A molybdenum-catalyzed oxidative system forming oxazines (hetero-Diels-Alder adducts) from primary aromatic amines, hydrogen peroxide, and conjugated dienes

Article abstract of DOI:10.1021/jo9608127

The development of a new molybdenum-catalyzed procedure for the formation of oxazines-hetero-Diels-Alder adducts - from primary aromatic amines, hydrogen peroxide, and conjugated dienes is presented. The method is based on a molybdenum-peroxo complex, which in the presence of hydrogen peroxide as the terminal oxidant selectively catalyzes the oxidation of primary aromatic amines to the corresponding dienophilic nitroso compounds. The molybdenum-peroxo catalyst is under the present reaction conditions not reactive toward conjugated dienes and substituents attached to the aromatic nuclei of the primary aromatic amines. Several oxazines are synthezised following this new procedure using primary aromatic amines having either electron-withdrawing or electron-donating substituents and 1,3-cyclohexadiene as the standard diene. The scope of the new procedure is also demonstrated by the preparation of several oxazines using different alkyland phenyl-substituted conjugated dienes and 4-chloroaniline as precursor for the dienophile. Moderate diastereomeric excesses are found when the reaction is carried out with 1-(2-aminophenyl)-ethanol and 1,3-cyclohexadiene or (E)-1-phenyl-1,3-butadiene. The stereochemical and electronic factors governing the reaction course are briefly discussed.

Full text of DOI:10.1021/jo9608127

5770
J . Org. Chem. 1996, 61, 5770-5778
A Molybd en u m -Ca ta lyzed Oxid a tive System F or m in g Oxa zin es
(Heter o-Diels-Ald er Ad d u cts) fr om P r im a r y Ar om a tic Am in es,
Hyd r ogen P er oxid e, a n d Con ju ga ted Dien es
Eval Rud Møller and Karl Anker J ørgensen*
Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
Received May 3, 1996X
The development of a new molybdenum-catalyzed procedure for the formation of oxazinesshetero-
Diels-Alder adductssfrom primary aromatic amines, hydrogen peroxide, and conjugated dienes
is presented. The method is based on a molybdenum-peroxo complex, which in the presence of
hydrogen peroxide as the terminal oxidant selectively catalyzes the oxidation of primary aromatic
amines to the corresponding dienophilic nitroso compounds. The molybdenum-peroxo catalyst is
under the present reaction conditions not reactive toward conjugated dienes and substituents
attached to the aromatic nuclei of the primary aromatic amines. Several oxazines are synthezised
following this new procedure using primary aromatic amines having either electron-withdrawing
or electron-donating substituents and 1,3-cyclohexadiene as the standard diene. The scope of the
new procedure is also demonstrated by the preparation of several oxazines using different alkyl-
and phenyl-substituted conjugated dienes and 4-chloroaniline as precursor for the dienophile.
Moderate diastereomeric excesses are found when the reaction is carried out with 1-(2-aminophenyl)-
ethanol and 1,3-cyclohexadiene or (E)-1-phenyl-1,3-butadiene. The stereochemical and electronic
factors governing the reaction course are briefly discussed.
In tr od u ction
The catalytic properties of the molybdenum(VI) com-
plexes are closely associated with the ability of the metal
to react with peroxides to form molybdenum-peroxo
compounds 1 or molybdenum-peroxide complexes. The
reaction between a molybdenum(VI) complex and H2O2
gives 1, while the use of other organic peroxides may lead
to 1 as well as molybdenum-peroxide complexes depend-
ing on the peroxide.8,9
Control of chemical reactions by use of catalysts is an
area with increasing importance. One of the challenges
in this field is to apply metal complexes in an attempt to
control the chemo-, regio-, and stereoselectivity, and in
recent years numerous improvements have been achieved.
In the field of catalytic oxidations mediated by transi-
tion-metal complexes, several new organic reactions have
been developed.1 Among the early transition-metal
complexes, molybdenum(VI) complexes occupy a central
position because they are able to catalyze a variety of
oxidation reactions such as aromatic carbon-hydrogen
bonds to the corresponding alcohols,2-6 alkenes to
epoxides,7-10 alcohols to carbonyl compounds,11,12 sulfides
to sulfoxides,13,14 sulfoxides to sulfones,15 and amines to
a variety of oxidized products.16-21
The activity of molybdenum-peroxo complexes is in
part controlled by the co-ligands, and it has been found
that even “minor” modifications of the ligand occupancy
can change the properties of the complex dramati-
cally.11,22,23
The control of the reaction course is one of the major
problems and challenges in the transition-metal-cata-
lyzed oxidation of organic nitrogen compounds. We have
recently developed a molybdenum-catalyzed method which
selectively oxidizes primary aromatic amines to the
corresponding nitroso compounds.24 Many of the prob-
lems associated with the classical methods for prepara-
tion of nitroso compounds by oxidation of primary aro-
matic amines, such as overoxidation and formation of
X Abstract published in Advance ACS Abstracts, August 1, 1996.
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Organic Compounds; Academic Press: New York, 1981.
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1992, 125, 2439-2442.
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1143.
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1983, 19, 331-343.
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Catal. 1993, 83, 311-322.
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Chem. Soc., Perkin Trans. 2 1989, 417-423.
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S. J . Org. Chem. 1990, 55, 1736-1744.
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P. J . Mol. Catal. 1981, 11, 107-118.
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37-50.
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11814-11822.
S0022-3263(96)00812-2 CCC: $12.00 © 1996 American Chemical Society

Mo-Catalyzed Oxidative System Forming Oxazines
J . Org. Chem., Vol. 61, No. 17, 1996 5771
coupling byproducts, are suppressed by the molybdenum-
catalyzed procedure.24 The oxidation of primary aromatic
amines 2 to the corresponding nitroso compounds 3 can
either be performed as a catalytic reaction using oxo-
peroxo(2,6-pyridinedicarboxylato-O,N,O′)(hexamethylphos-
phortriamide)molybdenum(VI) (4) as the catalyst and
H2O2 as the terminal oxidant (eq 1) or as a stoichiometric
reaction which utilizes the molybdenaoxaziridine 5.24 The
latter procedure is based on the reaction of 2 with 4
giving 5, which upon treatment with H2O2 gives the
desired aromatic nitroso compound 3 and regenerates the
molybdenum-peroxo complex 4.
The pivotal element of the new method presented in
eq 2 is the catalytic properties of 4, which in the presence
of H2O2 transforms primary aromatic amines to the
corresponding nitroso compounds (eq 1). The success of
this method derives from the chemoselectivity of the
oxidation reaction, leaving the conjugated dienes and
substituents bound to the aromatic nuclei of the primary
aromatic amines unaffected.
The development and results of the catalytic reaction
outlined in eq 2 will be presented in the following.
Furthermore, the scope of the reaction by the reaction of
different primary aromatic amines, including compounds
having chiral substituents, with various dienes will be
presented.
Resu lts a n d Discu ssion
The formation of the HDA adducts, 3-aryl-2-oxa-3-
azabicyclo[2.2.2]oct-5-enes 7a -l, has been examined us-
ing a series of aromatic amines (2a -l), H2O2, and 1,3-
cyclohexadiene (6a ) in the presence of a catalytic amount
of the molybdenum-peroxo complex 4, eq 3. Several of
the HDA adducts are, according to the best of our
knowledge, described here for the first time. The results
for these reactions are presented in Table 1 (for further
details, see Experimental Section).
Nitroso compounds are synthetic useful reagents in
organic chemistry.25-33 One of the most useful reactions
of nitroso compounds is the cycloaddition reaction with
conjugated dienes which form oxazines, hetero-Diels-
Alder (HDA) adducts. These HDA adducts can be
transformed by different procedures to a variety of
products,25,29 such as mitomycin and other compounds
with pharmaceutical interest.34-36
One of the major general problems associated with the
formation of oxazines from HDA reactions is the synthe-
sis of the nitroso functionality. This work presents a new
approach for the preparation of oxazines 7 from primary
aromatic amines 2, H2O2, and conjugated dienes 6 in the
presence of the molybdenum-peroxo catalyst 4, eq 2. The
new procedure for oxazine formation has several advan-
tages as compared with the classical methods since the
isolation, purification, and handling of mutagene37 nitroso
compounds are avoided. Moreover, a wide range of
substituted primary aromatic amines are commercially
available, allowing the synthesis of several oxazines
which previously have only been prepared with great
difficulty or not at all.27
It appears from the results in Table 1 that the reaction
outlined in eq 3 in most cases leads to a smooth formation
of the HDA adducts, 3-aryl-2-oxa-3-azabicyclo[2.2.2]oct-
5-enes 7a -i,k ,l. The selectivity of the molybdenum-
peroxo catalyst 4 is notable, leaving oxidizable substit-
uents attached to the aromatic nuclei of the primary
aromatic amines untouched. Furthermore, 1,3-cyclo-
hexadiene (6a ) and other conjugated dienes (vide infra)
are neither oxidized to the corresponding epoxide or other
oxidized products nor polymerized when treated with 4
and H2O2. In relation to the latter, it should be noted
that polymerization of conjugated dienes in the presence
of transition-metal catalysts and peroxides has been
observed.38 Both primary aromatic amines having elec-
tron-donating substituents 2b,c,k ,l (Table 1, entries 2,
(25) Boger, D. L.; Weinreb, S. M. In Hetero Diels-Alder Methodology
in Organic Synthesis; Wasserman, H. H., Ed.; Academic Press, Inc.:
San Diego, 1987; Vol. 47, pp 71-93.
(26) Boyer, J . H. In The Chemistry of the Nitro and Nitroso Groups;
Patai, S., Ed.; Wiley Interscience: New York, 1969; pp 215-299.
(27) Hamer, J .; Ahmad, M. In 1,4-Cycloaddition Reactions; Hamer,
J ., Ed.; Academic Press: New York, 1967; Vol. 8; pp 419-452.
(28) Kirby, G. W. Chem. Soc. Rev. 1977, 6, 1-24.
(29) Kresze, G.; Firl, J . Fortschr. Chem. Forsch. 1969, 11, 245-284.
(30) Streith, J .; Defoin, A. Synthesis 1994, 1107-1117.
(31) Waldmann, H. Synthesis 1994, 535-551.
(32) Weinreb, S. M.; Staib, R. R. Tetrahedron 1982, 38, 3087-3128.
(33) Zuman, P.; Shah, B. Chem. Rev. 1994, 94, 1621-1641.
(34) Benbow, J . W.; McClure, K. F.; Danishefsky, S. J . J . Am. Chem.
Soc. 1993, 115, 12305-12314.
(35) McClure, K. F.; Danishefsky, S. J . J . Am. Chem. Soc. 1993, 115,
6094-6100.
(36) McClure, K. F.; Benbow, J . W.; Danishefsky, S. J . J . Am. Chem.
Soc. 1991, 113, 8185-8186.
(37) Gupta, R. L.; Singh, M.; J uneja, T. R. Indian J . Exp. Biol. 1987,
25, 445-449.
(38) Sheng, M. N.; Zajacek, J . G. J . Org. Chem. 1970, 35, 1839-
1843.

5772 J . Org. Chem., Vol. 61, No. 17, 1996
Møller and J ørgensen
Ta ble 1. Resu lts for th e F or m a tion of th e HDA Ad d u cts,
3-Ar yl-2-oxa -3-a za bicyclo[2.2.2]oct-5-en e 7a -l, fr om
P r im a r y Ar om a tic Am in es 2a -l, 1,3-Cycloh exa d ien e (6a )
in th e P r esen ce of th e Molybd en u m -P er oxo Ca ta lyst 4,
a n d H2O2 a s Oxid a n t
in Table 1 show that the two effects in most cases are
appropriately balanced, because reasonable good yields
of the HDA adducts, 3-aryl-2-oxa-3-azabicyclo[2.2.2]oct-
5-enes 7a -i,j,k are found using 4-substituted primary
aromatic amines having either electron-donating or
electron-withdrawing substituents. An example of a
reaction where the overall reaction rate exclusively is
determined by the first step is given in Table 1, entry
10, where the formation of 1-nitro-4-nitrosobenzene (3j)
is very slow, giving a low yield of the HDA adduct 7j. It
is noteworthy that no attempts were made to optimize
the reaction conditions.
The synthetic aspects of the new method outlined in
eq 2 are clearly demonstrated by the results presented
in Table 1, as according to the best of our knowledge,
the only previous reported HDA adducts are 7a 47-51 and
7d .52 Further investigation of the the synthetic aspects
were undertaken using different conjugated dienes 6b-
h , 4-chloroaniline (2d ) as a standard primary aromatic
amine, H2O2, and the molybdenum-peroxo catalyst 4.
This standard amine was choosen because it gave high
yield in the catalyzed reaction with 1,3-cyclohexadiene
(Table 1) and because the isolated yield (69%) of 7d was
comparable to the yield of 7d in the crude material
determined by NMR spectroscopy (77%). Both cyclic
dienes (6b,c) and the noncyclic alkyl- (6d -f) and phenyl-
substituted dienes (6g,h ) were examined.
entry
Ar-NH2
HDA adduct
yield (%)a
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
7a
7b
7c
7d
7e
7f
7g
7h
7i
55
60
81
77
43
60
45
66
41
7
10
11
12
2j
2k
2l
7j
7k
7l
40
52
a
Yields are based on 1H NMR spectroscopy (see text).
3, 11, and 12) and those having electron-withdrawing
substituents 2d -i (entries 4-9) can be used to prepare
the HDA adducts. The yield of the HDA adduct is
generally good, with the exception of 7j where 4-nitro-
aniline (2j) is the dienophile precursor (entry 10). This
can be ascribed to a slow oxidation of 2j (vide infra). All,
but one (7b), of the HDA adducts in Table 1 were purified
by TLC. In most cases the isolated yield of the product
was 10-20% lower than the yield determined by NMR
spectroscopy of the crude product. The decrease in yield
of the HDA adduct by workup is probably due a chro-
matographic, photoinduced, or thermal transformation
which previously has been observed for analogues HDA
adducts.39-44
The formation of the HDA adduct is most likely to be
a two-step process: (i) the initial step being the oxidation
of the primary aromatic amine to the corresponding
nitroso compound followed by (ii) a cycloaddition reaction
of the aromatic nitroso dienophile with the diene. The
last step can take place either with or without interaction
of the molybdenum complex. Control experiments have
shown45 that the molybdenaoxaziridine complex 5 is not
reactive toward 1,3-cyclohexadiene (6a ) under the stan-
dard reaction conditions; thus 5 may be excluded as an
intermediate in the HDA cycloaddition reaction. The
kinetics of steps i and ii have different electronic de-
mands. A kinetics investigation of the reaction between
different 4-substituted primary aromatic amines and the
molybdenum-peroxo complex 4 producing the molybde-
naoxaziridines 5 gave a Hammett F value of -2.3,
showing that 4-substituted primary aromatic amines
having electron-donating substituents are the most reac-
tive.24 However, step ii proceeds faster for aromatic
nitroso compound having electron-withdrawing substit-
uents as compared to those with electron-donating sub-
stituents.46 Thus, two counteracting electronic effects
determine the overall reaction rate of this new method
for the formation of HDA adducts. The results presented
The use of cyclopentadiene (6b) produced 3-(4-chlo-
rophenyl)-2-oxa-3-azabicyclo[2.2.1]hept-5-ene (7m ) in
38% yield on the basis of NMR spectroscopy of the
crude material. Unfortunately, 7m could not be isolated
by chromatographic methods due to the retro-HDA
reaction.39,53,54 In relation to this it should be noted
that the equilibrium constant for the cycloaddition reac-
tion of 6b with nitrosobenzene (3a ) leading to the
corresponding HDA adduct is 13.23 M-1 53
The reacion
.
which used (Z,Z)-1,3-cyclooctadiene (6c) as diene was
found to proceed very slowly, and the HDA adduct could
not be detected. A very slow rate of HDA adduct
formation from 6c and 3d has also been described by
others.55
(47) Becker, Y.; Eisenstadt, A.; Shvo, Y. Tetrahedron Lett. 1972,
3183-3186.
(48) Becker, Y.; Eisenstadt, A.; Shvo, Y. Tetrahedron 1978, 34, 799-
806.
(39) Kresze, G.; Schulz, G. Tetrahedron 1961, 12, 7-12.
(40) Firl, J .; Kresze, G. Chem. Ber. 1966, 99, 3695-3706.
(41) Firl, J . Chem. Ber. 1968, 101, 218-225.
(42) Kresze, G.; Firl, J . Tetrahedron 1968, 24, 1043-1050.
(43) Scheiner, P.; Chapman, O. L.; Lassila, J . D. J . Org. Chem. 1969,
34, 813-816.
(49) J ohannsen, M.; J ørgensen, K. A. J . Org. Chem. 1995, 60, 5979-
5982.
(50) Maquestiau, A.; von Haverbeke, Y.; Flammang, R.; de Meyer,
C. Bull. Soc. Chim. Fr. 1974, 83, 139-146.
(51) McDonald, R. N.; Reineke, C. E. J . Org. Chem. 1967, 32, 1878-
1887.
(44) Rousselle, D.; Francotte, E.; Feneau-Dupont, J .; Tinant, B.;
Declercq, J . P.; Viehe, H. G. Tetrahedron 1991, 47, 8323-8330.
(45) Unpublished results.
(52) Kresze, G. Liebigs Ann. Chem. 1970, 738, 113-124.
(53) Ahmad, M.; Hamer, J . J . Org. Chem. 1966, 31, 2831-2833.
(54) Kresze, G.; Schultz, G.; Walz, H. Liebigs Ann. Chem. 1963, 666,
45-53.
(46) Kresze, G.; Firl, J .; Zimmer, H.; Wollnik, U. Tetrahedron 1964,
20, 1605-1611.
(55) Kresze, G.; Bathelt Tetrahedron 1973, 29, 2219-2228.

Mo-Catalyzed Oxidative System Forming Oxazines
J . Org. Chem., Vol. 61, No. 17, 1996 5773
previously been described that the cycloaddition reaction
of 1-chloro-4-nitrosobenzene (3d ) with 1-phenyl-1,3-buta-
diene (6g) only produced one regioisomer (7q)47,58,59 and
that the cycloaddition reaction of 3d with 1,3-pentadiene
(6i) gave a 58:42 ratio of 2-(4-chlorophenyl)-3-methyl-3,6-
dihydro-2H-[1,2]oxazine and 2-(4-chlorophenyl)-6-methyl-
3,6-dihydro-2H-[1,2]oxazine.58 Our finding of a 56:26
ratio of 7p -1 and 7p -2 shows that the directing effect of
the ethyl substituent in 6f is stronger than the methyl
substituent in 6i. A ratio of 79:11 of 7o-1 and 7o-2 shows
in a similar manner that the directing effect of the three
methyl substituents in 6e is notably stronger than the
directing effect of the single methyl substituent in 6i. The
increased regioselectivety in the latter example can be
accounted for by the pericyclic selection rules65 assuming
that the directing effects of the three methyl substituents
are additive.
In an attempt to perform diastereoselective reactions,
1-(2-aminophenyl)ethanol (2m ) was prepared, both as a
racemic mixture and as enantiomeric enriched com-
pounds (R)-2m and (S)-2m (the experimental details are
given in Experimental Section). The diastereoselectivi-
ties of the reaction of 2m and either 1,3-cyclohexadiene
(6a ) (eq 4) or (E)-1-phenyl-1,3-butadiene (6g) using the
oxidative conditions have been examined. In the reaction
with 6a two isomers of 1-[2-(2-oxa-3-azabicyclo[2.2.2]oct-
5-en-3-yl)phenyl]ethanol (7s) were formed in a 4:3 ratio.
The two HDA adducts could be isolated by chromatog-
raphy. Under similar reaction conditions, the reaction
of 2m and 6g gives two isomers of 1-[2-(6-phenyl-3,6-
dihydro[1,2]oxazin-2-yl)phenyl]ethanol (7t) in a 5:3 ratio.
These HDA adducts were separated by preperative
HPLC.
The reaction of the noncyclic dienes 6d -h and 4-chlo-
roaniline (2d ) under the present oxidative conditions
produces substituted 2-(4-chlorophenyl)-3,6-dihydro-2H-
[1,2]oxazines 7n -r in fair to good yields. Of these
adducts only 7n 56 and 7q42,46,57 have been described
previously. The reaction with 2,3-dimethyl-1,3-butadiene
(6d ) gave a 95% yield of 2-(4-chlorophenyl)-4,5-dimethyl-
2H-[1,2]oxazine (7n ) on the basis of NMR spectroscopy,
while the isolated yield of 7n was only 51%. It should
be noted that no attempts were made to optimize this or
the following reactions nor the isolation procedures. The
two new compounds 2-(4-chlorophenyl)-4,6,6-trimethyl-
3,6-2H-[1,2]oxazine (7o-1) and 2-(4-chlorophenyl)-3,3,5-
trimethyl-3,6-2H-[1,2]oxazine (7o-2) were formed in 49%
total yield in a ratio of 79:11 (NMR) from reaction with
2,4-dimethyl-1,3-pentadiene (6e). In the case of 1,3-
hexadiene (6f), two new adducts, 2-(4-chlorophenyl)-3-
ethyl-3,6-dihydro-2H-[1,2]oxazine (7p -1) and 2-(4-chlo-
rophenyl)-6-ethyl-3,6-dihydro-2H-[1,2]oxazine (7p-2), were
formed in 56% and 26% yields, respectively. Unsuccess-
ful attempts were made to separate 7p -1 and 7p -2 by
chromatography. However, NMR spectroscopy allowed
a satisfactory characterization of the products. The
phenyl-substituted noncyclic conjugated dienes (E)-1-
phenyl-1,3-butadiene (6g) and (E,E)-1,4-diphenyl-1,3-
butadiene (6h ) reacted smoothly under the standard
oxidation conditions. The reaction with 6g gave exclu-
sively 2-(4-chlorophenyl)-6-phenyl-3,6-2H-[1,2]oxazine (7q)
in 78% yield, and the analogous use of 6h afforded the
HDA adduct 2-(4-chlorophenyl)-3,6-diphenyl-3,6-2H-[1,2]-
oxazine (7r ) in 72% isolated yield.
Eight stereoisomers of both 1-[2-(2-oxa-3-azabicyclo-
[2.2.2]oct-5-en-3-yl)phenyl]ethanol (7s) and 1-[2-(6-phen-
yl-3,6-dihydro[1,2]oxazin-2-yl)phenyl]ethanol (7t) can be
produced in the two reactions if the nitrogen atoms are
regarded as chiral centers and if isomers arising from
restricted rotation around the nitrogen-aryl bond and
different ring conformations are excluded. With regard
to the inversion of the nitrogen atom in the present
systems, it should be noted that the inversion barrier of
the nitrogen atom of 3-methyl-2-oxa-3-azabicyclo[2.2.2]-
octane, an N-methyl-substituted saturated analogue of
7s, has been determined to be 14.9 kcal/mol and the
coalescence temperatures, Tc, were equal to 22 and 55
°C.66 Moreover, the inversion barriers of two N-alkyl-
substituted analogues of 7t have been found to be in the
order of 11 kcal/mol with a Tc ≈ 0 °C.67 Unfortunately
we have not been able to find thermodynamic data for
The regioselectivity of the cycloaddition reaction of
aromatic nitroso compounds to asymmetrically substi-
tuted dienes has gained much attention.42,58-64 It has
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(57) Kresze, G.; Firl, J . Tetrahedron 1963, 19, 1329-1334.
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Chem. Commun. 1995, 571-572.
(61) Kresze, G.; Korpiun, O. Tetrahedron 1966, 22, 2493-2504.
(62) Ha¨ussinger, P.; Kresze, G. Tetrahedron 1978, 34, 689-696.
(63) Kresze, G.; Mavromatis, A. Tetrahedron 1978, 34, 697-701.
(64) Kresze, G.; Dittel, W.; Melzer, H. Liebigs Ann. Chem. 1981,
224-232.
(65) Lowry, T. H.; Richardson, K. S. In Mechanism and Theory in
Organic Chemistry, 3 ed.; Berger, L. S., MacElree, E., Eds.; Harper &
Row: New York, 1987; pp 903-976.
(66) Riddell, F. G.; Turner, E. S.; Boyd, A. Tetrahedron 1979, 35,
259-261.
(67) J ones, R. A. Y.; Katritzky, A. R.; Saba, S. J . Chem. Soc., Perkin
Trans. 2 1974, 1737-1741.

5774 J . Org. Chem., Vol. 61, No. 17, 1996
Møller and J ørgensen
Ta ble 2. Selected NMR Da ta for
3-(4-Ch lor op h en yl)-2-oxa -3-a za bicyclo[2.2.2]oct-5-en e (7d )
a n d th e Ma jor a n d Min or F r a ction s of
1-[2-(2-Oxa -3-a za bicyclo[2.2.2]oct-5-en -3-yl)p h en yl]eth a n ol,
7s-1 a n d 7s-2, Resp ectively
7d
7s-1
4.19
6.24
6.77
3.80
7s-2
4.00
6.17
6.79
4.61
H4′′
H5′′
H6′′
OH
CH3
C4′′
C5′′
C6′′
4.38
6.13
6.58
25.1
21.8
56.4
129.6
131.4
57.1
129.4
133.1
56.4
128.9
133.2
N-aryloxazine compounds. The NMR spectra of both
isomers of 7s show no unexpected line broadening of the
signals at ambient temperature, which indicate either a
single preferred conformation with no nitrogen inversion
at room temperature or a fast inversion of the nitrogen
center.
F igu r e 1. Optimized structures of (1S,1′′R,4′′S)-1-[2-(2-oxa-
3azabicyclo[2.2.2]oct-5-en-3-yl)phenyl]ethanol ((SRS)-7s) (left)
and (1R,1′′R,4′′S)-1-[2-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-
phenyl]ethanol ((RRS)-7s) (right).
The conformations of the two isomeric pairs of 1-[2-
(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)phenyl]ethanol 7s
have been determined from an NMR analysis in combi-
nation with semiemperical theoretical calculations (AM168
and PM369). A comparison of the chemical shift values
of the two isomers of 7s-1 and 7s-2, the major and minor
isomer, respectively, with those of 3-(4-chlorophenyl)-2-
oxa-3-azabicyclo[2.2.2]oct-5-ene (7d ), presented in Table
2 show only minor, but still significant differences.
Therefore it must be expected that the spacial arrange-
ment of the aryl and the bicyclic fragment are very
similar in the three adducts, 7d , 7s-1, and 7s-2.
It has previously been found that dihydroxylation of
7d afforded only a single product. This result can be
explained by an endo conformation of 7d , whereby the
and 7s-2, respectively, proved to be rather similar. A
positive NOE of the integral of the H4′′ signal was found
upon irradiation of the methin proton in both 7s-1 and
7s-2. The NOEDIF results show that both isomers have
an anti conformation of the N-O bond relative to the
ethanol group on the benzene ring, which excludes the
possibility that the two adducts are two stable rotamers
of a single adduct.
Geometrical optimization of the two isomers,
(1S,1′′R,4′′S)-1-[2-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-
phenyl]ethanol ((SRS)-7s) and (1R,1′′R4′′S)-1-[2-(2-oxa-
3-azabicyclo[2.2.2]oct-5-en-3-yl)phenyl]ethanol ((RRS)-7s)
using either AM168 or PM369 gave the two conformers
shown in Figure 1 as the most stable. It appears from
Figure 1 that the two calculated endo conformations of
(SRS)-7s and (RRS)-7s are very similar, the major
difference being the configuration of the C1-carbon atom.
The calculated syn orientation of the methine proton
relative to the other 2′-substituent in both cases is in good
agreement with other experimental results found for
analogous compounds.76,77 Similar theoretical calcula-
tions of the endo conformation of 3-(4-chlorophenyl)-2-
oxa-3-azabicyclo[2.2.2]oct-5-ene (7d ) show that the N-O
bond is located in the plane of the aromatic ring in the
most stable conformation. Steric repulsion between the
H4′′ bridgehead hydrogen atom and the ethanol fragment
in both (SRS)-7s and (RRS)-7s forces the N-O bond out
of the plane of the aromatic ring, which is reflected in
the low-field shifts of the alkene nuclei in the 6′′ position
of (SRS)-7s and (RRS)-7s relative to 7d , as seen from
Table 2.
The different configurations of the C1-carbon atoms in
(1S,1′′R,4′′S)-1-[2-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-
phenyl]ethanol ((SRS)-7s) and (1R,1′′R,4′′S)-1-[2-(2-oxa-
3-azabicyclo[2.2.2]oct-5-en-3-yl)phenyl]ethanol ((RRS)-7s)
outlined in Figure 1 affect the 13C chemical shift values
of the methyl carbon atoms and may be used to determine
the conformation of the two isolated isomers of 7s. The
methyl substituent and the bicyclic fragment in (SRS)-
7s are located at opposite sides of the aromatic ring, and
the methyl 13C chemical shift value is found in the range
of other 2′-substituted 1-phenyl-1-ethanols (CF3 25.4
ppm, H 25.1 ppm, CH3 24.6 ppm, Br 23.5 ppm, OCH3
appropriate side of the double bond is shielded.52
A
search in the Cambridge Structural Database gave six
structures containing a 2-oxa-3-azabicyclo[2.2.2]oct-5-en-
3-yl unit,70 but unfortunately none of these structures
has an aryl substituent attached to the 3-aza position.
Five of the six structures have an endo orientation of the
3-aza substituent relative to the double bond.71-74 The
last structure showed a planar geometry at the 3-aza
position75 and must be regarded as a special case.
Semiempirical AM168 structural optimizations of the exo
conformations of 7s position the H3′ proton very close
(≈2.2 Å) to the H7′′exo proton which easily should be
confirmed by NOE experiments, but the NOE experi-
ments could not verify an exo conformation (for assign-
ments/numbering of the atoms see Experimental Sec-
tion). On the basis of the NMR spectroscopic data and
the structural data available, it is most likely that both
7s-1 and 7s-2 are endo isomers.
The NOEDIF spectra of the two isomeric pairs of 1-[2-
(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)phenyl]ethanol 7s-1
(68) Dewar, M. J . S.; Zoebisch, E. G.; Healey, E. F.; Stewart, J . J .
P. J . Am. Chem. Soc. 1985, 107, 3902-3909.
(69) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 221-264.
(70) Allen, F. H.; Kennard, O.; Taylor, R. Acc. Chem. Res. 1983, 16,
146-153.
(71) Boger, D. L.; Patel, M. J . Org. Chem. 1984, 49, 4098-4099.
(72) Baldwin, J . E.; Bailey, P. D.; Gallacher, G.; Otsuka, M.;
Singleton, K. A.; Wallace, P. M.; Prout, K.; Wolf, W. M. Tetrahedron
1984, 40, 3695-3708.
(73) Braun, H.; Felber, H.; Kresze, G.; Schmidtchen, F. P.; Prewo,
R.; Vasella, A. Liebigs Ann. Chem. 1993, 261-268.
(74) Tronchet, J . M. J .; J ean, E.; Barbalat-Rey, F.; Bernardinelli,
G. J . Chem. Res. Synop. 1992, 228-229.
(75) Tinant, B.; Declercq, J .-P. Acta Crystallogr., Sect. C: Cryst.
Struct. Commun. 1991, C47, 1266-1269.
(76) Anderson, J . E.; Pearson, H. J . Chem. Soc., Perkin Trans. 2
1974, 1779-1783.
(77) Pearson, H. J . Chem. Soc., Chem. Commun. 1975, 912-912.

Mo-Catalyzed Oxidative System Forming Oxazines
J . Org. Chem., Vol. 61, No. 17, 1996 5775
23.0 ppm).78,79 The methyl substituent and the bicyclic
fragment in (RRS)-7s are located on the same side of the
aromatic ring, with a distance between the C1 and C4′′
nulcei calculated to be ≈3.7 Å. A consequence of this
steric arrangement in (RRS)-7s is a 3.3 ppm high-field
shift of the methyl 13C chemical shift value (Table 2).
Similar high-field shifts are well-known for substituted
cyclohexanes, where methyl substitution in the axial
γ-position places two carbon atoms ≈3.0 Å apart and
causes a 6.4 ppm high-field shift, also known as the
γ-effect.80 Similar arguments can be used to explain the
different chemical shift values of the alcohol proton
(Table 2).
We have also, on the basis of the observed differences
in the NMR spectra, examined other conformations of
1-[2-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)phenyl]etha-
nol (7s-1) and 1-[2-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-
yl)phenyl]ethanol (7s-2) than those presented in Figure
1, but they have all been discharged. It could, for
example, be argued that the low-field locations of the
alcohol protons, 3.8 ppm and 4.6 ppm in 7s-1 and 7s-2,
respectively, relative to other 2′-substituted 1-phenyl-1-
ethanols (H 2.45 ppm, Br 2.45 ppm, CF3 2.50 ppm, OCH3
2.8 ppm)78 indicate conformations involving hydrogen
bonds, but then one of the isomers should have an exo
conformation which we previously have excluded. It was
also checked if the aromatic ring current could induce
the observed differences in the NMR spectra. But a
maximum difference of 0.27 ppm on the O-H protons
was found using the approximative formula (eq 5)80 for
the influence of the aromatic ring current, which does
not offer a satisfactory explanation of the observed
difference.
From comparison of the NMR spectroscopic data of 8
with those of other 2-substituted nitrosobenzenes81 it is
evident, that the NdO double bond is oriented anti to
the ethanol group. It is most likely (vide supra) that the
methine proton is located in the aromatic plane syn to
the nitroso substituent. Assuming that the cycloaddition
reaction between 8 and 1,3-cyclohexadiene (6a ) leads
directly to the two isolated adducts, it can be concluded
that the cycloaddition reaction to the nitroso face shielded
by the alcohol group and leading to (1S,1′′R,4′′S)- and
(1R,1′′S,4′′R)-1-[2-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-
phenyl]ethanol (7s-1) is less hindered than the methyl-
shielded face of the nitroso functionality which leads to
(1S,1′′S,4′′R)- and (1R,1′′R,4′′S)-1-[2-(2-oxa-3-azabicyclo-
[2.2.2]oct-5-en-3-yl)phenyl]ethanol (7s-2).
Con clu sion
A new molybdenum-catalyzed procedure for the forma-
tion of oxazines-hetero-Diels-Alder adductssfrom pri-
mary aromatic amines, H2O2, and conjugated dienes has
been developed. The catalystsa molybdenum-peroxo
complexsis chemoselective and catalyzes the oxidation
of the primary aromatic amine to the corresponding
dienophilic nitroso compound, leaving the conjugated
diene and substituents attached to the aromatic nuclei
of the primary aromatic amine untouched. A variety of
different oxazines are synthezised in reasonable yield by
this procedure using primary aromatic amines having
either electron-withdrawing or electron-donating sub-
stituents and various dienes. Moderate diastereomeric
excesses are found when the reaction is carried out with
1-(2-aminophenyl)ethanol and 1,3-cyclohexadiene or (E)-
1-phenyl-1,3-butadiene. The mechanism for the molyb-
denum-catalyzed procedure for the formation of oxazines
is probably first the oxidation of the primary aromatic
amine to the corresponding nitroso compound followed
by an off-metal cycloaddition reaction of the aromatic
nitroso dienophile with the diene.
µ(1 - cos2 θ)
∆δ (ppm) )
(5)
r3
On the basis of the arguments presented above, it can
be concluded that the major product in the reaction of
1,3-cyclohexadiene (6a ) and 1-(2-aminophenyl)ethanol
(2m ) under the oxidative conditions is a racemic mixture
of (1S,1′′R,4′′S)- and (1R,1′′S,4′′R)-1-[2-(2-oxa-3-azabicyclo-
[2.2.2]oct-5-en-3-yl)phenyl]ethanol (7s-1) and that the
minor product is a racemic mixture of (1S,1′′S,4′′R)- and
(1R,1′′R,4′′S)-1-[2-(2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)-
phenyl]ethanol (7s-2).
The two conformers of 1-[2-(6-phenyl-3,6-dihydro[1,2]-
oxazine-2-yl)phenyl]ethanol (7t) did not exhibit a similar
difference between the methyl substituents, and no
attempts were made to assign the absolute conformation
of these two products.
The use of enatiomeric enriched (S)-2m (90% ee) in eq
4 gives the same diastereoselectivity as observed for the
reaction with racemic 2m .
Exp er im en ta l Section
Ap p a r a tu s. NMR spectra were recorded on a Varian
Gemini 300 in CDCl3. SiMe4 was used as the internal
standard in 1H spectra, and CDCl3 (77.0 ppm) was used as
reference in 13C spectra. Enatiomeric excesses were deter-
mined using a l ) 30 m, i.d. ) 0.25 mm Chirasil-DEX CB
column from Chrompack or with a l ) 250 mm, i.d. ) 4.6 mm
Chiralcel OD HPLC column from Diacel.
Ch em ica ls. The primary aromatic amines 2a -l and the
conjugated dienes 6a ,c-f,h , (-)-DIP-Cl ) [(-)-B-chlorodiiso-
pinocampheylborane], 2′-nitroacetophenone, and 2′-aminoac-
etophenone are commercially available and were used without
further purification. Cyclopentadiene (6b) was prepared from
cracking of the dimer82 and (E)-1-phenyl-1,3-butadiene (6g)
was prepared according to the literature.83 The catalyst
oxoperoxo(2,6-pyridinedicarboxylato-O,N,O)(hexamethylphos-
In order to obtain further information about the
present reaction, the dienophile 1-(2′-nitrosophenyl)-
ethanol (8) was prepared from catalytic oxidation of
2m and then reacted with (E)-1-phenyl-1,3-butadiene
(6g). The results showed that the diastereomeric
excess in this reaction was similar to the one found
above.
(78) The Aldrich Library of 13C and 1H FT NMR Spectra, 1st ed.;
Aldrich Chemical Company Inc.: 1993; Vol. 2.
(79) Marshall, J . L.; Faehl, L. G.; Kattner, R.; Hansen, P. E. Org.
Magn. Reson. 1979, 12, 169-173.
(80) Abraham, R. J .; Loftus, P. Proton and Carbon-13 NMR Spec-
troscopy; Heyden: London, 1978.
(81) Gowenlock, B. G.; Cameron, M.; Boyd, A. S. F.; Altahou, B. M.;
Mckenna, P. Can. J . Chem. 1994, 72, 514-518.
(82) Korach, M.; Nielsen, D. R.; Rideout, W. H. Organic Syntheses;
Wiley: New York, 1973; Collect Vol. 5, pp 414-418.
(83) Grummitt, O.; Becker, E. J . Organic Syntheses; Wiley: New
York, 1963; Collect Vol. 4, pp 771-775.

5776 J . Org. Chem., Vol. 61, No. 17, 1996
Møller and J ørgensen
phortriamide)molybdenum(VI) (4) was prepared according to
the literature.24
(C7), 56.5 (C4), 69.1 (C1), 117.4 (C2′/6′), 122.0 (C4′), 128.3 (C3′/5′),
129.9 (C5), 131.6 (C6), 152.3 (C1′).
Gen er a l P r oced u r e for th e F or m a tion of Oxa zin es 7a -
t. The primary aromatic amine (1.0 mmol), the conjugated
diene (1.0 mmol), the catalyst oxoperoxo(2,6-pyridinedicar-
boxylato-O,N,O)(hexamethylphosphortriamide)molybdenum-
(VI) (4), and H2O2 (2.2 mmol) were mixed with 10 mL of
petroleum ether (bp < 50 °C) at rt. The mixture was stirred
for 18 h and filtered through a plug of HYFLO and the solvent
3-(4-Met h oxyp h en yl)-2-oxa -3-a za b icyclo[2.2.2]oct -5-
en e (7b). 1H NMR δ: 1.30-1.39 (m, 1H, H7), 1.51-1.60 (m,
1H, H8), 2.2-2.3 (m, 2H, H7, H8), 3.74 (s, 3H, OCH3), 4.24-
4.29 (m, 1H, H4), 4.65-4.69 (m, 1H, H1), 6.09-6.14 (m, 1H,
H5), 6.57-6.62 (m, 1H, H6), 6.77 (d, J ) 9.3 Hz, 2H, H3′/5′),
6.95 (d, J ) 9.3 Hz, 2H, H2′/6′). 13C NMR δ: 21.5 (C8), 23.8
(C7), 55.3 (OCH3), 57.1 (C4), 68.9 (C1), 113.5 (C3′/5′), 119.1 (C2′/6′),
129.7 (C5), 131.7 (C6), 145.6 (C1′), 155.1 (C4′).
removed.
A
1H NMR spectrum was recorded on the crude
3-(4-Tolyl)-2-oxa -3-a za bicyclo[2.2.2]oct-5-en e (7c). 1H
NMR δ: 1.31-1.40 (m, 1H, H7), 1.53-1.62 (m, 1H, H8), 2.2-
2.3 (m, 2H, H7, H8), 2.26 (s, 3H, CH3), 4.35-4.39 (m, 1H, H4),
4.67-4.70 (m, 1H, H1), 6.11-6.16 (m, 1H, H5), 6.55-6.61 (m,
1H, H6), 6.91 (d, J ) 8.8 Hz, 2H, H2′/6′), 7.02 (d, J ) 8.8 Hz,
2H, H3′/5′). 13C NMR δ: 20.5 (CH3), 21.3 (C8), 23.9 (C7), 56.5
(C4), 68.9 (C1), 117.4 (C2′/6′), 128.8 (C3′/5′), 129.9 (C5), 131.3 (C4′),
131.5 (C6), 149.8 (C1′).
3-(4-Ch lor op h e n yl)-2-oxa -3-a za b icyclo[2.2.2]oct -5-
en e (7d ). 1H NMR δ: 1.32-1.41 (m, 1H, H7), 1.54-1.63 (m,
1H, H8), 2.2-2.3 (m, 2H, H7, H8), 4.36-4.40 (m, 1H, H4), 4.69-
4.72 (m, 1H, H1), 6.10-6.15 (m, 1H, H5), 6.55-6.60 (m, 1H,
H6), 6.94 (d, J ) 8.8 Hz, 2H, H2′/6′), 7.17 (d, J ) 8.8 Hz, 2H,
H3′/5′). 13C NMR δ: 21.1 (C8), 23.7 (C7), 56.4 (C4), 69.1 (C1),
118.6 (C2′/6′), 126.6 (C4′), 128.1 (C3′/5′), 129.6 (C5), 131.4 (C6),
150.9 (C1′).
4-(2-Oxa-3-azabicyclo[2.2.2]oct-5-en -3-yl)ben zam ide (7e).
1H NMR δ: 1.35-1.43 (m, 1H, H7), 1.58-1.65 (m, 1H, H8), 2.2-
2.3 (m, 2H, H7, H8), 4.55-4.58 (m, 1H, H4), 4.74-4.77 (m, 1H,
H1), 5.6 (br, 1H, C(O)NHH), 5.9 (br, 1H, C(O)NHH), 6.16-
6.22 (m, 1H, H5), 6.54-6.59 (m, 1H, H6), 7.04 (d, J ) 8.8 Hz,
2H, H2′/6′), 7.68 (d, J ) 8.8 Hz, 2H, H3′/5′). 13C NMR δ: 21.1
(C8), 23.9 (C7), 55.8 (C4), 69.6 (C1), 116.5 (C2/6), 126.1 (C4′), 128.1
(C3′/5′), 130.1 (C5), 131.6 (C6), 155.7 (C1′), 168.9 (C)O).
E t h yl 4-(2-Oxa -3-a za b icyclo[2.2.2]oct -5-en -3-yl)b en -
zoa te (7f). 1H NMR δ: 1.35 (t, J ) 7.1 Hz, 3H, CH3), 1.34-
1.43 (m, 1H, H7), 1.53-1.60 (m, 1H, H8), 2.2-2.3 (m, 2H, H7,
H8), 4.32 (q, J ) 7.1 Hz, 2H, CH2), 4.54-4.58 (m, 1H, H4),
4.71-4.77 (m, 1H, H1), 6.14-6.19 (m, 1H, H5), 6.50-6.55 (m,
1H, H6), 7.01 (d, J ) 8.8 Hz, 2H, H2′/6′), 7.90 (d, J ) 8.8 Hz,
2H, H3′/5′). 13C NMR δ: 14.3 (CH3), 20.9 (C8), 23.8 (C7), 55.5
(C4), 60.4 (CH2), 69.5 (C1), 115.9 (C2′/6′), 123.2 (C4′), 130.0 (C5),
130.2 (C3′/5′), 131.4 (C6), 156.3 (C1′), 166.3 (CdO).
product. The product was purified using silica preparative
TLC or flash chromatography. For some of the reactions Et2O
was used as solvent because of the low solubility of the primary
aromatic amine and/or the HDA product in petroleum ether.
1H a n d 13C NMR Sp ectr a . Several coupling patterns are
described below as multiplets, but it may be noted that similar
multiplets in analogous compounds have been analyzed and
are fully understood.84-87 The chemical shifts of 7a were
assigned using several NMR experiments, and the numbering
of the atoms are given below. The aromatic protons were
assigned from the coupling pattern in a normal 1H NMR
experiment. The H4′′ proton was assigned from a NOEDIF
experiment with saturation of the H2′-signal. The assignment
of the remaining bicyclic protons was obtained from a COSY
experiment. It was not possible from these spectra to make
an exo/ endo assignment, but Kresze et al. have examined
bicyclic adducts very similar to 7a -l and assigned exo protons
to the chemical shift at ∼2.25 ppm and endo protons to be 1.60
ppm.88 The proton-substituted carbon nuclei was assigned
from the proton assignments and HETCOR experiments. The
chemical shift value for C1′ was finally identified from a normal
13C spectrum. Chemical shifts values of the adducts 7b-l were
assigned in agreement with the assigned 7a and tabulated
substituent effect values.89 Substituent effect values of sub-
stitution of 2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl on benzene
could be calculated from the data below as follows: 1H, Z2
)
-0.33 ( 0.08, Z3 ) -0.09 ( 0.05, Z4 ) -0.34; 13C, Z1 ) 23.8 (
0.6, Z2 ) -11.9 ( 0.9, Z3 ) 0.2 ( 0.7, Z4 ) -7.1 ( 1.1. An
asterisk indicates a quaternary carbon. The chemical shift
values of the adducts 7m -t were assigned by an analogous
procedure.
1-[4-(2-Oxa -3-a za b icyclo[2.2.2]oct -5-en -3-yl)p h en yl]-
eth a n on e (7g). 1H NMR δ: 1.40-1.45 (m, 1H, H7), 1.58-
1.65 (m, 1H, H8), 2.2-2.3 (m, 2H, H7, H8), 2.53 (s, 3H, CH3),
4.59-4.62 (m, 1H, H4), 4.75-4.78 (m, 1H, H1), 6.20-6.25
(m, 1H, H5), 6.54-6.60 (m, 1H, H6), 7.03 (d, J ) 8.8 Hz, 2H,
H2′/6′), 7.85 (d, J ) 8.8 Hz, 2H, H3′/5′). 13C NMR δ: 21.0 (C8),
23.9 (C7), 26.3 (CH3), 55.5 (C4), 69.8 (C1), 116.0 (C2′/6′), 129.4
(C3′/5′), 130.2 (C5), 130.6 (C4′), 131.6 (C6), 156.5 (C1′), 196.9
(CdO).
3-(4-(Tr iflu or om eth yl)ph en yl)-2-oxa-3-azabicyclo[2.2.2]-
oct-5-en e (7h ). 1H NMR δ: 1.34-1.45 (m, 1H, H7), 1.56-
1.65 (m, 1H, H8), 2.2-2.3 (m, 2H, H7, H8), 4.50-4.55 (m, 1H,
H4), 4.73-4.76 (m, 1H, H1), 6.14-6.19 (m, 1H, H5), 6.54-6.59
(m, 1H, H6), 7.06 (d, J ) 8.5 Hz, 2H, H2′/6′), 7.45 (d, J ) 8.5
Hz, 2H, H3′/5′). 13C NMR δ: 21.1 (C8), 23.9 (C7), 56.0 (C4), 69.5
(C1), 116.7 (C2′/6′), 123.4 (q, J C-F ) 32.3 Hz, C4′), 124.5 (q, J C-F
) 271 Hz, CF3), 125.7 (q, J C-F ) 4.0 Hz, C3′/5′), 129.9 (C5), 131.6
(C6), 155.3 (C1′).
4-(2-Oxa -3-a za bicyclo[2.2.2]oct-5-en -3-yl)ben zon itr ile
(7i). 1H NMR δ: 1.35-1.47 (m, 1H, H7), 1.57-1.73 (m, 1H,
H8), 2.2-2.3 (m, 2H, H7, H8), 4.55-4.60 (m, 1H, H4), 4.75-
4.78 (m, 1H, H1), 6.18-6.24 (m, 1H, H5), 6.53-6.58 (m, 1H,
H6), 7.04 (d, J ) 8.8 Hz, 2H, H2′/6′), 7.48 (d, J ) 8.8 Hz, 2H,
H3′/5′). 13C NMR δ: 20.8 (C8), 23.7 (C7), 55.3 (C4), 69.8 (C1),
103.7 (C4′), 116.6 (C2′/6′), 119.5 (CN), 130.0 (C5), 131.5 (C6), 132.6
(C3′/5′), 155.9 (C1′).
3-P h en yl-2-oxa -3-a za bicyclo[2.2.2]oct-5-en e (7a ). 1H
NMR δ: 1.35-1.39 (m, 1H, H7-endo), 1.53-1.60 (m, 1H, H8-endo),
2.2-2.3 (m, 2H, H7-exo, H8-exo), 4.40-4.43 (m, 1H, H4), 4.67-
4.70 (m, 1H, H1), 6.10-6.15 (m, 1H, H5), 6.53-6.59 (m, 1H,
H6), 6.92 (t, J ) 8.8 Hz, 1H, H4′), 6.99 (d, J ) 8.8 Hz, 2H, H2′/6′),
7.20 (t, J ) 8.8 Hz, 2H, H3′/5′). 13C NMR δ: 21.3 (C8), 24.0
(84) Labaziewicz, H.; Riddell, F. G. J . Chem. Soc., Perkin Trans. 1
1979, 2926-2929.
(85) Labaziewicz, H.; Lindfors, K. R. Heterocycles 1989, 29, 929-
938.
(86) Defoin, A.; Fritz, H.; Geffroy, G.; Streith, J . Helv. Chim. Acta
1988, 71, 1642-1658.
(87) Defoin, A.; Geffroy, G.; Le Noun, D.; Spileers, D.; Streith, J .
Helv. Chim. Acta 1989, 72, 1199-1215.
3-(4-Nitr oph en yl)-2-oxa-3-azabicyclo[2.2.2]oct-5-en e (7j).
1H NMR δ: 1.39-1.47 (m, 1H, H7), 1.58-1.68 (m, 1H, H8), 2.2-
2.3 (m, 2H, H7, H8), 4.65-4.67 (m, 1H, H4), 4.80-4.82 (m, 1H,
H1), 6.24-6.30 (m, 1H, H5), 6.55-6.60 (m, 1H, H6), 7.04 (d, J
) 9.1 Hz, 2H, H2′/6′), 8.11 (d, J ) 9.1 Hz, 2H, H3′/5′). 13C NMR
δ: 20.9 (C8), 23.7 (C7), 55.3 (C4), 70.2 (C1), 115.6 (C2′/6′), 124.9
(88) Kresze, G.; Kysela, E.; Dittel, W. Liebigs Ann. Chem. 1981,
210-223.
(89) Pretch, E.; Clerc, T.; Seibl, J .; Simon, W. Tables of Spectral Data
for Structure Determination of Organic Compounds, 2nd ed.; Springer-
Verlag: New York, 1989.

Mo-Catalyzed Oxidative System Forming Oxazines
J . Org. Chem., Vol. 61, No. 17, 1996 5777
(C3′/5′), 130.2 (C5), 131.7 (C6) 157.5 (C1′). C4′ not detected but
expected at 141.3 ppm.
3-(1-Na p h th yl)-2-oxa -3-a za bicyclo[2.2.2]oct-5-en e (7k ).
1H NMR δ: 1.46-1.52 (m, 1H, H7), 1.52-164 (m, 1H, H8),
2.33-2.42 (m, 1H, H7), 2.48-2.57 (m, 1H, H8), 4.35-4.38 (m,
1H, H4), 4.79-4.82 (m, 1H, H1), 5.93-5.99 (m, 1H, H5), 6.73-
6.78 (m, 1H, H6), 7.18 (m, 1H, H2′), 7.32 (m,1H, H3′), 7.47 (m,
2H, H6′, H7′), 7.53 (m, 1H, H4′), 7.81 (m, 1H, H5′/8′), 8.17 (d, J )
7.2 Hz, 1H, H5′/8′). The aromatic chemical shift values were
assigned according to estimated values using the calculated
substituent effect of the 2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl
substituent. 13C NMR δ: 22.1, 23.8, 56.7, 69.4, 116.6, 123.0,
123.8, 125.2, 125.3, 125.5, 126.4*, 128.2, 129.2, 131.9, 134.0*,
146.8*.
3-(2-Na p h th yl)-2-oxa -3-a za bicyclo[2.2.2]oct-5-en e (7l).
1H NMR δ: 1.43-1.44 (m, 1H), 1.58-1.66 (m, 1H), 2.24-2.38
(m, 1H), 4.53-4.57 (m, 1H), 4.77-4.81 (m, 1H), 6.07-6.12 (m,
1H), 6.57-6.62 (m, 1H), 7.19 (m, 1H, H3′), 7.31 (m, 1H, H6/7),
7.37 (m, 1H, H1), 7.40 (m, 1H, H6/7), 7.7 (m, 3H, H4 H5 H8), see
comment for 7k . 13C NMR δ: 21.4, 24.0, 56.4, 69.4, 113.5,
118.3, 124.0, 126.1, 127.2, 127.4, 128.1, 129.7, 131.5, 133.9*,
149.7*.
1-[2-(2-Oxa -3-a za b icyclo[2.2.2]oct -5-en -3-yl)p h en yl]-
eth a n ol (7s-1). 1H NMR δ: 1.4-1.6 (m, 2H, H7′′-endo, H8′′-endo),
1.55 (d, J ) 6.6 Hz, 3H, H2), 2.2-2.4 (m, 2H, H7′′-exo, H8′′-exo),
3.80 (br, 1H, OH), 4.19 (m, 1H, H4′′), 4.70 (m, 1H, H1′′), 5.24
(q, J )6.6 Hz, 1H, H1), 6.24 (m, 1H, H5′′), 6.77 (m, 1H, H6′′),
7.10 (m, 1H, H5′), 7.15 (m, 1H, H4′), 7.22 (m, 1H, H3′), 7.28 (m,
1H, H6′). 13C NMR δ: 22.5 (C8′′), 23.4 (C7′′), 25.1 (C2), 57.1 (C4′′),
67.3 (C1), 69.3 (C1′′), 122.7 (C3′), 125.2 (C5′), 126.0 (C6′), 127.0
(C4′), 129.4 (C5′′), 133.1 (C6′′), 137.3 (C1′), 148.1 (C2′).
3-(4-Ch lor op h en yl)-2-oxa -3-a za b icyclo[2.2.1]h ep t -5-
en e (7m ). 1H NMR δ: 1.8 (d, J ) 8 Hz, 1H), 2.1 (d, J ) 8 Hz,
1H), 4.9 (s, 1H), 5.1 (s, 1H), 5.9 (d, J ) 6 Hz, 1H), 6.4 (d, J )
6 Hz, 1H), 6.9 (d, J ) 9 Hz, 2H), 7.1 (d, J ) 9 Hz, 2H).
2-(4-Ch lor op h en yl)-4,5-d im eth yl-3,6-d ih yd r o-2H-[1,2]-
oxa zin e (7n ). 1H NMR δ: 1.63 (s, 3H, C5CH3), 1.72 (s, 3H,
C4CH3), 3.62 (s, 1H, C3CH2), 4.31 (s, 1H, C6CH2), 7.05 (d, J )
9.0 Hz, 2H, H2′/6′), 7.25 (d, J ) 9.0 Hz, 2H, H3′/5′). 13C NMR δ:
13.6 (C5CH3), 15.9 (C4CH3), 56.1 (C3), 72.0 (C6), 56.1 (C3), 117.0
(C2′/6′), 122.0, 124.9, 127.1 (C4′), 128.7 (C3′/5′), 149.0 (C1′).
2-(4-Ch lor oph en yl)-4,6,6-tr im eth yl-3,6-dih ydr o-2H-[1,2]-
oxa zin e (7o-1). 1H NMR δ: 1.35 (s, 6H, C6CH3), 1.78 (s, 3H,
C4CH3), 3.57 (s, 2H, H3), 5.51 (s, 1H, H5), 7.02 (d, J ) 8.8 Hz,
2H, H2′/6′), 7.24 (d, J ) 8.8 Hz, 2H, H3′/5′). 13C NMR δ: 20.1
(C3CH3), 26.1 (C6CH3), 53.8 (C3), 77.1 (C6), 116.4 (C2′/6′), 126.1
(C4), 128.3 (C4′), 128.6 (C3′/5′), 128.9 (C5), 149.1 (C1′).
2-(4-Ch lor oph en yl)-3,3,5-tr im eth yl-3,6-dih ydr o-2H-[1,2]-
oxa zin e (7o-2). 1H NMR δ: 1.09 (s, 6H, C3CH3), 1.69 (s, 3H,
C5CH3), 4.27 (s, 2H, H6), 5.39 (s, 1H, H4), 7.18 (d, J ) 8.8 Hz,
2H, H2′/6′), 7.27 (d, J ) 8.8 Hz, 2H, H3′/5′). 13C NMR δ: 17.8
(C3CH3), 23.7 (C5CH3), 59.5 (C3), 71.91 (C6), 124.9 (C2′/6′), 127.8
(C3′/5′), 129.7 (C4), 130.3 (C4′), 130.8 (C5), 145.9 (C1′).
2-(4-Ch lor op h e n yl)-6-e t h yl-3,6-d ih yd r o-2H -[1,2]ox-
a zin e (7p -1). 1H NMR δ: 1.06 (t, J ) 7.4 Hz, 3H, CH2CH3),
1.63 (m, 2H, CH2CH3), 3.69 (d, J ) 16 Hz, 1H, H3), 3.83 (d, J
) 16 Hz, 1H, H3), 4.48 (s, 1H, H6), 5.89 (m, 1H, H4(/5)), 5.92
(m, 1H, H(4/)5), 7.03 (d, J )9 Hz, 2H, H2′/6′), 7.24 (d, J )9 Hz,
2H, H3′/5′). 13C NMR δ: 10.0 (CH3), 26.5 (CH2CH3), 51.6 (C3),
79.1 (C6), 116.6 (C2′/6′), 122.6 (C(4/)5), 126.4 (C4′), 128.7 (C3′/5′),
129.8 (C4(/5)), 149.3 (C1′).
2-(4-Ch lor op h e n yl)-3-e t h yl-3,6-d ih yd r o-2H -[1,2]ox-
a zin e (7p -2). 1H NMR δ: 0.93 (t, J ) 7.4 Hz, 3H, CH2CH3),
1.68 (m, 2H, CH2CH3), 3.86 (s, 1H, H3), 4.28 (d, 1H, H6), 4.50
(d, 1H, H6), 5.93 (m, 1H, H4(/5)), 6.04 (m, 1H, H(4/)5), 6.98
(d, J ) 9 Hz, 2H, H2′/6′), 7.24 (d, J ) 9 Hz, 2H, H3′/5′). 13C
NMR δ: 10.5 (CH3), 23.4 (CH2CH3), 60.1 (C3), 67.5 (C6), 117.6
(C2′/6′), 125.3 (C4(/5)), 126.9 (C(4/)5), 126.7 (C4′), 128.8 (C3′/5′), 147.2
(C1′).
2-(4-Ch lor op h en yl)-6-p h en yl-3,6-d ih yd r o-2H -[1,2]ox-
a zin e (7q). 1H NMR δ: 3.83 (m, 1H, H3), 3.91 (m, 1H, H3),
5.59 (s, 1H, H6), 6.07 (m, 1H, H(4)/5), 6.11 (m, 1H, H4(/5)), 7.01
(d, 7.2H, H2′/6′), 7.21 (d, 7.2H, H3′/5′), 7.3-7.4 (m, 3H, H3′/5′′
H4′′), 7.43 (d, J ) 7.7 Hz, 2H, H2′/6′′). 13C NMR δ: 51.4 (C3),
79.9 (C6), 117.0 (C2′/6′), 123.5 (C4(/5)), 127.0 (C4′), 128.1 (C2′/6′′),
128.5 (C3′/5′′ C4′′), 128.6 (C3′/5′), 128.9 (C(4/)5), 138.6 (C1′′), 148.9
(C1′).
1-[2-(2-Oxa -3-a za b icyclo[2.2.2]oct -5-en -3-yl)p h en yl]-
eth a n ol (7s-2). 1H NMR δ: 1.4-1.6 (m, 2H, H7′′-endo, H8′′-endo),
1.57 (d, J ) 6.6 Hz, 3H, H2), 2.2-2.4 (m, 2H, H7′′-exo, H8′′-exo),
4.00 (m, 1H, H4′′), 4.58 (s, 1H, OH), 4.73 (m, 1H, H1′′), 5.26 (q,
J )6.6 Hz, 1H, H1), 6.17 (m, 1H, H5′′), 6.79 (m, 1H, H6′′), 7.10
(m, 1H, H5′), 7.14 (m, 1H, H4′), 7.17 (m, 1H, H3′), 7.29 (m, 1H,
H6′). 13C NMR δ: 21.8 (C2), 22.8 (C8′′), 23.3 (C7′′), 56.4 (C4′′),
65.2 (C1), 69.4 (C1′′), 122.4 (C3′), 125.2 (C5′), 125.6 (C6′), 127.1
(C4′), 128.9 (C5′′), 133.2 (C6′′), 137.1 (C1′), 148.2 (C2′).
1-[2-(6-P h en yl-3,6-d ih yd r o-[1,2]oxa zin e-2-yl)p h en yl]-
eth a n ol (7t-1). 1H NMR δ: 1.41 (d, J ) 6.6 Hz, 3H, H2), 3.67-
3.74 (m, 1H, H3′′), 3.8 (br, 1H, OH), 3.94-4.02 (m, 1H, H3′′),
5.17 (q, J ) 6.6 Hz, 1H, H1), 5.65-5.67 (m, 1H, H6′′), 6.05-
6.09 (m, 1H, H4′′/5′′), 6.16-6.21 (m, 1H, H4′′/5′′), 7.2-7.5 (m, 4H,
Haromat). 13C NMR δ: 23.5, 53.2, 66.8, 88.3, 120.9, 124.6, 126.2,
127.0, 127.9, 128.4, 128.5, 128.6, 138.6*, 140.7*, 146.7*. Sepa-
rated by preparative HPLC using a 250 mm, i.d. ) 16 mm
LiChrosorb CN column, 10 mL/min, tR ) 19 min.
1-[2-(6-P h en yl-3,6-d ih yd r o[1,2]oxa zin -2-yl)p h en yl]eth -
a n ol (7t-2). 1H NMR δ: 1.51 (d, J ) 6.6 Hz, 3H, H2), 3.62-
3.69 (m, 1H, H3′′), 3.95 (br, 1H, OH), 3.99-4.05 (m, 1H, H3′′),
5.14 (q, J ) 6.6 Hz, 1H, C1), 5.72 (s br, 1H, H6′′), 6.03-6.07
(m, 1H, H4′′/5′′), 6.15-6.20 (m, 1H, H4′′/5′′), 7.2-7.5 (m, 4H,
Haromat). 13C NMR δ: 23.4, 52.9, 66.9, 80.5, 121.1, 124.5, 126.5,
127.1, 128.0, 128.4, 128.5, 128.7, 138.2, 140.6, 146.8. Separated
by preparative HPLC using a 250 mm, i.d. ) 16 mm Li-
Chrosorb CN column, 10 mL/min, tR ) 16 min.
(R/S)-1-(2′-Am in op h en yl)eth a n ol (2n ) was prepared by
standard reduction of 2′-aminoacetophenone with NaBH4 in
MeOH. 1H NMR δ: 1.50 (d, J ) 6.6 Hz, 3H), 3.66 (br, 3H),
4.80 (q, J ) 6.6 Hz, 1H), 6.60 (d, J ) 7.7 Hz, 1H), 6.70 (t, J )
7.1 Hz, 1H), 7.02 (d, J ) 6.6 Hz, 1H), 7.06 (t, J ) 7.7 Hz, 1H).
13C NMR δ: 21.5, 69.5, 116.7, 118.2, 126.5, 128.4*, 128.5,
144.9*. 1H NMR data have been reported.90
(S)-1-(2′-Am in op h en yl)eth a n ol ((S)-2n ) was prepared by
asymmetric reduction of 2′-nitroacetophenone with (-)-DIP-
Cl at -40 °C according to a reported method.91 The ee of (S)-
1-(2′-nitrophenyl)ethanol was determined from GC to be >99%
which was higher than a previously reported value at -25 °C.92
Catalytic reduction using Raney nickel/H2 gave (S)-2n with
the ee reduced to 90%. The ee was determined by HPLC after
acylation of (S)-2n with benzoyl chloride in the presence of
Et3N yielding N-[2-(1-hydroxyethyl)phenyl]benzamide.93,94 The
two enantiomers of the amide separate nicely within 10 min.
2-(4-Ch lor op h en yl)-3,6-d ip h en yl-3,6-d ih yd r o-2H-[1,2]-
oxa zin e (7r ). 1H NMR δ: 5.10 (s, 1H, H3), 5.63 (s, 1H, H6),
6.14 (m, 1H, H4/5), 6.18 (m, 1H, H4/5), 6.88 (d, J ) 9.1 Hz, 2H,
H2′/6′), 7.08 (d, J ) 9.1 Hz, 2H, H3′/5′), 7.15-7.28 (m, 3H, HAr),
7.32-7.48 (m, 5H, HAr), 7.51 (d, J ) 8 Hz, 2H, HAr). 13C NMR
δ: 63.5 (C3), 79.5 (C6), 118.0 (C2′/6′), 126.5 ((C4′)), 127.6, 127.9,
128.0 (C4/5), 128.1 (C4/5), 128.2, 128.4 (C3′/5′), 128.6, 128.8,
137.7*, 138.3*, 127.1 (H1′).
(90) Fleming, I.; Loreto, M. A.; Wallace, I. H. M.; Michael, J . P. J .
Chem. Soc., Perkin Trans. 1 1986, 349-359.
(91) Chandrasekharan, J .; Ramachandran, P. V.; Brown, H. C. J .
Org. Chem. 1985, 50, 5446-5448.
(92) Dahr, R. K. Aldrichimica Acta 1994, 27, 43-51.
(93) Gribble, G. W.; Bousquet, F. P. Tetrahedron 1971, 27, 3785-
3794.
(94) Fu¨rstner, A.; Hupperts, A.; Ptock, A.; J anssen, E. J . Org. Chem.
1994, 59, 5215-5229.

5778 J . Org. Chem., Vol. 61, No. 17, 1996
Møller and J ørgensen
(R)-1-(2′-Am in op h en yl)eth a n ol ((R)-2n ) was prepared by
asymmetric reduction of 2′-aminoacetophenone with (-)-DIP-
Cl as described above. NMR data were identical to those of
the racemic compound. The ee was determined as described
for (S)-2n .
Th eor etica l Ca lcu la tion s. Geometries were optimized
using either PM369 or AM168 in the MOPAC program.
Ack n ow led gm en t. Thanks are expressed to Lise
Ravn-Petersen for peforming some of the experiments
and to Professor Henrik Bildsøe for fruitful NMR
discussions.
1-(2′-Nitr osop h en yl)eth a n ol (8) was prepared according
to a literature procedure for analogous compounds.24 Chemical
shifts were assigned from HETCOR and homonuclear decou-
pling of aromatic signals and by comparison with data for other
ortho-substituted nitrosobenzenes.81 1H NMR δ: 1.82 (d, J )
6.6 Hz, 3H, H2), 2.9 (br, 1H, OH), 6.23 (dd, J ) 8.2, 1.6 Hz,
1H, H3′), 6.63 (q, J ) 6.6 Hz, 1H), 7.25 (m, 1H, H4′), 7.74 (m,
Hz, 1H, H5′), 7.92 (d, J ) 6.6 Hz, 1H, H6). 13C NMR δ: 27.0
(C2), 67.1 (C1), 105.9 (C3′), 126.9 (C4′), 127.6 (C6′), 136.9 (C5′),
148.3 (C1′), 162.9 (C2′).
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C, NOEDIF,
HETCOR, and COSY NMR spectra (86 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O9608127