2(H)-1,4-Oxazin-2-ones as ambident azadienes

Article abstract of DOI:10.1016/j.tetlet.2004.03.183

3,5-Dichloro-6-phenyl-2(H)-1,4-oxazin-2-one 3, 5-chloro-3,6-dimethyl-2(H)- 1,4-oxazin-2-one 4, 5-chloro-6-methyl-3-phenyl-2(H)-1,4-oxazin-2-one 5 and 5-chloro-3,6-diphenyl-2(H)-1,4-oxazin-2-one 7, are ambident azadienes reacting efficiently and selectivel

Full text of DOI:10.1016/j.tetlet.2004.03.183

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3995–3998
2(H)-1,4-Oxazin-2-ones as ambident azadienes
Kamyar Afarinkia,a,* Akmal Bahar,a Judi Neussb and Andrea Ruggieroa
aDepartment of Chemistry, King’s College, Strand, London WC2R 2LS, UK
bCelltech R&D Ltd, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK
Received 20 February 2004; revised 25 March 2004; accepted 30 March 2004
Abstract—3,5-Dichloro-6-phenyl-2(H)-1,4-oxazin-2-one 3, 5-chloro-3,6-dimethyl-2(H)-1,4-oxazin-2-one 4, 5-chloro-6-methyl-3-
phenyl-2(H)-1,4-oxazin-2-one 5 and 5-chloro-3,6-diphenyl-2(H)-1,4-oxazin-2-one 7, are ambident azadienes reacting efficiently and
selectively with both electron rich and electron poor dienophiles.
Ó 2004 Elsevier Ltd. All rights reserved.
8
The Diels–Alder reaction of azadienes is a well estab-
lished and useful method in organic synthesis.1 In par-
R
7
R
Cl
Cl
5
ticular, the azadiene components of many aromatic
nitrogen-containing heterocycles have been utilised in
[4+2] cycloadditions.2 These include 1,2,4-triazines,3
oxazoles,4 thiazoles,5 pyrimidines,6 1,3-oxazin-2-ones,7
1,3-oxazin-6-ones8 and 1,4-oxazin-2-ones.9
N
4
O
N
O
3
6
O
O
1
Cl
Cl
Me
Me
Cl
8-endo cycloadduct
7-endo cycloadduct
O
R
N
R
R
O
Cl
Cl
Cl
During an investigation of the use of 2(H)-1,4-oxazin-2-
ones in the synthesis of azasugars,10 we became inter-
ested in an unusual feature of the Diels–Alder cycload-
ditions of 3,5-dichloro-6-methyl-2(H)-1,4-oxazin-2-one
1, which were originally reported by Hoornaert.9a;b This
compound was reported to undergo cycloadditions with
examples of electron deficient (methyl acrylate), electron
neutral (styrene), and electron rich (ethyl vinyl ether)
dienophiles (Scheme 1, Table 1). Although the reactions
were not regio- and stereoselective, to our knowledge
this was the only example of an ‘ambident’ 2-azadiene,
that is one which is capable of both normal and inverse
electron demand Diels–Alder cycloadditions. Curiously,
the only other known ambident dienes are derived from
2(H)-pyran-2-ones, for example, 3-bromo-2(H)-pyran-
2-one,11a 5-bromo-2(H)-pyran-2-one 2,11b;c and 3,5-
dibromo-2(H)-pyran-2-one,12 (Scheme 2, Table 2).
Therefore, it appears that 2(H)-1,4-oxazine-2-ones are 2-
azadiene counterparts of the well-investigated 2(H)-
pyran-2-one dienes. To complement our long standing
interest in the cycloaddition reactions of 2(H)-pyran-2-
ones11 and their synthetic applications,13 we decided to
N
O
O
N
Me
O
O
1
Cl
Cl
Me
Me
8-exo cycloadduct
7-exo cycloadduct
Scheme 1. Cycloadditions of 3,5-dichloro-6-methyl-2(H)-1,4-oxazin-2-
one.9
Table 1
R
Conditionsa
Ratio of cycloadducts
8-endo
7-endo
8-exo
7-exo
CO2Me
C6H5
OEt
A
B
C
35
53
73
33
20
0
32
18
27
0
9
0
a Conditions: A: 70 °C, 3 d; B: 70 °C,18 h; C: rt, 4 h.
evaluate the cycloaddition reactions of several 1,4-oxa-
zin-2-ones with the aim of exploring their potential for
synthesis.
3,5-Dichloro-6-methyl-2(H)-1,4-oxazin-2-one 1, and
3,5-dichloro-6-phenyl-2(H)-1,4-oxazin-2-one 3, were
prepared according to the method reported by Hoor-
naert.14 5-Chloro-3,6-dimethyl-2(H)-1,4-oxazin-2-one 4,
and 5-chloro-6-methyl-3-phenyl-2(H)-1,4-oxazin-2-one
Keywords: Cycloaddition.
* Corresponding author. Tel.: +44-207-848-2422; fax: +44-207-848-
2810; e-mail: kamyar.afarinkia@kcl.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.183

3996
K. Afarinkia et al. / Tetrahedron Letters 45 (2004) 3995–3998
8
5
R
R
7
6
R
R
Cl
Cl
5 N
4
O
O
8
N
4
O
O
3
3
6
7
O
O
O
O
1
1
Cl
Br
Br
Cl
Ph
Ph
Cl
5-endo cycloadduct
6-endo cycloadduct
8-endo cycloadduct
7-endo cycloadduct
3
O
O
R
R
N
R
R
R
R
O
Cl
Cl
O
5
Cl
Br
N
N
O
O
O
O
Ph
2
O
O
O
O
Br
Br
Cl
Cl
Ph
Ph
5-exo cycloadduct
6-exo cycloadduct
8-exo cycloadduct
7-exo cycloadduct
Scheme 2. Cycloadditions of 5-bromo-2(H)-pyran-2-one.11b;c
Scheme 4. Cycloadditions of 3,5-dichloro-6-phenyl-2(H)-1,4-oxazin-2-
one.
Table 2
Conditionsa
Ratio of cycloadducts
R
Table 3
5-endo 6-endo 5-exo
6-exo
R
Conditionsa
Ratio of cycloadducts
CO2Me
4-BrC6H4
OCH2CH2Cl
A
B
B
66
80
67
20
20
0
14
0
0
0
0
8-endo
7-endo
8-exo
7-exo
OBu
A
B
30
30
30
40
40
20
20
20
20
20
30
30
30
30
30
20
20
20
10
10
33
a Conditions A: rt, 4 d; B: 100 °C, 2 d.
CO2Me
4-BrC6H4
OAc
A
A
A
5, were prepared by the Stille coupling of 1 with
tetramethyltin and trimethylphenyltin, respectively
(Scheme 3). 5-Chloro-3-methyl-6-phenyl-2(H)-1,4-ox-
azin-2-one 6, and 5-chloro-3,6-diphenyl-2(H)-1,4-ox-
azin-2-one 7, were prepared by the Stille coupling of 3
with tetramethyltin and trimethylphenyltin, respectively
(Scheme 3).
a Conditions A: 70 °C, 2 d; B: rt, 4 d.
chromatography, recrystallisation or a combination of
both.
3,5-Dichloro-6-phenyl-2(H)-1,4-oxazin-2-one 3, under-
went a highly efficient but poorly selective cycloaddition
with methyl acrylate 8, 4-bromostyrene 10, vinylacetate
11 and butyl vinyl ether 12 (Scheme 4, Table 3). This
parallels the results obtained by Hoornaert for the
cycloadditions of the methyl analogue 1.9 Indeed, in
these cycloadditions all four possible cycloadducts were
seen in the crude NMR.
The oxazinones were treated with a range of electron
rich and electron deficient dienophiles (8–12, Fig. 1) at
room temperature or at 70 °C and the crude reaction
mixtures were analysed by NMR. The yields of the
cycloadditions were taken to be quantitative as no
starting material or impurity could be detected in the
unpurified reaction mixtures. Where possible, the cyclo-
adduct products from each reaction were isolated by
To test that the ratios of products obtained were not the
results of a thermodynamic equilibrium, we carried out
the reaction between 3 and butyl vinyl ether 12, at both
reflux and room temperatures. The proportions of the
cycloadducts were identical in both reactions. Further-
more, the ratio of cycloadducts remained unchanged
over a period of time beyond that required for the
completion of the cycloaddition reaction, confirming
that the cycloadditions were not reversible and that
these ratios are not thermodynamically derived.
Cl
R2
O
O
NC
OH
N
N
i
ii
O
O
R1
Cl
Cl
R1
R1
R1 = Me, 1 (60%);
1 = Ph, 3 (47%);
R1 = Me, R2 = Me, 4 (95%);
1 = Me, R2 = Ph, 5 (61%);
1 = Ph, R2 = Me, 6 (39%);
1 = Ph, R2 = Ph, 7 (71%).
R
R
R
R
Although the cycloadditions of 3,5-dichloro-6-phenyl-
2(H)-1,4-oxazin-2-one 3 were poorly stereoselective, in
each case two of the four possible isomers predominated
slightly. These were deduced to be the 8-endo and 8-exo
substituted cycloadducts based on NOE (nuclear Over-
hauser enhancement) data, and a comparison of the
chemical shifts with those of analogous reference com-
pounds.11d;15
Scheme 3. Preparation of 2(H)-1,4-oxazin-2-ones. (i) (COCl2), toluene,
reflux, 24 h; (ii) R2SnMe3, Pd(PPh3)4, toluene, reflux, 24 h.
O
OAc
CN
OBu
OMe
Br
8
9
10
11
12
This is demonstrated by the cycloadducts from the
reaction between 3 and butyl vinyl ether (Scheme 4,
Figure 1.

K. Afarinkia et al. / Tetrahedron Letters 45 (2004) 3995–3998
3997
Table 4
R ¼ OBu). In the cycloadduct assigned the 8-endo
R1
R2
Condi-
tionsa
Ratio of cycloadducts
configuration, we observed no NOE between H-8
(appearing distinctly at 4.25 ppm) and any of the aro-
matic protons. However, we did observe an NOE
between H-7endo (appearing at 2.33 ppm) and one of the
aromatic protons. Interestingly, H-7exo (appearing at
2.78 ppm) showed a considerably weaker NOE with the
same aromatic proton. Similarly, in the cycloadduct
assigned the 8-exo configuration, we observed no NOE
between H-8 (appearing distinctly at 4.08 ppm) and any
of the aromatic protons. However, we did observe an
NOE between H-7exo (appearing at 2.43 ppm) and one of
the aromatic protons. Interestingly, H-7endo (appearing
at 2.87 ppm) showed a considerably weaker NOE with
the same aromatic proton. The lower chemical shift of
the H-8 (4.08 ppm) in the compound assigned the 8-exo
configuration, compared to that of the H-8 (4.25 ppm) in
the compound assigned the 8-endo configuration is fully
consistent with the previously established literature
precedent.11d;15 For the cycloadducts assigned the 7-endo
and 7-exo configurations the H-7 signals appearing at
4.27 and 4.37, respectively, showed NOEs to an aro-
matic proton. The assignments of the cycloadducts from
the reaction between 3 and methyl acrylate 8, and
bromostyrene 10, were carried out in a similar fashion.
8-endo 7-endo 8-exo
7-exo
Me
CO2Me
CN
B
55
67
38
64
60
18
0
27
33
38
22
40
0
0
8
0
0
A
A
A
A
4-BrC6H4
OAc
OBu
16
14
0
Ph
CO2Me
CN
B
68
40
80
55
71
16
7
16
53
20
27
29
0
0
0
0
0
A
A
A
A
4-BrC6H4
OAc
OBu
0
18
0
a Conditions A: 70 °C, 2 d; B: rt, 4 d.
In contrast, we were unable to obtain pure cycloadducts
from the reactions of 6 with any of the dienophiles 8–12.
This heterocycle was found to be sensitive and decom-
posed significantly during the attempted cycloaddition
reactions.
We next turned our attention to the cycloadditions of 5-
chloro-3,6-diphenyl-2(H)-1,4-oxazin-2-one 7 (Scheme 6,
Table 5). This azadiene underwent facile and selective
cycloadditions to the dienophiles shown in Figure 1.
The configurations (endo/exo) of the two 8-substituted
isomers in the cycloaddition of bromostyrene, and vinyl
acetate where partial stereoselectivity was observed,
were deduced from the expectation of the predominance
of the endo isomer in the Diels–Alder cycloaddition, and
from the results obtained for the cycloadditions of 5-
chloro-3,6-diphenyl-2(H)-1,4-oxazin-2-one 7 (see later).
Since in the cycloadducts obtained in these reaction both
bridgehead substituents are phenyl, assignments of the
relative configurations of the cycloadducts based on
NOE data is not possible. Fortunately, however, the
major products in each of the cycloadditions to acrylo-
nitrile 9, 4-bromostyrene 10, and butyl vinyl ether 12,
were all crystalline and the relative configurations of all
The results of the cycloadditions with oxazines 4 and 5
are reported in Scheme 5 and Table 4. Again, it was
possible to assign the relative regiochemistry of the
cycloadducts based on NOE data. The configurational
(endo/exo) assignment of the two 8-substituted isomers
was deduced from the expectation of the predominance
of the endo isomer in the Diels–Alder cycloaddition. As
can be seen, the reactions were more selective than the
ones for 1 and 3, affording the 8-endo cycloadduct as the
major product followed typically by the 8-exo product.
The 7-exo product was only observed in trace quantities
in one reaction.
8
R
7
R
Ph
Ph
5 N
N
4
O
O
3
6
O
O
1
Cl
Cl
Ph
Ph
Ph
Ph
8-endocycloadduct
7-endo cycloadduct
O
R
N
R
R
O
Ph
Ph
Cl
N
N
O
O
O
O
Cl
Cl
Ph
Ph
8-exo cycloadduct
7-exo cycloadduct
R2
8
R2
7
Scheme 6. Cycloadditions of 5-chloro-3,6-diphenyl-2(H)-1,4-oxazin-2-
one.
R1
R1
5 N
N
4
O
O
3
6
O
O
1
Cl
Cl
Me
Me
R1
Table 5
8-endo cycloadduct
7-endo cycloadduct
O
R2
R1
R
Condi-
tionsa
Ratio of cycloadducts
N
R2
R1
R2
8-endo
7-endo
8-exo
7-exo
O
Cl
N
N
O
O
CO2Me
CN
B
80
77
10
8
10
15
0
0
Me
A
A
A
A
O
O
Cl
Cl
Me
Me
R
1 = Me 4
R1 = Ph 5
4-BrC6H4
OAc
OBu
>98
45
Trace
22
Trace
22
Trace
0
8-exo cycloadduct
7-exo cycloadduct
11
0
>98
0
Scheme 5. Cycloadditions of 5-chloro-3,6-dimethyl-2(H)-1,4-oxazin-2-
one and 5-chloro-6-methyl-3-phenyl-2(H)-1,4-oxazin-2-one.
a Conditions A: 70 °C, 2 d; B: rt, 4 d.

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K. Afarinkia et al. / Tetrahedron Letters 45 (2004) 3995–3998
three could be confirmed by X-ray crystallography. The
configurations of all three of the major cycloadducts
from the reaction between 7 and these three dienophiles
were found to be 8-endo. In other words, cycloadditions
between 7 and electron deficient, electron neutral or
electron rich dienophiles (Scheme 5, R ¼ CN,
4-BrC6H4, and OBu) all afforded selectively the same
configuration of cycloadduct.
References and notes
1. Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57,
6099.
2. (a) Boger, D. L. Tetrahedron 1983, 39, 2869; (b) Boger,
D. L. Chem. Rev. 1986, 86, 781.
3. (a) Sauer, J.; Heldmann, D. K. Tetrahedron Lett. 1998, 39,
2549; (b) Wan, Z. K.; Snyder, J. K. Tetrahedron Lett.
1998, 39, 2487; (c) Rykowski, A.; Branowska, D.; Kielak,
J. Tetrahedron Lett. 2000, 41, 3657.
The results for the cycloadditions of 2(H)-1,4-oxazin-2-
ones 3–5 and 7 demonstrate that the ambident nature of 1
is not unique and that the introduction of methyl and
phenyl substituents to the 3- and 6-positions of the 2(H)-
1,4-oxazin-2-one nucleus affords ambident azadienes
which react with both electron deficient dienophiles (e.g.,
methyl acrylate 8, and acrylonitrile 9) and electron rich
dienophiles (e.g., butyl vinyl ether 12), as well as weakly
activated dienophiles (e.g., 4-bromostyrene 10, and vinyl
acetate 11). Furthermore, the cycloadditions can be very
selective, but the selectivity depends on the substituents
present on the oxazinone ring. For example, in most
cases, oxazinone 7 affords only one major cycloadduct.
Finally and most importantly, the cycloadditions of these
2(H)-1,4-oxazin-2-ones always afford an 8-endo cyclo-
adduct either exclusively or as the major product
regardless of the electronic demand of the dienophile. This
configuration is similar to the major one obtained in the
cycloadditions of 3- and 5-bromo-2(H)-pyran-2-ones, the
regio- and stereoselectivity of which are also independent
of the electronic demand of the dienophile. Therefore,
there appears to be a strong parallel between the cyclo-
addition chemistry of 3- and 5-bromo-2(H)-pyran-2-ones
and 5-chloro-2(H)-1,4-oxazinones.
4. (a) Ohba, M.; Izuta, R.; Shimizu, E. Tetrahedron Lett.
2000, 41, 10251; (b) Ohba, M.; Izuta, R. Heterocycles
2001, 55, 823.
5. Kopka, I. E. Tetrahedron Lett. 1988, 29, 3768.
6. Brown, D. J.; England, B. T. Aust. J. Chem. 1970, 23, 625.
7. For example see: Baydar, A. E.; Boyd, G. V.; Lindley, P.
F.; Watson, F. J. Chem. Soc. Chem. Commun. 1979, 178.
8. Boger, D. L.; Wysocki, R. J., Jr. J. Org. Chem. 1989, 54,
714.
9. (a) Fannes, C.; Meerpool, L.; Hoornaert, G. J. Synthesis
1992, 705; (b) De Borggraeve, W.; Rombouts, F.; Van der
Eycken, E.; Hoornaert, G. J. Synlett 2000, 713; (c)
Vanaken, K. J.; Lux, G. M.; Deroover, G. G.; Meerpoel,
L.; Hoornaert, G. J. Tetrahedron 1994, 50, 5211; (d)
Tutonda, M. G.; Vandenberghe, S. M.; Van Aken, K. J.;
Hoornaert, G. J. J. Org. Chem. 1992, 57, 2935; (e)
Vanaken, K. J.; Lux, G. M.; Deroover, G. G.; Meerpoel,
L.; Hoornaert, G. J. Tetrahedron 1996, 52, 2591.
10. Afarinkia, K.; Bahar, A.; Neuss, J. Synlett 2003, 2341.
11. (a) Posner, G. H.; Nelson, T. D.; Kinter, C. M.; Afarinkia,
K. Tetrahedron Lett. 1991, 32, 5295; (b) Afarinkia, K.;
Posner, G. H. Tetrahedron Lett. 1992, 33, 7839; (c)
Afarinkia, K.; Daly, N. T.; Gomez-Farnos, S.; Joshi, S.
Tetrahedron Lett. 1997, 38, 2369; (d) For reviews see:
Afarinkia, K.; Nelson, T. D.; Vinader, M. V.; Posner, G.
H. Tetrahedron 1992, 48, 9111; (e) Woodward, B. T.;
Posner, G. H. Adv. Cycloaddition 1999, 5, 47.
12. (a) Cho, C.-G.; Park, J.-S.; Jung, I.-H.; Lee, H. Tetra-
hedron Lett. 2001, 42, 1065; (b) Cho, C.-G.; Kim, Y.-W.;
Lim, Y.-K.; Park, J.-S.; Lee, H.; Koo, S. J. Org. Chem.
2002, 67, 290.
13. Afarinkia, K.; Mahmood, F. Tetrahedron 1999, 55, 3129.
14. Meerpool, L.; Hoornaert, G. J. Synthesis 1990, 905.
15. Tomisawa, H.; Fujita, R.; Noguchi, K.; Hongo, H. Chem.
Pharm. Bull. 1970, 18, 941.
Acknowledgements
We thank Oxford GlycoSciences (UK) Ltd (now part of
Celltech R&D Ltd) for financial support (A.B.), and Dr.
Jon W. Steed (KCL) and Dr. Andrew J. P. White
(Imperial College) for expert X-ray analysis.