Investigation of the Diels-Alder cycloadditions of 2(H)-1,4-oxazin-2-ones

Article abstract of DOI:10.1021/jo051646i

A variety of 5-chloro-2(H)-1,4-oxazin-2-ones bearing a range of substituents at their 3- and 6-positions undergo Diels-Alder cycloaddition as a 2-azadiene component with electron-rich, electron-deficient, and electron-neutral dienophiles. These reactions

Full text of DOI:10.1021/jo051646i

Investigation of the Diels-Alder Cycloadditions of
2(H)-1,4-Oxazin-2-ones
Kamyar Afarinkia,*,† Akmal Bahar,† Michael J. Bearpark,‡ Ye´sica Garcia-Ramos,†
Andrea Ruggiero,† Judi Neuss,§ and Maushami Vyas†
Department of Chemistry, King’s College, Strand, London WC2R 2LS, U.K.,
Department of Chemistry, Imperial College, Exhibition Road, London SW7 2AY, U.K.,
and UCB, 216 Bath Road, Slough, Berkshire, SL1 4EN, U.K.
kamyar.afarinkia@kcl.ac.uk
Received August 5, 2005
A variety of 5-chloro-2(H)-1,4-oxazin-2-ones bearing a range of substituents at their 3- and 6-posi-
tions undergo Diels-Alder cycloaddition as a 2-azadiene component with electron-rich, electron-
deficient, and electron-neutral dienophiles. These reactions proceed with moderate regio- and
stereoselectivity to afford relatively stable and readily isolable bridged bicyclic lactone cycloadducts.
Chemical manipulation of these cycloadducts affords highly substituted and functionally rich
piperidines. The regio- and stereochemical preferences of the cycloadditions of 5-chloro-2(H)-1,4-
oxazin-2-ones are investigated computationally using density functional theory (B3LYP/6-31G*).
Introduction
tions with examples of electron-deficient (methyl acry-
late), electron-neutral (styrene), and electron-rich (ethyl
vinyl ether) dienophiles (Scheme 1). Although the reac-
The Diels-Alder reaction of azadienes is a long estab-
lished and useful method in organic synthesis.1 In
particular, the azadiene components of many aromatic
nitrogen-containing heterocycles have been utilized in [4
+ 2] cycloadditions.2 These include 1,2,4-triazines,3 oxa-
zoles,4 thiazoles,5 pyrimidines,6 1,3-oxazin-2-ones,7 and
1,3-oxazin-6-ones.8 More recently, Hoornaert reported the
use of 1(H)-pyrazin-2-ones9 and 1,4-oxazin-2-ones, such
as 3,5-dichloro-6-methyl-2(H)-1,4-oxazin-2-one 1, as a
2-azadiene component in Diels-Alder cycloaddi-
tions.9c,d,f,10 An intriguing and highly unusual feature of
the cycloadditions of 1 was that it underwent cycloaddi-
(9) (a) Tutonda, M.; Vanderzande, D.; Vekemans, J.; Toppet, S.;
Hoornaert, G. Tetrahedron Lett. 1986, 27, 2509. (b) Loosen, P. K.;
Khorasani, M. F.; Toppet, S. M.; Hoornaert, G. J. Tetrahedron 1991,
47, 9269. (c) Tutonda, M. G.; Vandenberghe, S. M.; Van Aken, K. J.;
Hoornaert, G. J. J. Org. Chem. 1992, 57, 2935. (d) Hoornaert, G. J.
Bull. Soc. Chim. Belg. 1992, 101, 53. (e) Vandenberghe, D. M.;
Hoornaert, G. J. Bull. Soc. Chim. Belg. 1994, 103, 185. (f) Hoornaert,
G. J. Bull. Soc. Chim. Belg. 1994, 103, 583. (g) Buysens, K. J.;
Vandenberghe, D. M.; Toppet, S. M.; Hoornaert, G. J. Tetrahedron
1995, 50, 12463. (h) Vandenberghe, S. M.; Buysens, K. J.; Meerpoel,
L.; Loosen, P. K.; Toppet, S. M.; Hoornaert, G. J. J. Org. Chem. 1996,
61, 304. (i) Tahri, A.; Buysens, K. J.; Van der Eycken, E. V.;
Vandenberghe, D. M.; Hoornaert, G. J. Tetrahedron 1998, 54, 13211.
(j) Tahri, A.; De Borggraeve, W.; Buysens, K.; Van Meervelt, L.;
Compernolle, F.; Hoornaert, G. J. Tetrahedron 1999, 55, 14675. (k)
Rombouts, F. J. R.; Vanraes, D. A. J.; Wynendaele, J.; Loosen, P. K.;
Luyten, I.; Toppet, S.; Compernolle, F.; Hoornaert, G. J. Tetrahedron
2001, 57, 3209. (l) Rombouts, F. J. R.; De Borggraeve, W.; Toppet, S.;
Compernolle, F.; Hoornaert, G. J. Tetrahedron Lett. 2001, 42, 7397.
(m) De Borggraeve, W. M.; Rombouts, F. J. R.; Verbist, B. M. P.; Van
der Eycken, E. V.; Hoornaert, G. J. Tetrahedron Lett. 2002, 43, 447.
(10) (a) Meerpoel, L.; Deroover, G.; Vanaken, K.; Lux, G.; Hoornaert,
G. J. Synthesis 1991, 765. (b) Fannes, C.; Meerpool, L.; Hoornaert, G.
J. Synthesis 1992, 705. (c) Fannes, C. C.; Hoornaert, G. J. Tetrahedron
Lett. 1992, 33, 2049. (d) Vanaken, K. J.; Lux, G. M.; Deroover, G. G.;
Meerpoel, L.; Hoornaert, G. J. Tetrahedron 1994, 50, 5211. (e) Vanaken,
K. J.; Lux, G. M.; Deroover, G. G.; Meerpoel, L.; Hoornaert, G. J.
Tetrahedron 1996, 52, 2591. (f) Lux, G.; Wu, X. J.; Toppet, S.;
Hoornaert, G. J. Bull. Soc. Chim. Belg. 1997, 106, 623. (g) De
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Synlett 2000, 713. (h) Wu, X. J.; Dubois, K.; Rogiers, J.; Toppet, S.;
Compernolle, F.; Hoornaert, G. J. Tetrahedron 2000, 56, 3043.
† King’s College.
‡ Imperial College.
§ UCB.
(1) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099.
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Chem. Rev. 1986, 86, 781.
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10.1021/jo051646i CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/20/2005
J. Org. Chem. 2005, 70, 9529-9537
9529

Afarinkia et al.
SCHEME 1
SCHEME 2
a wide range of substituted 2(H)-1,4-oxazin-2-ones. Dur-
ing his studies, Hoornaert had reported a method for the
preparation of 6-substituted 3,5-dichloro-2(H)-1,4-oxazin-
2-ones.16 This presented us with an ideal opportunity to
prepare a wide range of substituted 1,4-oxazin-2-ones,
both through Hoornaert’s original synthesis (through
variation of the 6-substituent) and also by chemical
manipulation of the chloro substituents.
Furthermore, to make this an efficient methodology,
the Diels-Alder cycloadditions should proceed in good
yield and with regio- and stereoselectivity. This can be
best achieved by matching the electronic demand of the
dienophile with that of the 2(H)-1,4-oxazin-2-one by
means of appropriate ring substitution. This approach
has been successfully used by Posner, who has demon-
strated that 3-phenylsulfenyl-2(H)-pyran-2-one 417 and
3-phenylsulfonyl-2(H)-pyran-2-one 518 react with electron-
deficient and electron-rich dienophiles, respectively, and
that the reactions proceed to give the isolable cycload-
ducts with excellent regio- and stereocontrol (Scheme 2).
A telling example from Hoornaert’s cycloaddition stud-
ies was that the only moderately selective cycloaddition
was that between ethyl vinyl ether, an electron-rich
dienophile, and 3,5-dichloro-6-methyl-2(H)-1,4-oxazin-2-
tions were not regio- and stereoselective, affording all four
possible stereo- and regioisomeric cycloadducts, this was
the only known example of an “ambident” 2-azadiene, i.e.,
one which is capable of both normal and inverse electron-
demand Diels-Alder cycloadditions. Curiously, the only
other known ambident dienes are halogenated 2(H)-
pyran-2-ones, e.g., 3-bromo-2(H)-pyran-2-one,11a 5-bromo-
2(H)-pyran-2-one 2,11b,c 5-chloro-2(H)-pyran-2-one 3,12 and
3,5-dibromo-2(H)-pyran-2-one.13 Therefore, it appears
that 2(H)-1,4-oxazin-2-ones are 2-azadiene counterparts
of the well-investigated 2(H)-pyran-2-one dienes. To
complement our long-standing interest in the cycloaddi-
tion reactions of 2(H)-pyran-2-ones11,12 and their synthetic
applications,14 we decided to evaluate the cycloaddition
reactions of several 1,4-oxazin-2-ones with the aim of
extending the scope of the reaction and exploring their
potential for synthesis of complex molecules.15
(14) (a) Afarinkia, K.; Mahmood, F. Tetrahedron 1999, 55, 3129. For
further examples of the use of 2-pyrone cycloadditions in the synthesis,
see: (b) Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B.
J.; McGarvey, T. J.; Thaisrivongs, S. J. Am. Chem. Soc. 1983, 105,
1988. (c) Boger, D. L.; Brotherton, C. E. J. Org. Chem. 1984, 49, 4050.
(d) Boger, D. L.; Mullican, M. D. J. Org. Chem. 1984, 49, 4033. (e)
Posner, G. H.; Wettlaufer, D. G. J. Am. Chem. Soc. 1986, 108, 7373.
(f) Ahmed, S. A.; Bardshiri, E.; Simpson, T. J. J. Chem. Soc., Chem.
Commun. 1987, 883. (g) Yamaguchi, R.; Otsuji, A.; Utimoto, K.;
Kozima, S. Bull. Chem. Soc. Jpn. 1992, 65, 298. (h) Posner, G. H.; Dai,
H.; Afarinkia, K.; Murthy, N. N.; Guyton, K. Z.; Kensler, T. W. J. Org.
Chem., 1993, 58, 7209. (i) Marko´, I. E., Seres, P.; Evans G. R.;
Swarbrick T. M. Tetrahedron Lett. 1993, 34, 7305. (j) Posner, G. H.;
Lee, J. K.; White, M. C.; Hutchings, R. H.; Dai, H. Y.; Kachinski, J. L.;
Dolan, P.; Kensler, T. W. J. Org. Chem. 1997, 62, 3299. (k) Kim, W.
S.; Lee, J. H.; Kang, J.; Cho C.-G. Tetrahedron Lett. 2004, 45, 1683. (l)
Vijgen, S.; Nauwelaerts, K.; Wang, J.; Van Aeschot, A.; Lagoja, I.;
Herdewijn, P. J. Org. Chem. 2005, 70, 4591.
Results and Discussion
Preparation of 2(H)-1,4-Oxazin-2-one. If 2(H)-1,4-
oxazin-2-ones are to be useful in synthesis, their cycload-
dition should be versatile and tolerate a range of sub-
stituents both on the azadiene (i.e., the 1,4-oxazin-2-one
ring) and dienophile. This requires convenient routes to
(15) For a preliminary communication, see: (a) Afarinkia, K.; Bahar
A.; Neuss, J.; Ruggerio, A. Tetrahedron Lett. 2004, 45, 3995. (b)
Afarinkia, K.; Bahar A.; Neuss, J.; Vyas, M. Tetrahedron Lett. 2004,
45, 7121.
(16) (a) Meerpool, L.; Hoornaert, G. J. Tetrahedron Lett. 1989, 30,
3183. (b) Meerpool, L.; Hoornaert, G. J. Synthesis 1990, 905. (c)
Vanaken, K. J.; Meerpoel, L.; Hoornaert, G. J. Tetrahedron Lett. 1992,
33, 2713.
(17) (a) Posner, G. H.; Wettlaufer, D. G. Tetrahedron Lett. 1986, 27,
667. (b) Posner, G. H.; Nelson, T. D.; Kinter, C. M.; Johnson, N. J.
Org. Chem. 1992, 57, 4083.
(18) (a) Posner, G. H.; Wettlaufer, D. G. J. Am. Chem. Soc. 1986,
108, 7373. (b) Posner, G. H.; Haces, A.; Harrison, W.; Kinter, C. M. J.
Org. Chem. 1987, 52, 4836. (c) Posner, G. H.; Kinter, C. M. J. Org.
Chem. 1990, 55, 3967. (d) Posner, G. H.; Nelson, T. D. Tetrahedron
1990, 46, 4573.
(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) Posner, G.
H.; Afarinkia, K.; Dai, H. Organic Synthesis 1995, 73, 231. For reviews,
see: (e) Afarinkia, K.; Nelson, T. D.; Vinader, M. V.; Posner, G. H.
Tetrahedron 1992, 48, 9111. (f) Woodward, B. T.; Posner, G. H. Adv.
Cyloaddition 1999, 5, 47.
(12) (a) Afarinkia, K.; Bearpark, M.; Ndibwami, A. J. Org. Chem.
2003, 68, 7158. (b) Afarinkia, K.; Bearpark, M.; Ndibwami, A. J. Org.
Chem. 2005, 70, 1122.
(13) (a) Cho C.-G.; Park, J.-S.; Jung, I.-H.; Lee, H. Tetrahedron 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. (c) Shin, J.-T.; Shin S.; Cho
C.-G. Tetrahedron Lett. 2004, 45, 5857.
9530 J. Org. Chem., Vol. 70, No. 23, 2005

Diels-Alder Cycloadditions of 2(H)-1,4-Oxazin-2-ones
SCHEME 3 a
SCHEME 4
6-methyl-2(H)-1,4-oxazin-2-one 17 and 5-chloro-3-phen-
ylsulfenyl-6-phenyl-2(H)-1,4-oxazin-2-one 18 were pre-
pared by treatment of 1 and 6 with thiophenol and
aluminum trichloride (Scheme 3).10d,16c,19
Cycloadditions of 2(H)-1,4-Oxazin-2-one. The cy-
cloadditions were carried out with a range of electron-
deficient dienophiles methyl acrylate 19 and acrylonitrile
20, electron-“neutral” dienophile 4-bromostyrene 21,
electron-rich dienophiles vinyl acetate 22, and butyl vinyl
ether 23. It became immediately clear that 2(H)-1,4-
a Key: (i) condition A: (COCl)2, Me3N‚HCl, toluene, reflux, 24
h; condition B: (COCl)2, Me3N‚HCl, chlorobenzene, 90 °C, 24 h;
(ii) HBr, acetic acid, rt, 1 h; (iii) condition A: R2SnMe3, Pd(PPh3)4,
toluene, reflux, 24 h; condition B: R2SnBu3, Pd(PPh3)4, toluene,
reflux, 24 h; (vi) condition A: methanol, HCl, rt, 2 h; condition B:
thiophenol, AlCl3, CH2Cl2, rt, 15 h.
one, which having a chloro substituent at its 3-position
can be considered an electron-deficient azadiene. There-
fore, one of our key objectives was to prepare further
examples of 2(H)-1,4-oxazin-2-one, particularly ones with
electron-donating groups at the 3-position of the ring, and
attempt their cycloadditions.15
3,5-Dichloro-2(H)-1,4-oxazin-2-ones 1, 6, and 7 were
prepared by treatment of the corresponding cyanohydrins
with oxalyl chloride in the presence of an external source
of chloride ions (such as trimethylammonium chloride)
according to Hoornaert’s procedure (Scheme 3).16 It is
expected that the chloro substituent at the 3-position is
more reactive than the one at the 5-position, and there-
fore, there were no issues relating to regioselectivity of
further functionalization of these heterocyclic compounds.
However, although aromatic chlorides undergo a diverse
range of reactions, we found it useful to have access to
potentially more reactive 3-bromo derivative 8. This was
prepared by treatment with hydrogen bromide in acetic
acid. Stille coupling on 3,5-dichloro-2(H)-1,4-oxazin-2-
ones afforded the corresponding 3-methyl- and 3-phenyl-
2(H)-1,4-oxazin-2-ones 9-12. However, introduction of
allyl and vinyl groups by Stille coupling of allyl- and
vinylstannane failed since both reagents undergo a more
facile Diels-Alder cycloaddition, rather than a coupling.
Nevertheless, the more reactive 3-bromo-5-chloro-2(H)-
1,4-oxazin-2-one 8 did afford the corresponding 3-hydro
and 3-stannyl derivatives 13 and 14, but unfortunately,
these proved to be highly sensitive compounds and
decomposed quickly and, therefore, could not be used for
further derivatization reactions or in cycloadditions.
5-Chloro-3-methoxy-6-methyl-2(H)-1,4-oxazin-2-one 15
and 5-chloro-3-methoxy-6-phenyl-2(H)-1,4-oxazin-2-one
16 were prepared by treatment of 1 and 6 with metha-
nolic hydrogen chloride.10d,16c,19 5-Chloro-3-phenylsulfenyl-
oxazin-2-ones are highly reactive azadienes and undergo
cyloadditions with all these dienophiles at room temper-
ature or with a relatively short reaction time at elevated
temperatures. The cycloadditions were also highly ef-
ficient with only the cycloadducts (as well as unreacted
starting materials, had the reaction not gone to comple-
tion) observed by NMR in crude product mixtures. The
cycloadducts were quite stable; however, on prolonged
exposure to silica gel during chromatography, we ob-
served partial or significant decomposition in some cases,
mainly due to hydrolysis of the imidoyl chloride function
in the cycloadducts. The results of the cycloadditions are
shown in Scheme 4 and Tables 1-3. The regio- and
stereochemical assignment of the cycloadducts was based
on the analysis of the NMR spectra of the cycloadducts
according to the criteria which will be discussed shortly.
One of the first issues that we needed to address was
whether the ratio of cycloadducts were determined by the
thermodynamic stability of each configurational isomer.
The issue of the kinetic or thermodynamic control in
Diels-Alder reaction is complex. As a general rule with
cyclic dienes, and particularly with 2(H)-pyran-2-ones
and closely related 2(H)-pyridin-2-ones,20 the endo cy-
cloadducts are considered to be kinetic products whereas
(20) (a) Beteneli, L.; Shusherina, N. P.; Stepanyants, A. U.; Tarkha-
nova, E. A. J. Org. Chem. USSR 1977, 13, 1787. (b) Shusherina, N.
P.; Pilipenko, V. S.; Kireeva, O. K.; Geller, B. I.; Stepanyants, A. U. J.
Org. Chem. USSR 1980, 16, 2047. (c) Pilipenko, V. S.; Shusherina, N.
P. J. Org. Chem. USSR 1981, 17, 1891. (d) Posner, G. H.; Vinader, M.
V.; Afarinkia, K. J. Org. Chem. 1992, 57, 4088.
(19) Meerpoel, L.; Joly, G. J.; Hoornaert, G. J. Tetrahedron 1993,
49, 4085.
J. Org. Chem, Vol. 70, No. 23, 2005 9531

Afarinkia et al.
TABLE 1
TABLE 3
a Conditions A: Reaction was carried out for 2 days at 70 °C.
Conditions B: Reaction was carried out for 4 days at room
temperature. b Ratio of cycloadducts are normalized so as to total
100%. c Values taken from ref 10. d Values taken for the cycload-
dition to styrene from ref 10. e Values taken for the cycloaddition
to ethyl vinyl ether from ref 10.
a Conditions: Reaction was carried out for 2 days at 70 °C.
b Ratio of cycloadducts are normalized so as to total 100%. c Values
in brackets are the yield of isolated cycloadducts after purification
by chromatography. d Cycloadducts partially decomposed during
chromatography. e Cycloadducts decomposed during chromatog-
raphy. f Using (2-chloroethyl) vinyl ether as dienophile.
TABLE 2
SCHEME 5
of dimethyl maleate dienophile was preserved during
cycloaddition affording exclusively cis cycloadduct 26
(Scheme 5). Had the reaction been a two-step process
involving nucleophilic addition to dimethyl maleate as
the first step, we would expect some trans cycloadduct
27. However, this cycloadduct, an authentic sample of
which is obtained in the cycloaddition of 1 and dimethyl
fumarate 25 (Scheme 5), was absent from the reaction
mixture. The results of this experiment further support
an irreversible, single step cycloaddition step mechanism
under the proposed reaction conditions.
As can be seen, the key features of the cycloaddition
chemistry of 2(H)-1,4-oxazin-2-ones are as follows. 6-Alkyl-
and 6-aryl-5-chloro-2(H)-1,4-oxazin-2-ones are ambident
dienes reacting efficiently with examples of electron-rich,
electron-deficient, and electron-neutral dienophiles. In-
troduction of substituents at the 3-position of 2(H)-1,4-
oxazin-2-ones does not significantly affect the ambident
reactivity of the azadiene. For example, 2(H)-1,4-oxazin-
2-ones bearing an electron-donating substituent at their
3-position still react efficiently with electron-rich dieno-
a Conditions A: Reaction was carried out for 2 days at 70 °C.
Conditions B: Reaction was carried out for 4 days at room
temperature. b Ratio of cycloadducts are normalized so as to total
100%.
the exo products, which have less steric congestion, are
considered to be the thermodynamic products. To ascer-
tain this, we followed the progress of a typical thermal
cycloaddition, that between 6 and butyl vinyl ether, by
NMR. We found that the ratio of the cycloadduct products
did not change as the reaction progressed, and once the
reaction was complete, the ratio of the cycloadduct
products did not change on prolonged heating. Further-
more, we analyzed the outcome of the thermal cycload-
dition between 1 and dimethyl maleate 24 and dimethyl
fumarate 25, by NMR. We found that the stereochemistry
9532 J. Org. Chem., Vol. 70, No. 23, 2005

Diels-Alder Cycloadditions of 2(H)-1,4-Oxazin-2-ones
SCHEME 6
philes, and 2(H)-1,4-oxazin-2-ones bearing an electron-
withdrawing substituent at their 3-position still react
efficiently with electron-deficient dienophiles. However,
matching the electronic demand of 2(H)-1,4-oxazin-2-ones
with that of dienophiles can result in a significant im-
provement in regioselectivity of the reaction. For ex-
ample, 2(H)-1,4-oxazin-2-ones bearing an electron-with-
drawing substituent at their 3-position react efficiently
with electron-deficient dienophiles to exclusively afford
8-substituted cycloadducts. An important observation
which further confirms the role of matching the elec-
tron demand between dienophiles and 2(H)-1,4-oxa-
zin-2-ones is that although the reactions are all efficient
and afford near quantitative yield of cycloadducts, there
is a significant difference between the rates of reac-
tions. For example, using competition experiments we
established that the rate of cycloaddition of butyl vinyl
ether is at least five times faster with its electronically
matched azadiene, 3,5-dichloro-6-phenyl-2(H)-1,4-oxazin-
2-one 6, than with 5-chloro-3,6-diphenyl-2(H)-1,4-oxazin-
2-one 12. Similarly, the rate of the cycloaddition of methyl
acrylate is at least 10 times faster with its electronically
matched azadiene, 5-chloro-3,6-diphenyl-2(H)-1,4-oxazin-
2-one 12, than with 3,5-dichloro-6-phenyl-2(H)-1,4-oxa-
zin-2-one 6.
In contrast, stereoselectivity of the cycloadditions
remains modest even when the electron demand of the
azadiene and dienophile are matched, except when the
2(H)-1,4-oxazin-2-one has a bulky substituent at its 3-
and 6-positions. The role of sterically bulky substituents
in improving the endo selectivity in cycloadditions of
2(H)-1,4-oxazin-2-ones is presumably related to similar
observations by Sammes, who demonstrated that aryl
substituents at the 3- and 6-position of 2(H)-pyridin-2-
ones significantly improves the endo selectivity in their
cycloadditions.21
1,4-oxazin-2-ones, which affords 2-oxa-5-azabicyclo[2.2.2]-
oct-5-en-3-one. This confirms a strong similarity between
the cycloaddition chemistry of 2(H)-pyran-2-ones and
2(H)-1,4-oxazinones.
Although it was possible to obtain crystal structures
of the major cycloadducts in the cycloadditions of 12 and
hence absolutely prove the configurational assignment
of the major cycloadducts in these cases, we needed to
devise an alternative proof of structure which did not rely
on crystallography. As part of the investigation of the
Diels-Alder reaction of substituted 2(H)-pyran-2-ones,
our group had established a protocol for the determina-
tion of the configuration of cycloadducts from 2(H)-
pyrones.11c,e,12 This protocol involves a comparison of the
magnitude of the coupling constants between bridgehead
protons (at position 1- or 4- of the 2(H)-pyrone cycload-
duct and protons at position 5- or 6- of the 2(H)-pyrone
cycloadduct, see Scheme 6). Since in the cycloadducts
from 2(H)-1,4-oxazine-2-ones both bridgehead positions
are substituted the relative configurations could not be
determined by this protocol. Hoornaert had devised
another protocol-based on long-range coupling between
protons and 13C of the bridging carboxyl function. Al-
though this is an established protocol, it lacks practicality
as large sample quantities are required. Therefore, we
required another general, reliable, and robust protocol
for assignment of the configuration of our cycloadducts.
The protocol that we have developed uses a combina-
tion of NOESY (Nuclear Overhauser Enhancement Spec-
troscopY) and observation of the chemical shifts of the
protons at the 7- and 8-positions of the cycloadducts. To
start, the signal due to the methyne and methylene
protons at either the 7- or 8-position are easily distin-
guishable by the pattern of their couplings. Methylene
protons have a large (11-13 Hz) geminal coupling to each
other as well as a small (2-6 Hz) coupling to the adjacent
syn or a medium (7-11 Hz) coupling to the adjacent
gauche methyne. Similarly, the methyne proton has a
small (2-6 Hz) coupling to the syn hydrogen and a
medium (7-11 Hz) coupling to the gauche hydrogen of
the adjacent methylene group. Analysis of the degree of
nuclear Overhauser enhancement is then used to deter-
mine the regiochemistry of the cycloadduct. For example,
a methyne proton signal showing significant enhance-
ment with irradiation of C-4 substituent suggest that the
cycloadduct is an 8-substituted isomer, whereas signifi-
However, the most important observation is that the
preference in the cycloadditions of 2(H)-1,4-oxazin-2-one
is for the cycloadducts with an 8-endo configuration
regardless of the electronic demand of the dienophile.
Assignment of the Configuration of Cycload-
ducts. We were fortunate to obtain the major cycload-
ducts from the reactions of 5-chloro-3,6-diphenyl-2(H)-
1,4-oxazin-2-one 12 with acrylonitrile 20, 4-bromostyrene
21, and butyl vinyl ether 23 as crystalline compounds.
Hence, it was possible to confirm the relative configura-
tions of all three by X-ray crystallography (see the
Supporting Information). The configurations of all three
of the major cycloadducts from the reaction between
5-chloro-3,6-diphenyl-2(H)-1,4-oxazin-2-one 12 and these
three dienophiles were found to be 8-endo. In other words,
cycloadditions of 12 afforded the same configuration as
the major cycloadduct regardless of the electronic demand
of the dienophile. Interestingly, 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. It should be noted
that the numbering system in cycloadducts from 2(H)-
pyran-2-ones is different from the cycloadducts from 2(H)-
(21) (a) Gisby, G. P.; Royall, S. E.; Sammes P. G. J. Chem. Soc.,
Perkin Trans. 1 1982, 169. (b) Sammes P. G.; Weller D. J. Synthesis
1995, 1205.
J. Org. Chem, Vol. 70, No. 23, 2005 9533

Afarinkia et al.
CHART 1
SCHEME 7 a
cant enhancement of methylene proton signals with C-4
substituent suggest that the cycloadduct is a 7-substi-
tuted isomer. Although this rationale requires a proton
containing substituent either at C-1 or C-4 bridgehead,
in our experience this protocol was infallible in determi-
nation of regiochemistry of cycloadducts.
The key feature which allows us to assign the relative
stereochemical configuration (endo versus exo) of a pair
of regioisomeric cycloadducts is that due the magnetic
anisotropy of the imine bond, protons at the endo position
will always resonate at lower chemical shift than other-
wise expected. This feature was first reported by Tomis-
awa and Hongo22 in 2-aza[2.2.2]cycloctenes (cycload-
ducts from 2(H)-pyridin-2-ones) and later by Hisano and
Harano23 and Posner20d in 2-oxa[2.2.2]cycloctenes (cy-
cloadducts from 2(H)-pyran-2-ones). For instance, as can
be seen in the following example (Chart 1), the chemical
shift of a proton at an endo position is always lower than
that of the corresponding proton in an exo position.
We could further confirm the assignment of relative
configuration of the cycloadducts by chemical manipula-
tion. To demonstrate this, we carried out the cycloaddi-
tion of 5-chloro-3,6-dimethyl-2(H)-1,4-oxazine-2-one 9
with the symmetrically substituted dienophile, vinylene
carbonate. The cycloaddiction afforded two cycloadducts
in a ratio of 3:1 which could not be separated. However,
after the chloro substituents in each of the cycloadduct
had been replaced with a methyl group using palladium
catalyzed Stille coupling, the two bridged bicyclic ester-
imines 31 and 32 were separable and were isolated in
65% and 27% yields respectively (Scheme 7). The major
product was assigned an endo configuration based on the
observation that the chemical shifts for H-7 and H-8
protons in this compound were 4.74 and 4.77 ppm,
whereas the same protons resonate at 4.53 and 4.57 ppm
in the minor product. Hydride reduction of the imine
functionality of the endo-assigned bridged ester selec-
tively gave a single product with the relative configura-
tion given as amine 33. The selectivity of the reduction
step is precedented by earlier observations during hy-
drogenolysis of the structurally related bridged bicyclic
lactones14a and is due to the steric encumbrance by the
a Key: (i) toluene, reflux, 24 h, vinylene carbonate, 74%;
(ii) toluene, reflux, 48 h, Me4Sn, Pd(PPh3)4, 92%; (iii) AcOH,
Na(AcO)3BH, rt, 24 h, 68%.
carbonate bridge. Close analysis of the NMR of compound
33 revealed a fine coupling (1.5 Hz) between H-6 and H-7.
The presence of this W coupling strongly supports the
proposed configuration of the reduction product and
excludes other possible configurations.
To summarize, 6-alkyl-5-chloro-2(H)-1,4-oxazin-2-ones
are ambident dienes reacting efficiently with examples
of electron-rich, electron-deficient, and electron-neutral
dienophiles. Introduction of electronically biased substit-
uents at the 3-position of 2(H)-1,4-oxazin-2-ones does not
significantly affect the ambident reactivity of azadiene.
Matching the electronic demand of 2(H)-1,4-oxazin-2-ones
with that of dienophiles can result in regiospecificity of
the reaction; however, stereoselectivity of the cycloaddi-
tions remains modest except when the 2(H)-1,4-oxazin-
2-one has bulky substituents at its 3- and 6-positions.
Finally, the observed preference in the cycloadditions of
2(H)-1,4-oxazin-2-one is for the cycloadduct with an
8-endo configuration regardless of the electronic demand
of the dienophile.
(22) Tomisawa, H.; Fujita, R.; Noguchi, K. J.; Hongo, H. Chem.
Pharm. Bull. 1970, 18, 941. Also see: Tori, K.; Moneyuki, R.; Takano,
Y.; Tanida, H.; Tsuji, T.; Hata, Y. Can J. Chem. 1964, 42, 926.
(23) Harano, K.; Aoki, T.; Eto, M.; Hisano, T. Chem. Pharm. Bull.
1990, 38, 1182.
9534 J. Org. Chem., Vol. 70, No. 23, 2005

Diels-Alder Cycloadditions of 2(H)-1,4-Oxazin-2-ones
A Comparison between the Cycloadditions of
2(H)-1,4-Oxazin-2-ones and 2(H)-Pyran-2-ones. It is
clear from these observations that the reactivity, as well
as regio and stereoselectivity of the cycloadditions of 2(H)-
1,4-oxazin-2-ones does parallel closely those of 2(H)-
pyran-2-ones. In particular, the favored cycloadduct in
the cycloadditions of 2(H)-1,4-oxazin-2-ones has the cor-
responding configuration to those obtained in the cy-
cloadditions of 2(H)-pyran-2-ones. Therefore, in a broad
sense, 2(H)-1,4-oxazin-2-ones can be considered 2-azadi-
ene analogues of 2(H)-pyran-2-one dienes. As such, highly
advantageous synthetic methodologies based on cycload-
ditions of 2(H)-pyran-2-ones which afford highly substi-
tuted six-membered carbocycles can be translated to
analogous methodologies based on cycloadditions of 2(H)-
1,4-oxazin-2-ones to afford highly substituted piperidine
rings. Indeed, both Hoornaert and we have shown the
value of this methodolgy in target synthesis.24
However, the cycloaddition chemistry of 2(H)-1,4-
oxazin-2-ones is clearly more subtle than that of 2(H)-
pyran-2-ones both in the scope of dienophiles they react
with, and in the role of ring substituents on the control
of the electron demand of the cycloaddition. Since in
cycloadditions of 2(H)-1,4-oxazin-2-ones a wider range of
substituents are tolerated both on the diene and dieno-
phile, this is a more versatile synthetic method and can
afford a more diverse range of heavily substituted six-
membered rings. 2(H)-1,4-Oxazin-2-ones are also more
reactive than 2(H)-pyran-2-ones in the sense that they
react with dienophiles regardless of their electronic
demand, and sometimes even with their electronically
mismatched dienophiles. This results in less stereose-
lectivity in cycloadditions, although it is possible to
control the regiochemistry of cycloadditions by matching
the electron demand between oxazinone diene and di-
enophiles.
ether and 2-chloroethyl vinyl ether.12 The partnering of
electron-deficient 3,5-dichloro-6-methyl-1,4-oxazin-2-one,
1, with methyl vinyl ether (MVE) represents a matching
of electron demands between the diene and dienophile,
whereas partnering of this 1,4-oxazin-2-one with methyl
acrylate (MA) represents a “mismatch”.
Calculations were performed using Gaussian 01.25 All
transition structures were initially optimized with AM126,27
and then reoptimized using B3LYP/6-31G*.28 Frequency
calculations were carried out at all computed B3LYP/
6-31G* transition structures. Each was shown to have
only one vibrational mode with an imaginary frequency.
These were animated to confirm that they were transition
structures for the reactions being investigated. This DFT
method (model chemistry) has been previously shown by
Houk to be a reliable method for predicting the regio-
and stereoselectivity of the cycloaddition of Danishefsky’s
diene with acrylonitrile29 and by us to be a reliable
method for predicting the regio- and stereoselectivity of
the cycloadditions of halogen-substituted 2(H)-pyran-2-
ones.12
The calculated relative energies of transition states
leading to the four possible cycloadducts from the reaction
of each of the oxazin-2-ones with methyl acrylate (MA)
and methyl vinyl ether (MVE), along with the yields of
each cycloadduct obtained experimentally, are shown in
Table 4 (yields of cycloaddition with butyl vinyl ether
were used in place of that for methyl vinyl ether). Table
4 also contains information on the distance between the
bond-forming atoms in diene and dienophile in each case.
This information indicates the degree of asynchronicity
in the bond formation during the Diels-Alder cycload-
dition and is further evidence in support of the lack of
significant change in electron demand of the cycloaddi-
tions.
The computational data can be used to proximately
predict the ratio of the cycloadducts obtained in these
reactions. We can expect that of the four transition states,
the ones with the lower energy are likely to be favored
and cycloadducts resulting from them will be observed
in larger proportion in the final product mixture. There-
fore, one expects a correlation between the calculated
energy of the four transition states and the yield of the
four cycloadducts.
Computational Results and Discussion
As discussed earlier, 2(H)-1,4-oxazin-2-ones undergo
cycloaddition with dienophiles regardless of their elec-
tronic demand. In this sense, 2(H)-1,4-oxazin-2-ones
appear to be 2-azadiene analogues of the well-established
halo substituted 2(H)-pyran-2-ones. We had previously
shown that the regio- and stereochemical outcome of the
cycloadditions of 2(H)-pyran-2-one can be predicted com-
putationally.12 We decided to carry out a similar inves-
tigation of 2(H)-1,4-oxazin-2-ones in order to understand
and predict the regio and stereoselectivity in their
cycloadditions. Hence, we carried out a range of calcula-
tions on the four transition states (TS) leading to the four
possible stereoisomers, namely the 8-endo, the 7-endo,
the 8-exo, and the 7-exo cycloadducts, in the cycloaddi-
tions of 3,5-dichloro-6-methyl-1,4-oxazin-2-one, 1, and
5-chloro-3-methoxy-6-methyl-1,4-oxazin-2-one, 15, with
methyl acrylate (MA) and methyl vinyl ether (MVE).
Methyl vinyl ether was chosen as a typical electron-rich
dienophile for computations. Although this was not one
of the dienophiles used in the cycloaddition experiments,
we are confident that the results obtained computation-
ally for MVE can be used for comparison with results
obtained experimentally for closely related butyl vinyl
As can be seen from the tables, the theory is partially
successful in its predictions. For the cycloadditions of the
(25) Gaussian 01, Development Version (Revision B.01): Frisch, M.
J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Kudin,
K. N.; Burant, J. C.; Millam, J. M.; Stratmann, R. E.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Iyengar,
S.; Petersson, G. A.; Ehara, M.; Toyota, K.; Nakatsuji, H.; Adamo, C.;
Jaramillo, J.; Cammi, R.; Pomelli, C.; Ochterski, J.; Ayala, P. Y.;
Morokuma, K.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.;
Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian,
Inc., Pittsburgh, PA, 2001.
(26) Dewar, M. J. S., Zoebisch, E. G. THEOCHEM 1988, 41, 1.
(27) Dewar, M. J. S., Zoebisch, E. G.; Healy, E. F.; Stewart J. J. P.
J. Am. Chem. Soc. 1985, 107, 3902.
(28) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(29) Ujaque, G.; Norton, J. E.; Houk, K. N. J. Org. Chem. 2002, 67,
7179.
(24) Afarinkia, K.; Bahar A.; Neuss, J. Synlett 2003, 2341.
J. Org. Chem, Vol. 70, No. 23, 2005 9535

Afarinkia et al.
TABLE 4. Comparison between the Calculated Energy of Transition States Leading to the Four Possible Cycloadducts
and the Experimentally Derived Ratios from the Reactions of 5-Chloro-6-methyl-1,4-oxazin-2-ones 1 and
5-Chloro-6-methoxy-1,4-oxazin-2-ones 15 with Methyl Acrylate (MA) and Methyl Vinyl Ether (MVE)
a Difference in the calculated barrier heights, with the lowest energy transition state taken as the energy zero. b Experimentally obtained
(see Tables 1-3).
yellow residue was purified by flash chromatography, eluting
with 10% v/v ether in petrol ether (60-80 °C) to give 200 mg
(71%) of a yellowish powder: mp 146-149 °C; 1H NMR δ
7.42-7.61 (m, 6H, Ph), 7.99-8.01 (m, 2H, Ph), 8.40-8.42
(m, 2H, Ph); 13C NMR δ 125.29 (C-5), 127.55 (2 × CH, Ph),
127.63 (2 × CH, Ph), 128.95 (2 × CH, Ph), 128.99 (Cipso),
129.13 (2 × CH, Ph), 129.41 (Cipso), 131.67 (CH, Ph), 132.31,
CH, Ph), 133.16 (C-3), 146.87 (C-6), 152.88 (C-2); IR 1595, 1739
cm-1; m/z 283 (M+, 71), 255 (57), 220 (43); HRMS calcd for
C16H10NO235ClNa (MNa+) 306.0019, found 306.0035.
two 2(H)-oxazin-2-ones with electron rich dienophile
methyl vinyl ether (MVE), the two observed products are
those which theory predicted to have lower activation
energies. Although the computations fail to correctly
predict the major isomer in the cycloaddition of the
matched diene/dienophile pair 1 and MVE, this can be
put down to the relatively small energy gaps involved.
For the cycloadditions of the two 2(H)-oxazin-2-ones with
electron-deficient dienophile methyl acrylate (MA), again
the two observed products are those which theory pre-
dicted to have lower activation energies. However, theory
is less successful in predicting the ratio of the cycload-
ducts and significantly underestimates the likelihood of
the formation of the 8-exo cycloadduct.
In other words, the model chemistry used in these
computations, although not sophisticated enough to
predict the exact ratios of cycloadducts of 2(H)-oxazin-
2-ones, is able to predict which cycloadducts are likely
to be formed. This is in contrast to the excellent agree-
ment between computational and experimental results
in the cycloadditions of halo substituted 2(H)-pyran-2-
ones. Nevertheless, DFT (B3LYP/6-31G*) provides a
useful tool for predicting the regio- and stereochemical
preferences in the cycloadditions of 2(H)-oxazin-2-ones
to first approximation.
5-Chloro-3-methoxy-6-methyl-2(H)-1,4-oxazin-2-one, 15.
3,5-Dichloro-6-methyl-2(H)-1,4-oxazin-2-one 116b (1.00 g, 5.56
mmol) was dissolved in anhydrous methanol (30 mL) and
cooled to 0 °C. To the ice-cold mixture was added acetic acid
(30 mL) dropwise over 15 min. The mixture was warmed to
room temperature and stirred for a further 2 h. The solvent
was removed under reduced pressure, and the residue was
purified by flash chromatography, eluting with 10% v/v ethyl
acetate in petrol ether (60-80 °C) to give 760 mg (78%) of a
1
white solid: mp 66-68 °C; H NMR δ 2.27 (s, 3H, CH3), 3.98
(s, 3H, OCH3); 13C NMR δ 15.14 (CH3), 54.69 (OCH3), 120.62
(C-5), 141.10 (C-3), 148.79 (C-6), 149.28 (C-2); IR 1573, 1751
cm-1; m/z 176 (MH+, 29), 175 (M+, 100), 132 (58); HRMS calcd
for C6H6NO335ClNa (MNa+) 197.9929, found 197.9936.
5-Chloro-6-phenyl-3-phenylsulfenyl-2(H)-1,4-oxazin-2-
one 18. Aluminum chloride (0.61 g, 4.5 mmol) was added to a
stirred solution of 3,5-dichloro-6-phenyl-2(H)-1,4-oxazin-2-one
616b (1.0 g, 4.1 mmol) in dichloromethane (50 mL) at room
temperature over 15 min. Thiophenol (0.46 mL, 4.5 mmol) was
added dropwise, and the reaction was allowed to stir overnight.
The reaction mixture was quenched by pouring over ice and
was extracted with chloroform (3 × 100 mL). The combined
chloroform extracts were dried with MgSO4, and solvent was
removed under reduced pressure to afford a brown/orange
solid. Recrystallization from hexane/chloroform mixture af-
forded 628 mg (48%) of the title compound as long yellow
needles: mp 110-112 °C; Rf ) 0.44 (10% ethyl acetate in
petroleum); 1H NMR δ 7.49-7.55 (6H, m, HPh), 7.60 (2H, t,
Experimental Section
3,5-Dichloro-6-methyl-2(H)-1,4-oxazin-2-one 1,16b 3,5-dichloro-
6-phenyl-2(H)-1,4-oxazin-2-one 6,16b 3,5-dichloro-2(H)-1,4-oxa-
zin-2-one 7,16b 3-bromo-5-chloro-6-methyl-2(H)-1,4-oxazin-2-one
8,10d 5-chloro-3,6-dimethyl-2(H)-1,4-oxazin-2-one 9,10h 5-chloro-
6-methyl-3-phenyl-2(H)-1,4-oxazin-2-one 10,10d and 5-chloro-
6-methyl-3-phenylsulfenyl-2(H)-1,4-oxazin-2-one 1710d were
prepared according to literature procedures. An illustrative
selection of experimental procedures for the preparation and
cycloadditions of 2(H)-1,4-oxazin-2-ones is given below. For
other experimental procedures, refer to the Supporting Infor-
mation.
5-Chloro-3,6-diphenyl-2(H)-1,4-oxazin-2-one, 12. Tri-
methyl(phenyl)tin (0.19 mL, 1.10 mmol) and tetrakis(tri-
phenylphosphine)palladium(0) (38 mg, 0.03 mmol) were added
to a stirred solution of 3,5-dichloro-6-phenyl-2(H)-1,4-oxazin-
2-one 616b (240 mg, 1.00 mmol) in dry toluene (20 mL) at room
temperature under an inert atmosphere of argon. After 10 min,
the mixture was brought to reflux. After approximately 48 h,
the solvent was removed under reduced pressure and the
H
Ph), 7.90 (2H, d, J ) 1.43 Hz, HPh); 13C NMR δ 126.51 (C-5),
128.86 and 129.89 (4 × CPhH), 128.90 and 130.55 (4 ×
PhH), 129.41 (CPh-ipso), 130.24 (CPh-ipso), 131.11 (CPhH), 135.40
C
(CPhH), 144.35 (C-3), 152.22 (C-6), 154.73 (C-2); IR 1566, 1764
cm-1; m/z 343 (4, M+), 315 (9), 287 (4); HRMS calcd for
C16H10O2N35ClSNa (M+Na) 338.0016, found 337.2340. Anal.
Calcd for C16H10O2NClS: C, 60.86; H, 3.19; N, 4.44. Found:
C, 60.80; H, 3.11; N, 4.37.
Typical Cycloaddition: Reaction of 5-Chloro-3,6-di-
phenyl-2(H)-1,4-oxazin-2-one and Methyl Acrylate. A
sealed pressure tube was charged with 5-chloro-3,6-phenyl-
2(H)-1,4-oxazin-2-one 12 (176 mg, 0.62 mmol), methyl acrylate
9536 J. Org. Chem., Vol. 70, No. 23, 2005

Diels-Alder Cycloadditions of 2(H)-1,4-Oxazin-2-ones
(2.0 mL, 22 mmol), and a few crystals of 2,6-di-tert-butyl-4-
methylphenol (acting as anti-polymerization agent) and a
small magnetic stirrer bar. The pressure tube was sealed and
immersed in an oil bath maintained at 70 °C. After 2 days,
the tube was cooled to room temperature and the contents were
stripped of volatile materials. Chromatography using 10-15%
v/v diethyl ether in petrol ether afforded methyl 6-chloro-1,4-
diphenyl-3-oxo-2-oxa-5-azabicyclo[2.2.2]oct-5-ene-8endo-carboxy-
late as a beige solid (229 mg, 100%): 1H NMR δ 2.77 (1H, dd,
J ) 9.4, 13.8 Hz, H7-exo), 3.00 (1H, dd, J ) 3.6, 13.8 Hz, H7-endo),
3.32 (3H, s, Me), 3.63 (1H, dd, J ) 3.6, 9.4 Hz, H8-exo), 7.40
(3H, m, HPh), 7.49 (2H, m, HPh), 7.59 (3H, m, HPh), 7.82 (2H,
m, HPh); 13C NMR δ 34.58 (C-7), 44.83 (C-8), 51.50 (C-12), 70.63
(C-4), 84.62 (C-1), 126.65-127.84 (9 × CHPh), 132.60 (CPh),
133.04 (CPh-ipso), 164.56 (C-6), 166.65 (C-3), 168.94 (C-9); IR
1610, 1736, 1767 cm-1; m/z 369 (13, M+), 325 (89), 290 (10);
HRMS calcd for C20H16ClNO4Na (MNa+) 392.0663, found
392.0643. Anal. Calcd for C20H16ClNO4: C, 64.96; H, 4.36; N,
3.79. Found: C, 64.85; H, 4.16; N, 3.63.
Typical Cycloaddition: Reaction of 5-Chloro-3,6-di-
phenyl-2(H)-1,4-oxazin-2-one and Butyl Vinyl Ether. A
sealed pressure tube was charged with 5-chloro-3,6-phenyl-
2(H)-1,4-oxazin-2-one 12 (175 mg, 0.62 mmol), butyl vinyl ether
(2.0 mL, 15.5 mmol), and a few crystals of 2,6-di-tert-butyl-4-
methylphenol (acting as anti-polymerization agent) and a
small magnetic stirrer bar. The pressure tube was sealed and
immersed in an oil bath maintained at 70 °C. After 2 days,
the tube was cooled to room temperature and the contents were
stripped of volatile materials. Chromatography using 10-15%
v/v diethyl ether in petroleum ether afforded 8endo-butoxy-4,6-
dichloro-2-oxa-1-phenyl-5-azabicyclo[2.2.2]oct-5-en-3-one as a
1
beige solid (233 mg, 98%): mp 137-138 °C; H NMR δ 0.71
(3H, t, CH3, J ) 7.3 Hz), 0.83 (2H, m, MeCH2), 1.10 (2H, m,
EtCH2), 2.57 (1H, dd, J ) 2.0, 14.3 Hz, H7-endo), 2.90 (2H, m,
CH2O), 2.93 (1H, dd, J ) 7.7, 14.3 Hz, H7-exo), 4.38 (1H, dd, J
) 2.0, 7.7 Hz, H8-exo), 7.26 (3H, m, HPh), 7.47 (2H, m, HPh),
7.68 (3H, m, HPh), 7.87 (3H, m, HPh); 13C NMR δ 14.25 (CH3),
19.44 (MeCH2), 32.27 (EtCH2), 40.99 (C-7), 72.00 (CH2O), 76.01
(C-4), 78.28 (C-8), 85.11 (C-1), 126.66-129.57 (10 × CPhH),
134.49 and 136.45 (CPh-ipso), 164.52 (C-6), 168.48 (C-3); IR 1678,
1770 cm-1; m/z 383 (53, M+), 355 (47), 320 (73), 105 (97); IR
1678, 1770 cm-1; m/z 383 (53), 355 (47), 320 (73), 105 (97);
HRMS calcd for C22H22ClNO3Na (MNa+) 406.1183, found
406.1144. Anal. Calcd for C22H22ClNO3: C, 68.84; H, 5.78; N,
3.65. Found: C, 69.00; H, 5.70; N, 3.67.
Typical Cycloaddition: Reaction of 5-Chloro-3,6-di-
phenyl-2(H)-1,4-oxazin-2-one and 4-Bromostyrene. A
sealed pressure tube was charged with 5-chloro-3,6-phenyl-
2(H)-1,4-oxazin-2-one 12 (178 mg, 0.63 mmol), 4-bromostyrene
(2.0 mL, 15.3 mmol), and a few crystals of 2,6-di-tert-butyl-4-
methylphenol (acting as anti-polymerization agent) and a
small magnetic stirrer bar. The pressure tube was sealed and
immersed in an oil bath maintained at 70 °C. After 2 days,
the tube was cooled to room temperature, and the contents
were stripped of volatile materials. Chromatography using 15%
v/v diethyl ether in petrol ether afforded 8endo-(4-bromophenyl)-
6-chloro-1-methyl-4-phenyl-2-oxa-5-azabicyclo[2.2.2]oct-5-en-
Acknowledgment. We thank Oxford GlycoSciences
(UK) Ltd. (now part of UCB) for financial support (A.B.).
1
3-one as a white solid (290 mg, 99%): mp 201 °C; H NMR δ
Supporting Information Available: Experimental pro-
cedures and characterization of all previously unreported
compounds. Drawings, crystal data, and coordinates of all
crystal structures. Coordinates of all transition states and
absolute energies of all transition states. Figures showing the
computed transition structures leading to the cycloadducts of
3,5-dichloro-6-methyl-1,4-oxazin-2-one, 1, with MVE and MA
and the cycloadducts of 5-chloro-3-methoxy-6-methyl-1,4-oxa-
zin-2-one, 15, with MVE and MA. This material is available
free of charge via the Internet at http://pubs.acs.org.
2.71 (1H, dd, J ) 4.4, 14.4, Hz H7-endo), 3.17 (1H, dd, J ) 9.8,
14.4 Hz, H7-exo), 3.89 (1H, dd, J ) 4.4, 9.8 Hz, H8-exo), 6.75
(3H, m, HPh), 7.08 (2H, m, HPh), 7.29 (3H, m, HPh), 7.45 (2H,
m, HPh), 7.76 (2H, m, HPh), 7.95 (2H, m, HPh); 13C NMR δ 41.00
(C-7), 47.07 (C-8), 74.21 (C-4), 86.34 (C-1), 121.89 (CPh-ipso),
127.03-132.15 (14 × CPhH and CPhBr), 134.51, 135.01 and
137.48 (CPh-ipso), 165.54 (C-6), 169.03 (C-3); IR 1618, 1770 cm-1
;
m/z 466 (39, MH+), 422 (47), 387 (52), 105 (79); HRMS calcd
for C24H1781Br35ClNO2Na (MNa+) 488.0029, found 488.0013.
Anal. Calcd for C24H17BrClNO2: C, 61.50; H, 3.60; N, 3.00.
Found: C, 61.78; H, 3.29; N, 2.97.
JO051646I
J. Org. Chem, Vol. 70, No. 23, 2005 9537