Nitroso alkenes were generated in situ from α-halooximes and underwent [4 + 2]-cycloadditions with enamines as dienophiles formed from aldehydes and pyrrolidine (10 mol%) as an organocatalyst, The presence of a suitable heterogeneous buffer system was found to be essential and best results were obtained with sodium acetate trihydrate. The resulting 5,6-dihydro-4H-oxazines were obtained in moderate to good yields under mild reaction conditions. A catalytic cycle has been proposed and evidence for the cycloaddition mechanism has been obtained. Moderate asymmetric induction (42% ee) was observed when a chiral secondary amine was used.

Full text of DOI:10.1039/b316518c

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The first catalytic inverse-electron demand hetero-Diels–Alder
reaction of nitroso alkenes using pyrrolidine as an organocatalyst
Tobias C. Wabnitz, Steen Saaby and Karl Anker Jørgensen*
The Danish National Research Foundation: Center for Catalysis, Department of Chemistry,
Aarhus University, 8000 Aarhus C, Denmark. E-mail: kaj@chem.au.dk;
Fax: (ϩ45) 8619-6199; Tel: (ϩ45) 8942-3910
Received 17th December 2003, Accepted 29th January 2004
First published as an Advance Article on the web 16th February 2004
The first catalytic inverse-electron demand hetero-Diels–Alder reaction of nitroso alkenes has been developed.
Nitroso alkenes were generated in situ from α-halooximes and underwent [4 ϩ 2]-cycloadditions with enamines
as dienophiles formed from aldehydes and pyrrolidine (10 mol%) as an organocatalyst. The presence of a suitable
heterogeneous buffer system was found to be essential and best results were obtained with sodium acetate trihydrate.
The resulting 5,6-dihydro-4H-oxazines were obtained in moderate to good yields under mild reaction conditions.
A catalytic cycle has been proposed and evidence for the cycloaddition mechanism has been obtained. Moderate
asymmetric induction (42% ee) was observed when a chiral secondary amine was used.
base-mediated dehydrohalogenations of the readily available
α-halooximes and furnish the cycloadducts 1 in a highly
Introduction
Over the last years, 5,6-dihydro-4H-oxazines have been shown
regioselective fashion.
to be versatile synthetic intermediates for the preparation of a
Although numerous applications of this reaction have been
large number of diverse products. It has been demonstrated in
reported, severe restrictions have remained in place. Due to their
several reports that these oxazine derivatives of the generalised
high reactivity, only very few, sterically encumbered nitroso
structure
1 can be readily converted into oxazinones,
alkenes have been isolated and characterised.4 It is also known
that processes involving these intermediates are prone to side
reactions such as polymerisations. Similarly, long reaction times
of up to 10 days are necessary to minimise the concentration
of free nitroso alkenes and large excesses of the dienophiles
are required in order to obtain acceptable yields. Furthermore,
the requirement to preform reactive dienophiles such as enol
ethers has limited the practicability of this otherwise very useful
conversion.
pyrrolidines, pyrroles, amino alcohols, amines, 1,3-dicarbonyl
compounds and other products via simple oxidations,
reductions or hydrolysis reactions (Scheme 1).1
In order to increase the reaction scope and enable its
application to a large number of substrates, our investigations
focused on the development of a catalytic hetero-Diels–
Alder reaction of nitroso alkenes using inexpensive and readily
available reagents and catalysts, with possible extensions to
enantioselective variants. The results of these investigations are
presented in this article.
Results and discussion
Lewis acid catalysts need to be avoided in processes involving
nitroso alkenes as they are known to increase the high reactivity
of these species even further and lead to the formation of
undesired dimerisation products and polymers.5 Encouraged
by recent advances in organocatalytic cycloaddition reactions,
we decided to pursue such an approach.6 Mixtures of alde-
hydes and catalytic amounts of secondary amines such as
pyrrolidine can reversibly generate electron-rich enamines.
These compounds are suitable dienophiles for cycloadditions
with inverse electron demand. The envisaged catalytic cycle is
shown in Scheme 3.
Initial experiments with the preformed enamine 4, formed
from isovaleraldehyde and pyrrolidine, and α-bromoaceto-
phenone oxime (2a) revealed that both the anticipated amino-
acetal 1a as well as the desired dihydro oxazine 1b were formed
in this reaction (Scheme 4). Both products 1a and 1b could be
isolated as mixtures of diastereomers. However, low yields and
the formation of several unidentified by-products indicated that
there were several challenges inherent to this reaction sequence
which needed to be addressed.
Scheme 1 Transformations of 5,6-dihydro-4H-oxazines 1.
As outlined in Scheme 2, the oxazines 1 are in turn easily
accessible from α-halooximes 2 and olefinic substrates such
as enol ethers, enamines, alkenes or allenes. Owing to the
fundamental studies of Gilchrist et al. and the thorough
investigations performed by Reißig and coworkers, these pro-
cesses have been identified as hetero-Diels–Alder reactions with
inverse-electron demand involving transient nitroso alkenes 3.2,3
These highly reactive intermediates can be generated through
Scheme 2 Synthesis of 5,6-dihydro-4H-oxazines 1 via hetero-Diels–
Alder reactions involving transient nitroso alkenes.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 2 8 – 8 3 4
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
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Scheme 3 Catalytic cycle of the pyrrolidine-mediated hetero-Diels–Alder reaction of nitroso alkenes with enamines leading to 5,6-dihydro-4H-
oxazines.
Table 1 Effect of solid bases/buffers on catalytic turnover
Entry
Base
Conversion (%)
30
Ratio 1a : 1b
1
2
3
4
5
6
7
8
9
No base
Na2CO3
Na2CO3ؒH2O
Na2CO3ؒ10H2O
NaHCO3
KH2PO4
Na2HPO4ؒ2H2O
Na2C2O4
Na3C6H5O7ؒ2H2O
NaOAc
30 : 70
(100 : 0)
(100 : 0)
(100 : 0)
20 : 80
30 : 70
20 : 80
30 : 70
30 : 70
10 : 90
5 : 95
a
—
—
—
Scheme 4 Reaction of α-halooximes with preformed enamines.
a
a
It is well known that nitroso alkenes are highly susceptible
to conjugate additions of heteroatom nucleophiles, especially
amines.4 It was confirmed in the present case that an instant-
aneous addition of pyrrolidine to α-bromoacetophenone oxime
(2a) took place at room temperature and the resulting tertiary
amine 5 was isolated in high yield (Scheme 5).7 However,
this side reaction could be completely suppressed when the
oxime was added as the last reaction component to a solution
containing the amine catalyst and an excess of the aldehyde,
thereby shifting the initial equilibrium towards the enamine (see
Scheme 3).
50
30
40
30
30
80
95
10
11
12
NaOAcؒ3H2O
NaOAcؒ3H2Ob
—
—
c
a Decomposition. b No pyrrolidine added. c No conversion.
α-chloroacetophenone oxime (2b), isovaleraldehyde and
catalytic amounts of pyrrolidine (10 mol%). The results of
these studies are summarised in Table 1.
As expected, only moderate amounts of the hetero-Diels–
Alder adducts were observed in the absence of base and conver-
sion ceased after approximately 30% of the starting material
had been consumed (Table 1, entry 1).9 Sodium carbonate
(Na2CO3) and hydrates thereof (Na2CO3ؒnH2O), which are
the most commonly used bases for dehydrohalogenations of
α-halooximes, were employed in initial experiments but were
found to induce serious decomposition reactions and could
not be used. Only traces of the aminoacetal 1a were detected
in these cases (entries 2–4). In the presence of the less basic
sodium hydrogen carbonate (NaHCO3), conversion to the
desired products was slightly enhanced (entry 5). In contrast,
phosphate, oxalate and citrate salts turned out to be unsuitable
buffers and virtually identical conversions compared to the
base-free reaction were detected (entries 6–9). Sodium acetate
(NaOAc), on the other hand, dramatically accelerated catalytic
turnover to the desired hemiacetal 1b (entry 10) and an even
more rapid reaction took place when sodium acetate trihydrate
(NaOAcؒ3H2O) was used (entry 11).10 It is likely that the acetate
Scheme 5 Reaction of α-bromoacetophenone oxime with pyrrolidine.
Although pyrrolidine, or the corresponding enamines, were
sufficiently basic to induce dehydrohalogenation of the α-halo-
oxime, one equivalent of acid liberated in this process has to
be neutralised in order to achieve catalytic turnover and the
presence of a base is therefore necessary. In contrast, the hydro-
lytic cleavage of the intermediate aminoacetal to release
the amine catalyst (see Scheme 3) calls for a slightly acidic
medium.6a In order to balance these apparently irreconcilable
requirements we decided to employ heterogeneous buffer
systems in order to keep the proton concentration in solution
approximately constant throughout the reaction.8 Various
buffers were examined for their ability to neutralise acid and
enhance hydrolytic cleavage in the model reaction comprising
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 2 8 – 8 3 4
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Table 2 Effect of different solvents on catalytic turnover
dienophile precursor due to rapid condensation reactions in the
presence of pyrrolidine (entry 7).15 Both the α-chlorooxime 2b
and the analogous bromooxime 2a could be used and very
similar yields were obtained (entry 1 vs. 8). Aldehydes bearing
additional substituents in the α-position such as isobutyralde-
hyde and 2,2-diphenylacetaldehyde did not lead to the
formation of the desired oxazine hetero-Diels–Alder adducts,
probably due to increased steric demand and decreased reac-
tivity of the corresponding enamines (entries 9,10). Similarly,
electron-rich nitroso alkenes are known to be much less reactive
than those bearing electron-withdrawing groups.1j Therefore, it
was not surprising when no conversion was observed with α-
chloro-4-methoxyacetophenone oxime (2c) under the standard
reaction conditions (entries 11,12). However, the desired
product could be obtained when stoichiometric amounts of
pyrrolidine were used (entry 13). In contrast, the electron-poor
α-bromo-4-nitroacetophenone oxime (2d) was found to be
highly reactive and the oxazines 1i–1k were obtained in reduced
reaction times (entries 14–16). In a similar manner, reactions
with 3-bromopyruvate oxime (2e) furnished the hetero-Diels–
Alder adducts within 24 h, but yields were lower than expected
due to side reactions of the starting material (entries 17–20). In
addition, NaOAcؒ3H2O could not be used as a buffer in these
cases because of competitive reactions of the starting material
with acetate and a NaHCO3-based buffer had to be used
instead.16
It is to be expected that the studies presented herein will
greatly facilitate the development of a corresponding enantio-
selective access to oxazine derivatives. Initial experiments along
this route were carried out using stoichiometric amounts of
the chiral amine (S)-(ϩ)-1-(2-pyrrolidinylmethyl)pyrrolidine
and first results are promising as the oxazinone 8 could be
obtained with 42% ee after oxidation of the hemiacetal 1h with
pyridinium chlorochromate() (PCC) (Scheme 7). Preliminary
studies on catalytic enantioselective reactions revealed that
such processes are possible, but due to slower rates of the
enamine formation and cycloaddition steps (see Scheme 3)
yields were low and substantial amounts of by-products
were formed. These drawbacks will be addressed in further
studies.
Entry
Solvent
Conversion (%)
Ratio 1b : 6
1
2
3
4
5
6
7
CH2Cl2
CHCl3
Et2O
PhCH3
THF
CH3CN
CH3NO2
95
95
20
100 : 0
100 : 0
75 : 25
90 : 10
10 : 90
5 : 95
70
100
100
100
0 : 100
buffer provides the correct combination of basicity/acidity as
well as low nucleophilicity. A control experiment also con-
firmed that the role of NaOAcؒ3H2O was indeed solely as a
buffer as no product formation was observed in the absence of
pyrrolidine (entry 12).
With a suitable buffer system in hand, further studies aimed
at finding the optimum reaction conditions for the hetero-
Diels–Alder reaction of the nitroso alkene generated from the
α-chlorooxime 2b were carried out (Table 2). While the reaction
proceeded rapidly in dichloromethane and chloroform (entries
1,2), slower conversion and formation of the undesired ester 6
were observed in ether and toluene (entries 3,4). When more
polar solvents such as THF, acetonitrile or nitromethane were
used, 6 turned out to be the main product (entries 5–7). In these
cases, the ester 6 is either formed via conjugate addition of
acetate to the transient nitroso alkene or via a nucleophilic
substitution pathway which is expected to be facilitated in
dipolar aprotic solvents.11
Although Gilchrist and Reißig and their coworkers presented
compelling evidence for the electrocyclic nature of oxazine
formation from α-halooximes (as a source of transient nitroso
alkenes) and dienophiles, these findings cannot be transferred
directly to reactions of enamines as these compounds are
known to be strongly polarised and highly nucleophilic.2,3 To
assess the ease of nucleophilic substitution reactions in the
present system, the α-bromo- and α-chloro-O-methyloximes 7a
and 7b were synthesised and employed under the established
reaction conditions (Scheme 6). These α-halooximes are unable
to generate nitroso alkenes via dehydrohalogenation, hence
additions of enamines to these compounds have to proceed
through substitution mechanisms. No products were detected
after 5 days, confirming the involvement of intermediate
nitroso alkenes and pointing towards a hetero-Diels–Alder
cycloaddition pathway when the non-O-alkylated α-halooximes
2 are employed as substrates.12–14
Scheme 7 Formation of oxazine derivatives mediated by a chiral
secondary amine.
Conclusion
In summary, the first catalytic hetero-Diels–Alder reaction of
nitroso alkenes using simple and inexpensive catalysts and
reagents such as pyrrolidine, aldehydes and NaOAcؒ3H2O has
been developed. Underlying mechanistic principles and key
stages in the catalytic cycle as well as potential side reactions
have been identified and a number of 5,6-dihydro-4H-oxazines
have been prepared in moderate to good yields in one step
from α-halooximes under mild reaction conditions. Preliminary
results indicate that a catalytic enantioselective reaction is
possible.
Scheme 6 Reaction of O-methylated α-halooximes 7 with enamines.
Based on these results, the scope of the newly developed
organocatalytic hetero-Diels–Alder reaction of nitroso alkenes
was investigated using NaOAcؒ3H2O as a heterogeneous buffer
in dichloromethane (Table 3). Good yields of the cycloaddition
products were obtained when α-chloroacetophenone oxime
(2b) and α-unbranched aldehydes were used (entries 1–6). In
this category, only acetaldehyde turned out to be an unsuitable
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 2 8 – 8 3 4
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Table 3 Organocatalytic synthesis of oxazine derivatives from α-halooximes and aldehydes
Entry
Oxime
R1
Hal
R2
R3
t/h
Product
Yield (%)
1
2
3
4
5
2b
2b
2b
2b
2b
2b
2b
2a
2b
2b
2c
2c
2c
2d
2d
2d
2e
2e
2e
2e
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
iPr
Me
Et
H
H
H
H
H
H
H
H
Me
Ph
H
H
H
H
H
H
H
H
H
H
72
72
72
72
72
72
24
72
72
72
72
72
2
24
24
24
24
24
24
24
1b
1c
1d
1e
1f
1g
–
1b
–
–
–
81
69
89
77
87
68
nPr
Ph
Bn
H
6
7a
8
–
b
iPr
Me
Ph
iPr
Bn
iPr
iPr
Bn
Me
iPr
ePr
Et
75
c
9
Ph
Ph
–
–
–
–
c
10
11
12
13d
14
15
16
17e
18e
19e
20e
c
p-MeO–C6H4
p-MeO–C6H4
p-MeO–C6H4
p-NO2–C6H4
p-NO2–C6H4
p-NO2–C6H4
EtO2C
EtO2C
EtO2C
EtO2C
c
–
1h
1i
1j
1k
1l
1m
1n
1o
58
59
68
52
48
50
44
57
Bn
a Reaction at 5 ЊC. b Decomposition. c No reaction. d Pyrrolidine (1.0 equiv.) was used. e NaHCO3 (2.0 equiv.) and TFA (0.2 equiv.) were used as
buffer.
applicable, conversion was determined by NMR analysis of a
filtered aliquot of the reaction mixture. Upon complete con-
Experimental
General details
version of the α-halooxime, the mixture was adsorbed to silica
gel (ca. 1.5 g) and the solvent was evaporated in vacuo. The
product was purified by column chromatography. Diastereo-
NMR spectra were acquired on a Varian AS 400 spectrometer,
running at 400 MHz (1H) or 100 MHz (13C), respectively.
Chemical shifts (δ) are reported in ppm relative to residual
1
meric ratios were estimated from the H NMR signals of the
hemiacetal methine protons of the products.19 Deviations from
this procedure are noted with the individual experiments.
1
solvent signals. The multiplicities of H signals are designated
by the following abbreviations: s = singlet; d = doublet; t =
triplet; q = quartet; br = broad; m = multiplet, app = apparent.
All coupling constants, J, are reported in Hertz. 13C NMR
spectra were acquired on a broad band decoupled mode and
the multiplicities were obtained using DEPT sequences. The
following symbolisms are used for the multiplicities in 13C
spectra: q = primary methyl; t = secondary methylene; d =
tertiary methine; s = quaternary. Mass spectra were recorded
on a micromass LCT spectrometer using electrospray (ESϩ)
ionisation techniques or on a Kratos MS890MS using electron
ionisation (EIϩ) techniques. Flash column chromatography
was carried out using Fluka Kieselgel 60 (230–400 mesh).
Analytical thin layer chromatography (TLC) was performed
using precoated aluminium-backed plates (Merck Kieselgel 60
F254) and visualised by ultraviolet irradiation or vanillin dip.
Analytical grade solvents were used. All commercially avail-
able reagents were used as received. The α-halooximes 2a–e
and the enamine 4 were prepared according to literature
procedures.2b,12,17 The ester 6 was identified through comparison
with data reported in the literature.18 The methylene protons of
6 at δH 4.98 and 5.31 (for trans- and cis-isomers, respectively)
and the hemiacetal methine protons of the dihydro oxazines 1
were used to estimate conversion by 1H NMR of crude reaction
mixtures.
5-Isopropyl-3-phenyl-6-(pyrrolidin-1-yl)-5,6-dihydro-4H-[1,2]-
oxazine (1a). α-Bromoacetophenone oxime (2a) (214 mg,
1.00 mmol) was dissolved in a suspension of Na2CO3 (159 mg,
1.50 mmol) in CH2Cl2 (3 ml). The enamine 1-((E)-3-methylbut-
1-enyl)-pyrrolidine (4) (328 µl, 2.00 mmol) was added drop-
wise at ambient temperature. After 2 h, the starting material
had been completely consumed and the reaction products were
separated by column chromatography. Apart from compound
1b (75 mg, 34%), two diastereomers of compound 1a were
obtained as colourless oils (major diastereoisomer: 35 mg, 13%,
minor diastereoisomer: 22 mg, 8%). Major diastereoisomer: Rf
0.60 (1 : 3 pentane : ether); δH (400 MHz, CDCl3) 0.80 (3H,
d, J 7.0, CH3), 0.91 (3H, d, J 7.0, CH3), 1.66–1.78 (4H, m,
2 × CH2), 1.90–2.16 (2H, m, 2 × CH ), 2.34 (1H, dd, J 17.8,
11.2, N=CCHH), 2.59 (1H, dd, J 17.8, 7.4, N᎐CCHH ), 2.84–
᎐
3.02 (4H, m, 2 × NCH2), 4.48 (1H, d, J 10.0, OCH ), 7.24–7.31
(3H, m, ArH ), 7.62 (2H, m, ArH ); δC (100 MHz, CDCl3)
16.1 (q), 20.6 (q), 23.8 (t), 25.2 (t), 26.9 (d), 38.2 (d), 47.0 (t),
92.5 (d), 125.5 (d), 128.6 (d), 129.4 (d), 136.2 (s), 155.1 (s);
m/z (ESϩ) 273 (100%, MHϩ) [Found: (MHϩ) 273.1970. C17H25-
N2O requires MH, 273.1967]. Minor diastereoisomer: Rf 0.21
(1 : 3 pentane : ether); δH (400 MHz, CDCl3) 0.98 (3H, d, J 6.8,
CH3), 1.02 (3H, d, J 6.8, CH3), 1.75–1.91 (5H, m, 2 × CH2,
CH ), 2.03–2.10 (1H, m, (CH3)2CH ), 2.62 (1H, dd, J 17.2, 6.1,
General procedure for the preparation of 5,6-dihydro-4H-
oxazines. Pyrrolidine (4 µl, 0.05 mmol) and the aldehyde
(1.5 mmol) were added to a suspension of NaOAcؒ3H2O
(136 mg, 1.00 mmol) in CH2Cl2 and stirred for 5 min at ambient
temperature. The α-halooxime (0.5 mmol) was added to this
mixture and the reaction was monitored by TLC. Where
N᎐CCHH), 2.80–2.89 (2H, m, NCH ), 3.08 (1H, dd, J 17.2, 9.1,
᎐
2
N᎐CCHH ), 3.38–3.42 (2H, m, NCH ), 4.98 (1H, d, J 6.7,
᎐
2
OCH ), 7.38–7.48 (3H, m, ArH ), 8.35–8.41 (2H, m, ArH );
δC (100 MHz, CDCl3) 19.4 (q), 20.3 (q), 24.9 (t), 31.2 (t), 31.5
(t), 41.4 (d), 47.9 (t), 93.3 (d), 127.3 (d), 128.6 (d), 130.2 (d),
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 2 8 – 8 3 4
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138.8 (s), 155.6 (s); m/z (ESϩ) 273 (100%, MHϩ) [Found: (MHϩ)
273.1974. C17H25N2O requires MH, 273.1967].
5-Phenyl-3-phenyl-5,6-dihydro-4H-[1,2]oxazin-6-ol
(1f ).
Compound 1f was prepared according to the general procedure
and after 72 h the product was isolated as a yellow solid
(110 mg, 87%). Rf 0.35 (3 : 1 pentane : THF); δH (400 MHz,
acetone-d6, ca. 60 : 40 mixture of diastereomers) 2.82 (0.6H, dd,
5-Isopropyl-3-phenyl-5,6-dihydro-4H-[1,2]oxazin-6-ol
(1b).
Compound 1b was prepared according to the general procedure
and after 72 h the product was isolated as a yellow solid (88 mg,
81%). Rf 0.50 (1 : 3 pentane : ether); δH (400 MHz, acetone-d6,
ca. 60 : 40 mixture of diastereomers) 0.94–1.06 (6H, m,
2 × CH3), 1.43–1.83 (2H, m, 2 × CH ), 2.33 (0.6H, dd, J 17.6,
J 17.4,5.5, N᎐CCHH), 2.84 (0.4H, dd, J 18.2, 5.5, N᎐CCHH),
᎐
᎐
3.05 (0.6H, dd, J 17.4, 13.1, N᎐CCHH ), 3.16 (0.4H, dd, J 18.2,
᎐
7.4, N᎐CCHH ), 3.24–3.32 (1H, m, CH ), 5.40 (0.4H, br d, J 4.6,
᎐
O2CH ), 5.56 (0.6H, br d, J 2.3, O2CH ), 7.20–7.54 (8H, m,
ArH ), 7.77–7.83 (2H, m, ArH ); δC (100 MHz, CDCl3) 23.7 (t),
24.9 (t), 39.5 (d), 39.6 (d), 92.8 (d), 94.5 (d), 125.9 (2 × d), 127.6
(d), 127.7 (d), 127.9 (d), 128.6 (2 × d), 128.8 (d), 128.9 (2 × d),
130.0 (d), 130.2 (d), 135.5 (s), 135.6 (s), 139.4 (s), 140.5 (s), 156.2
(s), 156.9 (s); m/z (ESϩ) 276 (100%, MNaϩ) [Found: (MNaϩ)
276.1007. C16H15NaNO2 requires MNa, 276.1000].
12.5, N᎐CCHH), 2.54 (0.4H, dd, J 18.0, 4.5, N᎐CCHH), 2.70
᎐
᎐
(0.6H, dd, J 17.6, 6.0, N᎐CCHH ), 2.79 (0.4H, dd, J 18.0, 6.4,
᎐
N᎐CCHH ), 5.46 (0.6H, br d, J 4.0, O CH ), 5.83 (0.4H, br d,
᎐
2
J 4.0, O2CH ), 7.26–7.42 (3H, m, ArH ), 7.70–7.81 (2H, m,
ArH ); δC (100 MHz, acetone-d6) 18.9 (q), 19.3 (q), 19.8 (q), 20.0
(q), 21.1 (t), 21.8 (t), 27.9 (d), 29.9 (d), 39.9 (d), 40.0 (d), 90.8
(d), 93.5 (d), 125.5 (d), 125.6 (d), 128.5 (2 × d), 129.3 (d), 129.4
(d), 136.8 (2 × s), 154.2 (2 × s); m/z (ESϩ) 242 (100%, MNaϩ)
[Found: (MNaϩ) 242.1156. C13H17NaNO2 requires MNa,
242.1157].
5-Benzyl-3-phenyl-5,6-dihydro-4H-[1,2]oxazin-6-ol
(1g).
Compound 1g was prepared according to the general procedure
and after 72 h the product was isolated as a yellow solid (91 mg,
68%). Rf 0.38 (3 : 1 pentane : THF); δH (400 MHz, CDCl3,
ca. 60 : 40 mixture of diastereomers) 2.24–2.58 (3H, m, CH,
5-Methyl-3-phenyl-5,6-dihydro-4H-[1,2]oxazin-6-ol
(1c).
Compound 1c was prepared according to the general procedure
and after 72 h the product was isolated as a dark yellow solid
(66 mg, 69%). Rf 0.38 (3 : 1 pentane : THF); δH (400 MHz,
acetone-d6, ca. 60 : 40 mixture of diastereomers) 1.02 (1.2H, d,
J 7.0, CH3), 1.10 (1.8H, d, J 7.0, CH3), 2.05–2.20 (1H, m, CH ),
PhCH ), 2.71–2.90 (2H, m, N᎐CCH ), 5.25 (0.4H, br d, J 2.8,
᎐
2 2
O2CH ), 5.32 (0.6H, br d, J 2.8, O2CH ), 7.09–7.41 (8H, m,
ArH ), 7.62–7.70 (2H, m, ArH ); δC (100 MHz, CD3NO2, 60 ЊC)
22.6 (t), 23.1 (t), 35.1 (d), 35.2 (d), 36.9 (t), 37.6 (d), 91.9 (d),
93.8 (d), 125.5 (2 × d), 126.4 (2 × d), 128.2 (2 × d), 128.5 (2 × d),
129.2 (d), 129.3 (d), 129.5 (d), 129.6 (d), 136.4 (s), 136.6 (s),
139.5 (2 × s), 155.3 (s), 155.5 (s); m/z (ESϩ) 290 (100%, MNaϩ)
[Found: (MNaϩ) 290.1162. C17H17NaNO2 requires MNa,
290.1157].
2.31 (0.6H, dd, J 17.6, 12.0, N᎐CCHH), 2.34 (0.4H, dd, J 18.0,
᎐
4.2, N᎐CCHH), 2.61 (0.6H, dd, J 17.6, 6.4, N᎐CCHH ), 2.86
᎐
᎐
(0.4H, dd, J 18.0, 6.8, N᎐CCHH ), 5.06 (0.4H, br d, J 3.8,
᎐
O2CH ), 5.30 (0.6H, br d, J 2.0, O2CH ), 7.31–7.45 (3H, m,
ArH ), 7.66–7.79 (2H, m, ArH ); δC (100 MHz, acetone-d6) 16.2
(q), 24.6 (t), 25.4 (t), 28.2 (d), 28.4 (d), 30.1 (q), 92.9 (d), 95.3
(d), 125.4 (2 × d), 128.5 (2 × d), 129.3 (d), 129.4 (d), 136.7 (s),
136.9 (s), 153.5 (s), 154.0 (s); m/z (ESϩ) 214 (100%, MNaϩ)
[Found: (MNaϩ) 214.0844. C11H13NaNO2 requires MNa,
214.0844].
5-Isopropyl-3-(4-methoxyphenyl)-5,6-dihydro-4H-[1,2]oxazin-
6-ol (1h). Compound 1h was prepared according to the general
procedure in the absence of NaOAcؒ3H2O, using a stoichio-
metric amount of pyrrolidine (42 µl, 0.5 mmol). The product
was isolated as a colourless solid after 2 h (72 mg, 58%). Rf 0.43
(4 : 1 CH2Cl2 : ether); δH (400 MHz, CDCl3, ca. 75 : 25 mixture
of diastereomers) 0.93 (0.75H, d, J 6.0, CH3), 0.98–1.01 (5.25H,
m, CH3), 1.54–1.80 (2H, m, 2 × CH ), 2.35 (0.75H, dd, J 17.6,
5-Ethyl-3-phenyl-5,6-dihydro-4H-[1,2]oxazin-6-ol (1d). Com-
pound 1d was prepared according to the general procedure and
after 72 h the product was isolated as a yellow solid (91 mg,
89%). Rf 0.41 (3 : 1 pentane : THF); δH (400 MHz, acetone-d6,
ca. 60 : 40 mixture of diastereomers) 0.98 (1.2H, t, J 7.4, CH3),
1.03 (1.8H, t, J 7.4, CH3), 1.42–1.66 (2H, m, CH2CH3), 1.81–
12.4, N᎐CCHH), 2.42 (0.25H, dd, J 17.6, 3.6, N᎐CCHH), 2.60
᎐
᎐
(0.75H, dd, J 17.6, 3.4, N᎐CCHH ), 2.76 (0.25H, dd, J 18.0, 6.8,
᎐
N᎐CCHH ), 3.82 (3H, s, OCH ), 5.39 (0.25H, d, J 2.8, O CH ),
᎐
3
2
5.55 (0.75H, d, J 2.4, O2CH ), 6.86–6.92 (2H, m, ArH ), 7.63–
7.69 (2H, m, ArH ); δC (100 MHz, CDCl3) 19.6 (2 × q), 20.1 (q),
20.3 (q), 20.8 (t), 21.9 (t), 28.0 (d), 29.6 (d), 39.5 (d), 39.8 (d),
55.3 (2 × q), 90.8 (d), 93.2 (d), 113.7 (2 × d), 126.8 (d), 126.9 (d),
128.1 (s), 128.2 (s), 155.3 (s), 156.6 (s), 160.6 (s), 160.7 (s);
m/z (ESϩ) 272 (100%, MNaϩ) [Found: (MNaϩ) 272.1262.
C14H19NNaO3 requires MNa, 272.1263].
1.96 (1H, m, CH ), 2.31 (0.6H, dd, J 17.6, 12.5, N᎐CCHH), 2.40
᎐
(0.4H, dd, J 18.0, 3.9, N᎐CCHH), 2.65 (0.6H, dd, J 17.6, 6.1,
᎐
N᎐CCHH ), 2.84 (0.4H, dd, J 18.0, 6.8, N᎐CCHH ), 5.08 (0.4H,
᎐
᎐
br d, J 3.8, O2CH ), 5.38 (0.6H, br d, J 2.0, O2CH ), 7.38–7.42
(3H, m, ArH ), 7.66–7.80 (2H, m, ArH ); δC (100 MHz, acetone-
d6) 10.4 (q), 10.8(q), 22.9 (t), 23.2 (t), 24.0 (t), 24.8 (t), 34.9 (d),
35.3 (d), 91.8 (d), 94.1 (d), 125.4 (2 × d), 128.5 (2 × d), 129.2 (d),
129.3 (d), 136.8 (s), 136.9 (s), 153.8 (s), 154.0 (s). m/z (ESϩ)
228 (100%, MNaϩ) [Found: (MNaϩ) 228.0994. C12H15NaNO2
requires MNa, 228.1000].
5-Isopropyl-3-(4-nitrophenyl)-5,6-dihydro-4H-[1,2]oxazin-6-ol
(1i). Compound 1i was prepared according to the general pro-
cedure and after 24 h the product was isolated as a yellow oil
(78 mg, 59%). Rf 0.32 (3 : 1 pentane : THF); δH (400 MHz,
CDCl3, ca. 75 : 25 mixture of diastereomers) 0.95–1.03 (6H, m,
2 × CH3), 1.58–1.85 (2H, m, 2 × CH ), 2.42 (0.75H, dd, J 17.6,
5-Propyl-3-phenyl-5,6-dihydro-4H-[1,2]oxazin-6-ol
(1e).
Compound 1e was prepared according to the general procedure
and after 72 h the product was isolated as a yellow solid (84 mg,
77%). Rf 0.38 (3 : 1 pentane : THF); δH (400 MHz, acetone-d6,
ca. 60 : 40 mixture of diastereomers) 0.94–0.99 (3H, m, CH3),
1.40–1.58 (4H, m, 2 × CH2), 1.89–1.99 (1H, m, CH ), 2.30
12.1, N᎐CCHH), 2.48 (0.25H, dd, J 18.0, 3.0, N᎐CCHH), 2.62
᎐
᎐
(0.75H, dd, J 17.6, 5.9, N᎐CCHH ), 2.83 (0.25H, dd, J 18.0, 7.0,
᎐
N᎐CCHH ), 5.43 (0.25H, br d, J 2.6, O CH ), 5.60 (0.75H, br d,
᎐
2
J 2.0, O2CH ), 7.82–7.90 (2H, m, ArH ), 8.18–8.26 (2H, m,
ArH ); δC (100 MHz, CDCl3) 19.8 (q), 20.0 (q), 20.3 (q), 20.6
(q), 20.9 (t), 22.2 (t), 28.0 (d), 29.8 (d), 39.1 (d), 39.4 (d), 91.6
(d), 93.4 (d), 123.9 (d), 124.0 (d), 126.6 (2 × d), 141.8 (s), 141.9
(s), 148.5 (2 × s), 154.4 (s), 154.8 (s); m/z (EIϩ) 264 (36%, Mϩ)
[Found: (Mϩ) 264.1108. C13H16N2O4 requires M, 264.1110].
(0.6H, dd, J 17.6, 12.5, N᎐CCHH), 2.39 (0.4H, dd, J 18.0, 3.2,
᎐
N᎐CCHH), 2.61 (0.6H, dd, J 17.6, 6.0), 2.84 (0.4H, dd, J 18.0,
᎐
6.6, N᎐CCHH ), 5.14 (0.4H, br d, J 3.8, O CH ), 5.38 (0.6H,
᎐
2
br d, J 2.8, O2CH ), 7.35–7.46 (3H, m, ArH ), 7.70–7.81 (2H, m,
ArH ); δC (100 MHz, acetone-d6) 13.8 (q), 13.9 (q), 19.4 (t), 19.8
(d), 23.1 (t), 23.5 (t), 33.0 (d), 33.4 (d), 33.5 (t), 34.2 (t), 92.0 (d),
94.3 (d), 125.4 (2 × d), 128.5 (2 × d), 129.2 (d), 129.3 (d), 136.8
(s), 136.9 (s), 153.9 (s), 154.1 (s); m/z (ESϩ) 242 (100%, MNaϩ)
[Found: (MNaϩ) 242.1150. C13H17NaNO2 requires MNa,
242.1157].
5-Benzyl-3-(4-nitrophenyl)-5,6-dihydro-4H-[1,2]oxazin-6-ol
(1j). Compound 1j was prepared according to the general pro-
cedure and after 24 h the product was isolated as a yellow oil
(106 mg, 68%). Rf 0.34 (3 : 1 pentane : THF); δH (400 MHz,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 2 8 – 8 3 4
832

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CDCl3, ca. 60 : 40 mixture of diastereomers) 2.28–2.58 (3H, m,
CH, ArCH ), 2.71–2.93 (2H, m, N᎐CCH ), 5.29 (0.4H, br d,
and CF3CO2H (8 µl, 0.1 mmol) as a buffer) and after 24 h the
product was isolated as a colourless oil (44 mg, 44%). Rf 0.16
(1 : 1 pentane : ether); δH (400 MHz, CDCl3, ca. 60 : 40 mixture
of diastereomers) 0.93 (1.2H, t, J 7.6, CH2CH3), 0.96 (1.8H,
J 7.6, CH2CH3), 1.33 (3H, app t, J 7.2, OCH2CH3), 1.35–
1.56 (2H, m, CH2CH3), 1.66–1.76 (0.6H, m, CH ), 1.83–1.92
᎐
2
2
J 2.6, O2CH ), 5.36 (0.6H, br d, J 2.2, O2CH ), 7.18–7.38 (5H,
m, ArH ), 7.80–7.88 (2H, m, p-NO2–ArH ), 8.18–8.26 (2H, m,
p-NO2–ArH ); δC (100 MHz, CDCl3) 22.0 (t), 23.3 (t), 34.0 (d),
34.7 (d), 37.2 (t), 38.0 (t), 92.0 (d), 93.2 (d), 123.9 (d), 124.0 (d),
126.5 (d), 126.6 (d), 126.9 (2 × d), 128.9 (2 × d), 129.2 (d), 129.3
(d), 138.3 (s), 138.4 (s), 141.6 (s), 141.8 (s), 148.6 (2 × s), 154.1
(s), 154.6 (s); m/z (EIϩ) 312 (15%, Mϩ) [Found: (Mϩ) 312.1111.
C17H16N2O4 requires M, 312.1110].
(0.4H, m CH ), 2.13 (0.6H, dd, J 18.8, 12.7, N᎐CCHH), 2.32
᎐
(0.4H, dd, J 19.1, 2.8, N᎐CCHH), 2.53 (0.6H, dd, J 18.8, 6.0,
᎐
N᎐CCHH ), 2.59 (0.4H, dd, J 19.1, 7.1, N᎐CCHH ), 4.29 (2H,
᎐
᎐
app q, J 7.2, OCH2CH3), 5.29 (0.4H, br d, J 2.0, O2CH ), 5.44
(0.6H, br d, J 1.4, O2CH ); δC (100 MHz, CDCl3) 11.0 (q), 11.4
(q), 14.3 (2 × q), 21.4 (t), 21.8 (t), 23.7 (t), 24.4 (t), 33.6 (d), 33.8
(d), 62.3 (2 × t), 93.1 (d), 94.6 (d), 150.4 (s), 150.9 (s), 163.5 (s),
163.6 (s); m/z (ESϩ) 224 (100%, MNaϩ) [Found: (MNaϩ)
224.0900. C9H15NaNO4 requires MNa, 224.0899].
5-Methyl-3-(4-nitrophenyl)-5,6-dihydro-4H-[1,2]oxazin-6-ol
(1k). Compound 1k was prepared according to the general pro-
cedure and after 24 h the product was isolated as a yellow oil
(61 mg, 52%). Rf 0.30 (3 : 1 pentane : THF); δH (400 MHz,
CDCl3, ca. 60 : 40 mixture of diastereomers) 1.05 (1.2H, d,
J 6.8, CH3), 1.15 (1.8H, d, J 6.8, CH3), 2.08–2.18 (1.8H, m,
CH ), 2.23–2.34 (1.2H, m, CH ), 2.30 (0.4H, dd, J 18.0, 3.2,
6-Hydroxy-5-benzyl-5,6-dihydro-4H-[1,2]oxazine-3-
carboxylic acid ethyl ester (1o). Compound 1o was prepared
according to the general procedure (with NaHCO3 (84 mg,
1 mmol) and CF3CO2H (8 µl, 0.1 mmol) as a buffer) and after
24 h the product was isolated as a colourless oil (75 mg, 57%).
Rf 0.13 (1 : 1 pentane : ether); δH (400 MHz, CDCl3, ca. 60 : 40
mixture of diastereomers) 1.31 (1.8H, t, J 7.2, CH2CH3), 1.34
N᎐CCHH), 2.44 (0.6H, dd, J 17.6, 11.9, N᎐CCHH), 2.54
᎐
᎐
(0.6H, dd, J 17.6, 6.5, N᎐CCHH ), 2.92 (0.4H, dd, J 18.0, 7.6,
᎐
N᎐CCHH ), 5.23 (0.4H, br d, J 3.0, O CH ), 5.42 (0.6H, br d,
᎐
2
J 2.5, O2CH ), 7.82–7.90 (2H, m, ArH ), 8.18–8.24 (2H, m,
ArH ); δC (100 MHz, CDCl3) 16.6 (q), 16.8 (q), 24.8 (t), 24.9 (t),
27.3 (d), 27.7 (d), 93.6 (d), 95.2 (d), 123.9 (2 × d), 126.5 (2 × d),
141.7 (s), 142.0 (s), 148.5 (2 × s), 153.5 (s), 154.2 (s); m/z (EIϩ)
236 (43%, Mϩ) [Found: (Mϩ) 236.0794. C11H12N2O4 requires M,
236.0797].
(1.2H, t, J 7.2, CH CH ), 2.09–2.82 (5H, m, CH, N᎐CCH ,
᎐
2
3
2
ArCH2), 4.28 (1.2H, q, J 7.2, CH2CH3), 4.31 (0.8H, q, J 7.2,
CH2CH3), 5.23 (0.4H, br d, J 2.5, O2CH ), 5.32 (0.6H, br d,
J 2.0, O2CH ), 7.15–7.34 (5H, m, ArH ); δC (100 MHz, CDCl3)
14.3 (2 × q), 21.3 (t), 22.0 (t), 33.6 (d), 34.3 (d), 37.0 (t), 37.7 (t),
62.3 (t), 62.4 (t), 92.6 (d), 93.7 (d), 126.8 (2 × d), 128.8 (d), 128.9
(d), 129.2 (d), 129.4 (d), 138.3 (s), 138.4 (s), 150.2 (s), 150.8 (s),
163.3 (s), 163.5 (s); m/z (ESϩ) 286 (100%, MNaϩ) [Found:
(MNaϩ) 286.1052. C14H17NaNO4 requires MNa, 286.1055].
6-Hydroxy-5-isopropyl-5,6-dihydro-4H-[1,2]oxazine-3-
carboxylic acid ethyl ester (1l). Compound 1l was prepared
according to the general procedure (with NaHCO3 (84 mg,
1 mmol) and CF3CO2H (8 µl, 0.1 mmol) as a buffer) and after
24 h the product was isolated as a colourless oil (52 mg, 48%).
Rf 0.25 (1 : 1 pentane : ether); δH (400 MHz, CDCl3, ca. 70 : 30
mixture of diastereomers) 0.90 (0.9H, d, J 6.7, CHCH3), 0.95
(0.9H, d, J 6.7, CHCH3), 0.96 (2.1H, d, J 6.7, CHCH3),
0.99 (2.1H, d, J 6.7, CHCH3), 1.33 (3H, app t, J 7.2, CH2CH3),
1-Phenyl-2-(pyrrolidin-1-yl)ethanone oxime (5). Pyrrolidine
(42 µl, 0.5 mmol) was added to a solution of α-bromoaceto-
phenone oxime (2a) (53 mg, 0.25 mmol) in CH2Cl2 (1 ml)
and the solution was stirred at ambient temperature. TLC
analysis immediately after addition of pyrrolidine revealed
complete conversion of 2a. Compound 5 was isolated as a
colourless oil after column chromatography (50 mg, 98%).
Rf 0.10 (1 : 1 pentane : ether); δH (400 MHz, CDCl3) 1.62–1.69
(4H, m, 2 × CH2), 2.42–2.52 (4H, 2 × NCH2), 3.43 (2H, s,
1.35–1.72 (2H, m, 2 × CH ), 2.11 (0.7H, dd, J 18.8, 12.8, N᎐
᎐
CCHH), 2.45 (0.3H, dd, J 19.1, 3.6, N᎐CCHH), 2.56 (0.3H, dd,
᎐
J 19.1, 6.8, N᎐CCHH ), 2.63 (0.7H, dd, J 18.8, 6.1, N᎐CCHH ),
᎐
᎐
4.31 (2H, app q, J 7.2, CH2CH3), 5.41 (0.3H, br d, J 3.1,
O2CH ), 5.56 (0.7H, br d, J 2.2, O2CH ); δC (100 MHz, CDCl3)
14.3 (2 × q), 19.5 (t), 19.8 (q), 19.9 (q), 20.3 (q), 20.5 (q), 20.7
(t), 27.7 (d), 29.6 (d), 38.3 (d), 38.9 (d), 62.3 (2 × t), 92.2 (d),
93.8 (d), 150.9 (s), 151.2 (s), 163.5 (2 × s); m/z (ESϩ) 238 (100%,
MNaϩ) [Found: (MNaϩ) 238.1056. C10H17NaNO4 requires
MNa, 238.1055].
N᎐CCH ), 7.23–7.34 (3H, m, ArH ), 7.46–7.51 (2H, m, ArH ),
᎐
2
9.8 (1H, br s, OH ); δC (100 MHz, CDCl3) 23.7 (t), 54.3 (t), 59.9
(t), 128.3 (d), 128.5 (d), 129.2 (d), 133.1 (s), 155.2 (s); m/z (ESϩ)
205 (100%, MHϩ) [Found: (MHϩ) 205.1348. C12H17N2O
requires MH, 205.1341].
6-Hydroxy-5-propyl-5,6-dihydro-4H-[1,2]oxazine-3-
2-Bromo-1-phenylethanone O-methyl-oxime (7a). α-Bromo-
acetophenone (3.98 g, 20.0 mmol) and O-methyl hydroxylamine
hydrochloride (2.50 g, 30.0 mmol) were dissolved in ethanol
(50 ml) containing one drop of concentrated sulfuric acid. The
mixture was stirred at ambient temperature for 2 h. The solvent
was evaporated in vacuo to near dryness. Ether (50 ml) was
added and the solution was washed with 1 M aqueous KHSO4
(2 × 20 ml), saturated aqueous NaHCO3 (20 ml) and water
(20 ml). The organic phase was dried over Na2SO4, filtered and
the solvent was evaporated in vacuo. Filtration of the crude
product (dissolved in 3 : 1 pentane : CH2Cl2) through a short
pad of silica gel and evaporation of the solvents in vacuo
afforded the product as a colourless liquid (3.40 g, ≈75%).20
Rf 0.40 (3 : 1 pentane : CH2Cl2); δH (400 MHz, CDCl3) 4.13 (3H,
s, CH3), 4.37 (2H, s, CH2), 7.40–7.48 (3H, m, ArH ), 7.72–7.78
(2H, m, ArH ); δC (100 MHz, CDCl3) 18.3 (t), 63.1 (q), 126.4
(d), 128.9 (d), 129.9 (d), 133.7 (s), 152.9 (s); m/z (ESϩ) 228 (88%,
MHϩ) [Found: (MHϩ) 228.0050. C9H11BrNO requires MH,
228.0024].
carboxylic acid ethyl ester (1m). Compound 1m was prepared
according to the general procedure (with NaHCO3 (84 mg,
1 mmol) and CF3CO2H (8 µl, 0.1 mmol) as a buffer) and after
24 h the product was isolated as a colourless oil (54 mg, 50%).
Rf 0.25 (1 : 1 pentane : ether); δH (400 MHz, CDCl3, ca. 60 : 40
mixture of diastereomers) 0.90 (1.2H, t, J 7.0, CH2CH3) 0.92
(1.8H, t, J 7.0, CH2CH3), 1.29–1.50 (7H, m, CH2CH2, CH2CH2,
CH2CH3), 1.81–1.90 (0.6H, m, CH ), 1.96–2.06 (0.4H, m, CH ),
2.12 (0.6H, dd, J 18.8, 12.8, N᎐CCHH), 2.32 (0.4H, dd, J 19.1,
᎐
2.5, N᎐CCHH), 2.53 (0.6H, dd, J 18.8, 6.0, N᎐CCHH ), 2.60
᎐
᎐
(0.4H, dd, J 19.1, 7.1), 4.32 (2H, app q, J 7.2, OCH2CH3), 5.26
(0.4H, br d, J 2.8, O2CH ) 5.42 (0.6H, br d, J 2.1, O2CH );
δC (100 MHz, CDCl3) 14.2 (q), 14.3 (q), 14.4 (2 × q), 19.5 (t),
19.9 (t), 21.5 (t), 21.9 (t), 31.5 (d), 31.8 (d), 32.8 (t), 33.5 (t), 62.3
(t), 62.4 (t), 93.2 (d), 94.7 (d), 150.5 (s), 151.1 (s), 163.4 (s), 163.5
(s); m/z (ESϩ) 238 (100%, MNaϩ) [Found: (MNaϩ) 238.1056.
C10H17NaNO4 requires MNa, 238.1055].
6-Hydroxy-5-ethyl-5,6-dihydro-4H-[1,2]oxazine-3-carboxylic
acid ethyl ester (1n). Compound 1n was prepared according
to the general procedure (with NaHCO3 (84 mg, 1 mmol)
2-Chloro-1-phenylethanone O-methyl-oxime (7b). Compound
7b was prepared from α-chloroacetophenone (1.54 g, 10.0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 2 8 – 8 3 4
833

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4 W. Höbold, U. Prietz and W. Pritzkow, J. Prakt. Chem., 1969, 311,
260–265.
5 J. Lee, L. Chen, A. H. West and G. B. Richter-Addo, Chem. Rev.,
2002, 102, 1019–1065.
6 For organocatalytic cycloadditions involving electron-rich
enamines, see: (a) K. Juhl and K. A. Jørgensen, Angew. Chem.,
Int. Ed., 2003, 42, 1498–1501; (b) D. B. Ramachary, N. S. Chowdari
and C. F. Barbas III, Angew. Chem., Int. Ed., 2003, 42, 4233–4237;
(c) D. B. Ramachary, N. S. Chowdari and C. F. Barbas, Tetrahedron
Lett., 2002, 43, 6743–6746.
mmol) and O-methyl hydroxylamine hydrochloride (1.25 g,
15.0 mmol), following an analogous procedure as described for
compound 7a. The product was obtained as a colourless liquid
(1.65 g, 90%). Rf 0.56 (1 : 1 pentane : CH2Cl2); δH (400 MHz,
CDCl3) 4.08 (3H, s, CH3), 4.53 (2H, s, CH2), 7.38–7.42 (3H, m,
ArH ), 7.69–7.73 (2H, m, ArH ); δC (100 MHz, CDCl3) 32.8 (t),
63.0 (q), 126.4 (d), 128.9 (d), 129.9 (d), 133.6 (s), 152.8 (s);
m/z (ESϩ) 184 (100%, MHϩ) [Found: (MHϩ) 184.0533. C9H11-
ClNO requires MH, 184.0529].
5-Isopropyl-3-(4-methoxyphenyl)-4,5-dihydro-[1,2]oxazin-6-
one (8). To an ice-cooled solution of 1h (27 mg, 0.11 mmol) in
CH2Cl2 (1.5 ml) was added PCC (17 mg, 0.08 mmol). After
stirring for 1.5 hours additional PCC (17 mg, 0.08 mmol)
was added and the reaction mixture was left to warm to room
temperature. After 16 hours the reaction product was separated
by column chromatography (colourless oil, 16 mg, 58%).
Rf 0.60 (9 : 1 CH2Cl2 : ether); δH (400 MHz, CDCl3) 1.01 (3H, d,
J 6.4, CH3), 1.07 (3H, d, J 6.8, CH3), 2.29 (1H, app oct, J 6.6,
CH(CH3)2), 2.51 (1H, app dt, J 10.0, 5.8, CHCO2), 2.87
(1H, dd, J 16.8, 9.8, N᎐CCHH), 2.98 (1H, dd, J 17.2, 6.4,
᎐
N᎐CCHH ), 3.86 (3H, s, OCH ), 6.96 (2H, d, J 9.2, ArH ), 7.70
᎐
3
(2H, d, J 8.8, ArH ); δC (100 MHz, CDCl3) 18.8 (q), 20.3 (q),
24.0 (t), 27.0 (d), 41.0 (d), 55.4 (q), 114.3 (d), 124.6 (s), 128.1
(d), 161.3 (s), 162.0 (s), 171.5 (s); m/z (ESϩ) 248 (100%,
MHϩ) [Found: (MHϩ) 248.1285. C14H18NO3 requires MH,
248.1287]. The enantiomeric excess was determined by HPLC
using Daicel Chiralpak AS columns (two columns in series)
7 An analogous reaction took also place with α-chloroacetophenone
oxime (2b).
8 The use of homogeneous bases such as triethylamine or HünigЈs
base led to immediate decomposition of the halooxime.
9 Conversion did not increase when the reaction time was extended.
10 The presence of water probably facilitates hydrolysis of 1a.
11 Protic solvents such as ethanol cannot be used as they undergo
conjugate addition reactions to nitroso alkenes.
(hexane–i-PrOH (98 : 2); flow rate 1.0 ml minϪ1; τmajor
123 min; τminor = 116 min).
=
12 These stark differences in reactivity of O-alkylated and non-
alkylated oximes have been noticed previously, see: H. C. J.
Ottenheijm, R. Plate, J. H. Noordik and J. D. M. Herscheid, J. Org.
Chem., 1982, 47, 2147–2154.
13 Evidence allowing the distinction between stepwise and concerted
mechanisms of the present hetero-Diels–Alder reactions was not
collected.
Acknowledgments
This work was made possible by a grant from The Danish
National Research Foundation and EU:HMPT-CT-2001-
00317.
14 Theoretical investigations predict concerted asynchronous
transition structures, see: J. Liu, S. Niwayama, Y. You and
K. N. Houk, J. Org. Chem., 1998, 63, 1064–1073 and references
cited therein.
15 Slow homoaldol reactions were observed in some cases upon
prolonged reaction times, but did not affect the reaction yield as an
excess of the aldehyde component was used.
16 Reactions with NaHCO3 as a buffer could be accelerated by
addition of 20% trifluoroacetic acid (TFA), probably due to
generation of water (which facilitates aminoacetal hydrolysis) and
generation of a non-nucleophilic carboxylate anion (which can act
as a proton shuttle).
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19 Hemiacetal diastereomers could not be separated in any case and
rapid equilibration via an open chain aldehyde intermediate is likely.
20 Small quantities of the chlorooxime 7b were formed through halide
exchange during this procedure and could not be separated from the
product.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 2 8 – 8 3 4
834