Synthesis of 1,3-oxazine derivatives by palladium-catalyzed cycloaddition of vinyloxetanes with heterocumulenes. Completely stereoselective synthesis of bicyclic 1,3-oxazines

Article abstract of DOI:10.1021/jo990430b

1,3-Oxazines were prepared by palladium-phosphine-catalyzed cycloaddition reactions of vinyloxetanes with heterocumulenes. 4-Vinyl-1,3- oxazin-2-imines were obtained in fine yields by the reaction of 2- vinyloxetanes with carbodiimides in THF at rt for 12 h using 1.5 mol % Pd₂(dba)₃ · CHCl₃ and 3 mol % bidentate phosphine ligands (dppe or dppp). When isocyanates were utilized in the reaction, moderate to good yields of 4- vinyl-1,3-oxazin-2-ones were achieved within 1-2 h at rt. Palladium-catalyzed cycloaddition of fused-bicyclic vinyloxetanes with heterocumulenes proceeds in a highly stereoselective fashion affording only the cis-3-aza-1-oxo-9- vinyl[4.4.0]decane derivatives in 43-98% yield.

Full text of DOI:10.1021/jo990430b

4152
J . Org. Chem. 1999, 64, 4152-4158
Syn th esis of 1,3-Oxa zin e Der iva tives by P a lla d iu m -Ca ta lyzed
Cycloa d d ition of Vin yloxeta n es w ith Heter ocu m u len es.
Com p letely Ster eoselective Syn th esis of Bicyclic 1,3-Oxa zin es
Chitchamai Larksarp and Howard Alper*
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada, K1N 6N5
Received March 10, 1999
1,3-Oxazines were prepared by palladium-phosphine-catalyzed cycloaddition reactions of vinyl-
oxetanes with heterocumulenes. 4-Vinyl-1,3-oxazin-2-imines were obtained in fine yields by the
reaction of 2-vinyloxetanes with carbodiimides in THF at rt for 12 h using 1.5 mol % Pd2(dba)3‚
CHCl3 and 3 mol % bidentate phosphine ligands (dppe or dppp). When isocyanates were utilized in
the reaction, moderate to good yields of 4-vinyl-1,3-oxazin-2-ones were achieved within 1-2 h at
rt. Palladium-catalyzed cycloaddition of fused-bicyclic vinyloxetanes with heterocumulenes proceeds
in a highly stereoselective fashion affording only the cis-3-aza-1-oxo-9-vinyl[4.4.0]decane derivatives
in 43-98% yield.
In tr od u ction
erocumulenes, the cycloaddition reaction proceeds with
retention of configuration.5 Several methods have been
described for the preparation of 1,3-oxazines by cycload-
dition of heterocumulenes with oxetanes.6 For example,
Baba and co-workers6a,b employed organotin halide-base
complexes as the catalyst for the addition of isocyanates
to an oxetane to form oxazines. The reaction of oxetane
with carbodiimides in the presence of triethylamine has
been described in a US patent.6c However, relatively high
reaction temperatures (100-200 °C) were needed in most
cases. Larock et al.7 have observed the palladium(0)-
catalyzed nucleophillic ring opening of 2-vinyloxetanes
in the synthesis of homoallyllic alcohols (eq 2). A π-allyl
complex may be a reaction intermediate, in analogy to
the 2-vinyloxiranes/heterocumulenes process.4 Therefore,
2-vinyloxetanes could, in principle, be used for cycload-
dition with heterocumulenes to prepare 4-vinyl-1,3-
oxazines.
The synthesis of 1,3-oxazines has attracted attention
in the past because of their potential as antibiotics,1a-d
antitumor,1e-g analgesics,1h,i and anticonvulsants.1j Sev-
eral methods for the preparations of 1,3-oxazine deriva-
tives have previously been reported,1k,l including the use
of heterocumulenes.2
The cycloaddition reaction of heterocumulenes with
three-membered heterocycles are of value for the forma-
tion of five-membered ring heterocycles.3 We previously
reported the use of isocyanates and carbodiimides as
substrates for cycloaddition reactions with oxiranes (X
) O)4 or aziridines (X ) NR)5 (eq 1) catalyzed by
palladium complexes, thus affording oxazolidine or imi-
dazolidine derivatives, respectively. Also, palladium-
catalyzed reaction of carbodiimides with vinyloxiranes in
the presence of BINAP or TolBINAP affords oxazolidin-
imines in high enantiomeric excess.4
Given the complete regio- and stereoselective nature
of the noted vinyloxirane-heterocumulene reactions, we
Furthermore, when enantiomerically pure aziridines
are used in the palladium-catalyzed reaction with het-
(3) (a) Osaki, S. Chem. Rev. 1972, 72, 457. (b) Gunar, V. I.;
Ovechkina, L. F.; Zavyalov, S. I. Chem. Abstr. 1965, 63, 8346 g. (c)
Pietsch, H.; Clauss, K.; Schmidt, E.; J ensen, H. Chem. Abstr. 1976,
84, 135684f. (d) Fukui, K.; Kitano, T. Kogyo Kagaku Zasshi, 1980, 63,
2062. (e) Hassner, A.; Rasmussen, J . K. J . Am. Chem. Soc. 1975, 97,
1451. (f) Karikomi, M.; Yamazaki, T.; Toda, T. Chem. Lett. 1993, 1965.
(g) Trost, B. M.; Sudhakar, A. R. J . Am. Chem. Soc. 1988, 110, 7933.
(h) Baba, A.; Fujiwara, M.; Matsuda, H. Tetrahedron Lett. 1986, 27,
77. (i) Fujiwara, M.; Baba, A.; Matsuda, H. J . Heterocycl. Chem. 1988,
25, 1351. (j) Baba, A.; Seki, K.; Matsuda, H. J . Heterocycl. Chem. 1990,
27, 1925.
(1) (a) Haneishi, T.; Okazaki, T.; Hata, T.; Tamura, C.; Nomura,
M., Naito, A., Seki, I.; Arai, M. J . Antibiot. 1971, 24, 797. (b) Sasaki,
K.; Kusakabe, Y.; Esumi, S. J . Antibiot. 1972, 25, 151. (c) Kusakabe,
Y.; Nagatsu, J .; Shibuya, M.; Kawaguchi, O.; Hirose, C.; Shirato, S. J .
Antibiot. 1972, 25, 44. (d) Kupchan, S. M.; Komoda, Y.; Court, W. A.;
Thomas, G. J . Smith, R. M. Karim, A.; Gilmore, C. J .; Haltivanger, R.
C.; Bryan, R. F. J . Am. Chem. Soc. 1972, 94, 1354. (e) Wani, M. C.;
Taylor, H. L. Wall, M. E. Chem. Soc., Chem. Commun. 1973, 390. (f)
J ohnson, P. Y.; Silver, R. B. J . Heterocycl. Chem. 1975, 10, 1029. (g)
Renullard, S.; Rebhun, L. I. Havic, G. A.; Kupchan, S. M. Science, 1975,
189, 1002. (h) Urban´ski, T.; Ghrne, D.; Szczerek, I.; Modaski, M. Polish
Patent, 54, 007, 1967. (i) Lesher, G. Y.; Surrey, A. R. J . Am. Chem.
Soc. 1955, 77, 636 (j) Mosher, H. S.; Frankel, M. B.; Gregory, M. J .
Am. Chem. Soc. 1953, 75, 5326. (k) Sainsbury, M. In Comprehensive
Heterocyclic Chemistry; Boulton, A. J ., Mckillop, A., Eds.; Pergamon
Press: Canada, 1984; Vol. 3, Part 2B, p 995. (l) Khumtaveeporn, K.;
Alper, H. J . Org. Chem. 1995, 60, 8142.
(4) (a) Larksarp, C.; Alper, H. J . Am. Chem. Soc. 1997, 119, 3709.
(b) Larksarp, C.; Alper, H. J . Org. Chem. 1998, 63, 6229.
(5) (a) Baeg, J . O.; Bensimon, C.; Alper, H. J . Am. Chem. Soc. 1995,
117, 4700. (b) Baeg, J . O.; Alper, H. J . Org. Chem. 1992, 57, 157.
(6) (a) Baba, A.; Kashiwagi, H.; Matsuda, H. Organometallics 1987,
6, 137. (b) Baba, A.; Shibata, I.; Fujiwara, M.; Matsuda, H. Tetrahedron
Lett. 1985, 26, 5167. (c) Metzger, S. H., J r. US Patent 3, 479, 351, 1969.
(7) (a) Larock, R. C.; Stolz-Dunn, S. K. Tetrahedron Lett. 1989, 30,
3487. (b) Larock, R. C.; Ding, S.; Chi, T. Synlett 1993, 145. (c) Larock,
R. C.; Stolz-Dunn, S. K. Synlett 1990, 341.
(2) (a) Eckstein, Z.; Urban´ski, T. Adv. Heterocycl. Chem. 1963, 2,
311. (b) Eckstein, Z.; Urban´ski, T. Adv. Heterocycl. Chem. 1978, 23, 1.
(c) Kato, T.; Katagiri, N.; Yamamoto, Y. Heterocycles 1980, 14, 133.
10.1021/jo990430b CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/07/1999

Stereoselective Synthesis of Bicyclic 1,3-Oxazines
J . Org. Chem., Vol. 64, No. 11, 1999 4153
Ta ble 2. Effect of Ad d ed P h osp h in e Liga n d s in th e
Cycloa d d ition Rea ction s of 2-Vin yloxeta n e 1a w ith
Dip h en ylca r bod iim id es 3a Usin g 1.5 m ol%
investigated the palladium-catalyzed cycloaddition reac-
tion of vinyloxetanes with heterocumulenes. We now
report that not only is the reaction of considerable scope
for monocyclic oxetanes, but we were gratified to observe
that bicyclic oxetanes reacted in a totally stereoselective
manner with heterocumulenes to form 3-aza-1-oxo-cis-
bicyclo[4.4.0]decanes.
a
P d 2(d ba )3‚CHCl3
Resu lts a n d Discu ssion
isolated yield
Cycloa d d it ion R ea ct ion of Vin yloxet a n es w it h
Heter ocu m u len es. To determine the viability of the
cycloaddition reaction of vinyloxetanes with heterocu-
mulenes, we initially examined the reaction of 2-vinyl-
oxetane (1b, R ) CH3) with phenyl isocyanate (2a ) in
anhydrous THF (Table 1) by using 5 mol % of Pd(PPh3)4
(eq 3). The latter has been used in the nucleophilic ring
opening reaction of 2-vinyloxetane with hard nucleophiles
to obtain allylic alcohol.7a The desired product, 4-vinyl-
entry
ligands
reaction time (h)b
of 5a (%)c
1
2
3
4
5
0.06 mmol of PPh3
0.03 mmol of dppe
0.03 mmol of dppp
0.03 mmol of dppb
0.03 mmol of dpppentane
12
12
12
12
24
79
97
98
94
78
a
Reaction conditions: 2-Vinyloxetane 1a (1.0 mmol), diphenyl-
carbodiimide 3a (1.0 mmol), Pd2(dba)3‚CHCl3 (0.015 mmol), 0.03
mmol of bidentate ligand or 0.06 mmol of PPh3, room temperature,
b
5 mL of THF, N2 atmosphere. Reaction times were based on the
complete conversion of the carbodiimide. c Isolated yield by pre-
parative TLC.
of PPh3 and dpppentane which can enhance dimerization
or trimerization of the carbodiimide.13 Therefore, dppe
and dppp are ligands of choice in the cycloaddition
reactions.
The cycloaddition reaction was successfully carried out
by treatment of 2-vinyloxetane (1a , R ) H, 1b, R ) CH3)
with heterocumulenes 2 or 3 in the presence of 2-3 mol
% Pd2(dba)3‚CHCl3 and 2 equiv of phosphine ligands in
anhydrous THF at room temperature. The reaction times
were 12 h when carbodiimides were utilized in the
cycloaddition, whereas in the case of isocyanates the
reaction times were always shorter (1-1.5 h).14 All
reactions were performed by using dppe and dppp and
some reactions utilized PPh3 in order to compare the
yields. The results are illustrated in Table 3 (for isocy-
anates) and Table 4. (for carbodiimides).
The cycloaddition reaction involving vinyloxetanes may
proceed in the same manner as for vinyloxirane,15,4 i.e.,
via zwitterionic π-allyl palladium intermediate 6 gener-
ated by oxidative addition of vinyloxetane 1 to a pal-
ladium(0) complex followed by reaction with heterocu-
mulenes. Intramolecular attack of the nitrogen nucleophile
at C-3 carbon of 7 would afford the six-membered-ring,
1,3-oxazine derivatives. (Scheme 1).
1,3-oxazine-2-one (4f) was obtained in 47% yield (Table
1, entry 1). We then investigated the optimum amount
of catalyst for this reaction by reducing the amount of
palladium catalyst, Pd(PPh3)4 (without additional of any
phosphine ligands), to 3 mol % (57% isolated yield of 4f),
2 mol % (53% isolated yield of 4f), and 1 mol % (38%
isolated yield of 4f). Therefore, 2-3 mol % of palladium
catalyst was used in the cycloaddition reactions.
Ta ble 1. Deter m in a tion of th e Op tim u m Am ou n t of P a l-
la d iu m Ca ta lyst for th e Cycloa d d ition Rea ction of 2-
Meth yl-2-vin yloxeta n e (1b) w ith P h en yl Isocya n a te (2a )a
mol % of Pd(PPh3)4 to 1 mol of
phenyl isocyanate
isolated yield
entry
of 4f (%)b
1
2
3
4
5
5
3
2
1
0
47
57
53
38
0
When using isocyanates for the reactions, product
yields were considerably less than using carbodiimides
as the substrate. The reaction conditions used might
enhance the rate of dimerization and/or trimerization of
isocyanates relative to the rate of cyclization. Lowering
the reaction temperature to 0 °C (68% yield), -20 °C (65%
yield), and -78 °C (40% yield) so as to reduce the rate of
a
Reaction conditions: 2-methyl-2-vinyloxetane 1b (1.0 mmol),
phenyl isocyanate 2a (1.0 mmol), Pd(PPh3)4, 5 mL of THF, room
b
temperature, N2 atmosphere. Purified by preparative TLC.
The presence of phosphine ligands was essential for
the reaction, as no conversion of heterocumulenes was
observed in the absence of a phosphine ligand.8 To
investigate the effect of the added phosphine ligands in
the reaction, different types of phosphine ligands were
employed when 2-vinyloxetane 1a was treated with
diphenylcarbodiimide 3a to form N-phenyl-3-phenyl-4-
vinyl-1,3-oxazin-2-imine, 5a (see Table 2). Triphenylphos-
phine and dpppentane9 were found to be less effective
than dppe,10 dppp,11 and dppb12 for the palladium-
catalyzed reaction. This may be due to the lower basicity
(10) dppe ) 1, 2-bis(diphenylphosphino)ethane [Diphos].
(11) dppp ) 1, 3-bis(diphenylphosphino)propane.
(12) dppb ) 1, 4-bis(diphenylphosphino)butane.
(13) (a) Trost, B. M.; Sudhakar, A. R. J . Am. Chem. Soc. 1987, 109,
3792. (b) Rahman, M. M.; Liu, H.-Y.; Eriks, K.; Prock, A.; Giering, W.
P. Organometallics 1989, 8, 1.
(14) Reaction times were based on the complete conversion of the
heterocumulenes (monitored by the shift of the IR absorption band of
the carbodiimide unit at ∼2100 cm-1 to the region of 1600 cm-1; the
absorption band of the isocyanate at about 2200 cm-1 was replaced by
the carbonyl absorption in the region of 1700 cm-1).
(8) The reaction was performed by using 1 mmol of 1b and 1 mmol
of 2a in the presence of 0.015 mmol of Pd2(dba)3‚CHCl3 (no phosphine
ligand was added) in THF and was stirred under nitrogen atmosphere
for 24 h.
(15) (a) Hayashi, T.; Yamamoto, A.; Hagihara, T.; Ito, Y. Tetrahedron
Lett. 1986, 27, 191. (b) Hayashi, T.; Yamamoto, A.; Ito, Y. Chem. Lett.
1987, 177. (c) Hayashi, T.; Konishi, M.; Kumada, M. Chem. Soc., Chem.
Commun. 1984, 107. (d) Fiaud, J .-C.; Legros, J .-Y. J . Org. Chem. 1990,
55, 4840. (e) Tsuji, J . Pure Appl. Chem. 1982, 54, 197.
(9) dpppentane ) 1, 5-bis(diphenylphosphino)pentane.

4154 J . Org. Chem., Vol. 64, No. 11, 1999
Larksarp and Alper
Ta ble 3. Cycloa d d ition Rea ction s of 2-Vin yloxeta n es 1 w ith Isocya n a tes 2 in th e P r esen ce of a P a lla d iu m (0) Com p lex
a n d a P h osp h in e Liga n d a
a
b
Refer to the Experimental Section for General Procedure. Purified by preparative TLC.
dimerization and/or trimerization proved to have no
beneficial effect on the rate of cyclization.16 In comparison
with reactions utilizing isocyanates containing a halogen
at the para-position of the phenyl ring, PPh3 was shown
to be the best ligand (entries 4 and 7, Table 3). Using
dppp as the added ligand gives better product yields in
most cases. However, reaction of p-methoxyphenyl iso-
cyanate 2d with 1b, and dppe afforded a higher yield of
isolated product (entry 8).
In the reaction using carbodiimides, good to excellent
isolated yields of the desired products were obtained with
1.5 mol % of Pd2(dba)3‚CHCl3 and 3 mol % of dppp being
the best catalytic system in most cases. In the reaction
using carbodiimides having halogen at the para-position
of the phenyl rings, dppe proved to be the best ligand for
the reactions (entries 5, 9, and 12, Table 4). The reaction
times were always longer when 2-vinyloxetanes were
used which contained a vinylic substituent (entries 11-
15, Table 4).
bicyclic vinyloxetanes has been described by Larlock and
co-workers.8 The reaction was found to proceed via a
π-allyl palladium intermediate. Reaction of bicyclic vi-
nyloxetanes with heterocumulenes is a simple route to
bicyclic oxazines. We first performed the reaction using
1 mmol each of 1c and diphenylcarbodiimide, 2a (eq 4),
and the reaction conditions were identical to those used
for monocyclic vinyloxetanes (1a ,b) (entry 1, Table 5), but
no conversion of the carbodiimides was observed. In-
creasing the amount of the palladium catalyst to 2.5 mol
% and the reaction temperature to 50 °C (entry 2) also
gave recovered heterocumulenes. However, complete
conversion occurred using 4.5 mol % of Pd2(dba)3‚CHCl3
and 9 mol % of dppp at 50 °C, with 8a isolated in 52%
yield (entry 4).
Cycloa d d ition Rea ction of Bicyclic Vin yloxeta n es
w ith Heter ocu m u len es. The synthesis of homoallylic
alcohols by palladium-catalyzed ring opening of fused-
(16) Repeating reaction in entry 1, Table 3, but with stirring at lower
temperature after addition of 1a and 2a to the mixture of Pd2(dba)3‚
CHCl3 and dppp in THF.

Stereoselective Synthesis of Bicyclic 1,3-Oxazines
J . Org. Chem., Vol. 64, No. 11, 1999 4155
Ta ble 4. Cycloa d d u cts Obta in ed fr om th e Rea ction s of 2-Vin yloxeta n es 1 a n d Ca r bod iim id es 3 in th e P r esen ce of 1.5
m ol % P d 2(d ba )3‚CHCl3 a n d a P h osp h in e Liga n d a
a
b
Refer to the Experimental Section for the General Procedure. Yield of isolated product after silica gel TLC.
The yield increased to 70% when the reaction was
carried out in a glass autoclave with 5 psi N2 at 80 °C
(entry 5). Increasing the reaction temperature to 100 °C
resulted in the formation of palladium black, and 8a was
formed in reduced yield.
8a . Consequently, the cycloaddition proceeds with com-
plete stereochemical control.
A series of heterocumulenes 2 and 3 were reacted with
bicyclic vinyloxetanes 1c, 1d , and 1e using Pd2(dba)3‚
CHCl3 and a bidentate phosphine ligand as the catalytic
system (eq 5), and the results are summarized in Table
Trans- and cis-fused bicyclic oxazine-2-imines (8a )
(Figure 1) are possible reaction products.
Spectral results17 and a single-crystal X-ray diffraction
determination (Figure 2) established the structure as cis-
(17) After complete conversion of 2a (monitored by IR), the reaction
solution was concentrated and separated by preparative silica gel TLC.
Only one isomer of the desired product was observed by TLC.

4156 J . Org. Chem., Vol. 64, No. 11, 1999
Larksarp and Alper
Sch em e 1
Ta ble 5. Op tim iza tion of Rea ction Con d ition s for th e
Cycloa d d ition of Bicyclic Vin yloxeta n e 1c w ith
Dip h en ylca r bod iim id e 3a a
reaction of bicyclic oxetanes with carbodiimides (entries
2, 4, 6, and 8, Table 6). However, dppp was a superior
ligand for the reaction of 1a with isocyanates. Lower
isolated product yields were observed using isocyanates
than carbodiimides in the cycloaddition reactions, analo-
gous to results observed using monocyclic vinyloxetanes.
The selective formation of cis-fused bicyclic [4.4.0]
heterocycles (8 or 9) may be due to a preference for the
formation of 10 rather than 11 (Scheme 2). Intramolecu-
lar nucleophilic addition in 10 may occur from the side
opposite to π-allyl palladium moiety resulting in the
formation of the cis-product.
entry
1
conditions
isolated yields,b %
0
0.015 mmol of Pd2(dba)3‚CHCl3,
0.03 mmol of dppp, RT, 48 h
0.025 mmol of Pd(PPh3)4,
2
3
4
5
0
0
0.025 mmol of PPh3, 50 °C, 48 h
0.045 mmol of Pd2(dba)3‚CHCl3,
0.09 mmol of dppp, RT, 48 h
0.045 mmol of Pd2(dba)3‚CHCl3,
0.09 mmol of dppp, 50 °C, 48 h
0.045 mmol of Pd2(dba)3‚CHCl3,
0.09 mmol of dppp, 80 °C, 48 hc
52
70
The cycloaddition of bicyclic vinyloxetanes 1d and 1e
bearing a methyl substituent on the cyclohexyl ring was
also stereoselective. An X-ray determination of the
structure of 8f revealed a trans relationship of the methyl
and vinyl groups in the cis-bicyclic oxazine imine (Figure
3). Excellent yields resulted from reactions of 1d or 1e
with carbodiimides 3a -c (entries 14-18, Table 6). What
these results demonstrate is the ability to achieve
complete regio- and stereoselective cycloaddition pro-
cesses using nonchiral ligands.
a
Reaction conditions: 1c (1 mmol), 3a (1 mmol), THF (10 mL),
b
under N2 atmosphere. Isolated yield of 8a (by preparative TLC).
c Reaction was stirred in a glass autoclave at 5 psi N2.
Con clu sion s
F igu r e 1. Two possible cycloaddition products which could
Mono and bicyclic oxazin-2-ones and oxazin-2-imines
were isolated in fine yields by the cycloaddition reaction
of 2-vinyloxetanes with heterocumulenes catalyzed by
palladium complexes and phosphine ligands. This process
is completely regioselective and stereoselective. A par-
ticularly novel feature of the cycloaddition process is its
use for the construction of bicyclic [4.4.0] systems by use
of Pd2(dba)3‚CHCl3 and a achiral ligand such as dppe.
The new reaction provides access to stereochemically
defined mono and bicyclic compounds some of which may
prove to exhibit significant pharmaceutical activity.
be obtained from the reaction.
Exp er im en ta l Section
F igu r e 2. X-ray structure of 8a .
Gen er a l Meth od s. Pd(PPh3)4 and isocyanates were pur-
chased from commercial sources and were used as received.
6. The reactions were carried out in a glass autoclave
under 5 psi N2 using 1 mmol of 1c, 1d , or 1e with 1
equimolar of heterocumulene (2 or 3) in the presence of
4-4.5 mol % of Pd2(dba)3‚CHCl3 and 8-9 mol % of
bidentate phosphine ligand (using carbodiimides), whereas
a mixture of 3.0 mol % of Pd2(dba)3‚CHCl3 and 6 mol %
of bidentate phosphine ligand was used for reactions
involving isocyanates. The reaction mixture was stirred
at 80 °C for carbodiimides and 50 °C for isocyanates, until
conversion of heterocumulenes was complete (monitored
by IR). The yields of the bicyclic cis-oxazin-2-imine (8)
were significantly higher using dppe than dppp for the
Carbodiimides18 and Pd2(dba)3‚CHCl3 were prepared accord-
19
ing to literature procedures. Organic solvents were dried and
distilled prior to use. Vinyloxetanes 1a and 1b were prepared
according to literature methods.20 Bicyclic vinyloxetanes, 1c-
e, were obtained by modification of literature procedures21
(18) Campbell, T. W.; Monagle, J . J .; Foldi, V. J . Am. Chem. Soc.
1962, 84, 3673.
(19) Ukai, T.; Kawazura, H.; Ishii, Y. J . Organomet. Chem. 1974,
65, 253.
(20) Portnyagin, Y, M.; Pak, N. E. J . Org. Chem. USSR 1971, 7,
1691.
(21) Portnyagin, Y, M.; Sova, V. V. J . Org. Chem. USSR 1968, 4,
1515.

Stereoselective Synthesis of Bicyclic 1,3-Oxazines
J . Org. Chem., Vol. 64, No. 11, 1999 4157
Ta ble 6. Cycloa d d ition Rea ction of F u sed -Rin g 2-Vin yloxeta n es 1c-e w ith Heter ocu m u len es 2 or 3 Ca ta lyzed by
P d 2(d ba )3‚CHCl3 a n d Bid en ta te P h osp h in e Liga n d sa
entry
1
XdCdY
Pd2(dba)3‚CHCl3 (mmol)
ligand (mmol)
reaction time, h
product
isolated yield,b %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1c
3a
0.045
dppp (0.09)
dppe (0.09)
dppp (0.08)
dppe (0.08)
dppp (0.08)
dppe (0.08)
dppp (0.08)
dppe (0.08)
dppe (0.09)
dppp (0.06)
dppp (0.06)
dppp (0.06)
dppp (0.06)
dppe (0.09)
dppe (0.09)
dppe (0.09)
dppe (0.09)
dppe (0.09)
24
24
48
48
48
48
48
48
48
24
12
12
12
12
24
24
24
24
8a
70
98
65
85
20
86
22
66
86
51
46
55
43
80
77
70
98
82
1c
1c
1c
3b
3c
3d
0.04
0.04
0.04
8b
8c
8d
1c
1c
1c
1c
1c
1d
1d
1d
1e
1e
3f
0.045
0.03
0.03
0.03
0.03
0.45
0.45
0.45
0.45
0.45
8e
9a
9b
9c
9d
8f
8g
8h
8i
2a
2b
2d
2e
3b
3a
3c
3b
3c
8j
a
See the Experimental Section for General Procedure for the Cycloaddition Reaction of Bicyclic Vinyloxetanes with Heterocumules.
Purified by column chromatography using silica gel.
b
phosphine ligand (0.02-0.03 mmol)] and THF (5 mL), was
stirred in a three-neck round-bottom flask under nitrogen at
room temperature for 30 min. The vinyloxetane 1a or 1b (1.0
mmol) and heterocumulene (1.0 mmol) were added, and the
mixture was then stirred under nitrogen at room temperature
until the conversion of the heterocumulenes was complete
[monitored by disappearance of the NdCdN IR-absorption
band in the free carbodiimide (∼2100 cm-1) and the appear-
ance of the CdN band in the region of 1620-1630 cm-1; the
absorption of the isocyanate (∼2200 cm-1) is replaced by the
carbonyl band at 1680-1690 cm-1]. After the reaction was
complete, the orange yellow solution was then concentrated
by rotary evaporation, and the residue was purified by silica
gel TLC using a mixture of pentane/ether as the developer.
Melting points, IR, NMR, MS, and analytical data for selected
samples of 4 and 5 are as follows (see Supporting Information
for all others 4 and 5).
Sch em e 2
N-P h en yl-4-vin yl-1,3-oxa zin -2-on e (4a ) (R ) H, R′ )
1
C6H5): mp ) 60-61 °C; IR (CdO) 1695 cm-1; H NMR (200
MHz, CDCl3) δ 1.97 (m, 1H), 2.30 (m, 1H), 4.31 (m, 3H), 5.15
(m, 2H), 5.71 (m, 1H), 7.13-7.34 (m, 5H); 13C NMR (300 MHz,
CDCl3) δ 27.63, 60.13 63.67, 118, 126.67, 126.94, 128.72,
135.97, 141.53, 152.63 (CdO); MS (m/e) 203 [M]+. Anal. Calcd
for C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found C, 71.28; H,
6.44; N, 6.70.
N-(p-Ch lor op h en yl)-4-vin yl-1,3-oxa zin -2-on e (4b) (R )
1
H, R′ ) p-ClC6H4): mp ) 68-69 °C; IR (CdO) 1696 cm-1; H
NMR (200 MHz, CDCl3) δ 2.06 (m, 1H), 2.40 (m, 1H), 4.41 (m,
3H), 5.17 (d, 1H, J ) 15.9 Hz), 5.23 (d, 1H, J ) 8.9 Hz), 5.79
(m, 1H), 7.20-7.37 (m, 4H); 13C NMR (300 MHz, CDCl3) δ
27.82, 60.38, 63.89, 118.59, 128.46, 129.04, 135.82, 131.84,
140.10, 152.59 (CdO); MS (m/e) 237 [M]+. Anal. Calcd for
C
12H12ClNO2: C, 60.64; H, 5.09; N, 5.89. Found C, 60.54; H,
5.06; N, 6.04.
N-P h en yl-3-p h en yl-4-vin yl-1,3-oxa zin -2-im in e (5a ) (R )
H, R′ ) C6H5): mp ) 90-91 °C; IR (CdN) 1636 cm-1; 1H NMR
(200 MHz, CDCl3), δ 2.05 (m, 1H), 2.39 (m, 1H), 4.25 (m, 2H),
4.44 (m, 1H), 5.20 (m, 2H), 5.87 (m, 1H), 6.86-7.41 (m, 10H);
13C NMR (300 MHz, CDCl3) δ 29.03, 59.23, 63.29, 117.51,
121.05, 123.32. 125.70, 127.03, 128.18, 128.73, 137.61, 143.74,
148.12, 148.97 (CdN); MS (m/e) 277 [M - 1]+, 278 [M]+. Anal.
Calcd for C18H18N2O: C, 77.67; H, 6.52; N, 10.06. Found C,
77.40; H, 6.42; N, 10.02.
F igu r e 3. X-ray structure of 8f.
(procedures and spectral data of 1c-e are available in Sup-
porting Information).
N-(p-Ch lor op h en yl)-3-(p-ch lor op h en yl)-4-vin yl-1,3-ox-
a zin -2-im in e (5b) (R ) H, R′ ) p-ClC6H4): mp ) 99-100 °C;
1
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Cy-
cloa d d ition Rea ction of 2-Vin yloxeta n es (1a ,b) w ith
Heter ocu m u len es. A mixture of the palladium complex and
a phosphine ligand [Pd(PPh3)4 (0.02 mmol) and PPh3 (0.04
mmol), or Pd2(dba)3‚CHCl3 (0.01-0.015 mmol) and a bidentate
IR (CdN) 1630 cm-1; H NMR (200 MHz, CDCl3) δ 2.08 (m,
1H), 2.40 (m, 1H), 4.32 (m, 3H), 5.18 (m, 2H), 5.84 (m, 1H),
7.11-7.34 (m, 4H); 13C NMR (300 MHz, CDCl3) δ 28.82, 59.46,
63.47, 118.09, 124.67, 128.17, 128.67, 128.96, 137.02, 126.59,
129.21, 141.91, 146.43, 149.04 (CdN); MS (m/e) 345 [M-1]+,

4158 J . Org. Chem., Vol. 64, No. 11, 1999
Larksarp and Alper
346 [M]+. Anal. Calcd for C18H16Cl2N2O: C, 62.26; H, 4.64; N,
8.07. Found C, 62.26; H, 4.68; N, 8.03.
126.99, 128.11, 129.10, 138.53, 143.30, 153.36. (CdO); MS (m/
e) 257 [M]+. Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44; N,
5.44. Found C, 74.65; H, 7.48; N, 5.45.
Gen er a l P r oced u r e for th e Cycloa d d ition Rea ction of
Bicyclic Vin yloxeta n es (1c-e) w ith Heter ocu m u len es
Ca ta lyzed by P d 2(d ba )3‚CHCl3 a n d a Bid en ta te P h os-
p h in e. A mixture of Pd2(dba)3‚CHCl3 (0.03-0.045 mmol) and
2 equiv of a bidentate phosphine ligand in THF (5 mL) was
stirred in a glass autoclave under nitrogen at room tempera-
ture for 30 min. The bicyclic vinyloxetane 1c-e (1.0 mmol),
heterocumulene (1.0 mmol), and another 5 mL of THF were
added. The glass autoclave was sealed and then pressurized
with N2 to 5 psi. The reaction mixture was then stirred (see
Table 6 for reaction time and temperature in each case) until
the conversion of the heterocumulene was complete (monitored
by IR). The resulting solution was then concentrated by rotary
evaporation, and the residue was purified by silica gel column
chromatography using mixture of pentane/ether as the eluant.
Melting points, IR, NMR, MS, and analytical data for selected
samples of 8 and 9 are as follows (see Supporting Information
for all others 8 and 9).
3-Aza -1-oxo-N-(p-ch lor op h en yl)-9-vin ylbicyclo[4.4.0]-
d eca n -2-on e (9b) (R1 ) H, R2 ) H, X ) p-ClC6H4N, Y ) O):
1
mp ) 167-168 °C; IR (CdO) 1676 cm-1; H NMR (200 MHz,
CDCl3) δ 1.52-2.21 (m, 9H), 4.45 (d, 1H, J ) 10.8 Hz), 4.98
(dd, 1H, J ) 10.8 and 2.2 Hz), 5.74 (d, 1H, J ) 17.3 Hz), 5.86
(d, 1H, J ) 10.8 Hz), 6.35 (dd, 1H, J ) 17.3 and 10.8 Hz), 7.70
(s, 4H); 13C NMR (300 MHz, CDCl3) δ 20.71, 24.23, 25.26,
32.77, 37.49, 62.95, 68.35, 117.14, 120.83, 130.85, 131.39,
137.71, 143.07, 153.20. (CdO); MS (m/e) 291 [M]+. Anal. Calcd
for C16H18ClNO2: C, 65.86; H, 6.22; N, 4.80. Found C, 66.03;
H, 6.28; N, 4.78.
Sin gle-Cr ysta l X-r a y Diffr a ction Stu d y of 8a a n d 8f.
Suitable crystals were selected, mounted on thin glass fibers
using viscous oil, and cooled to the data collection temperature.
Data were collected on a Bruker AX SMART 1k CCD diffrac-
tometer using 0.3° ω-scans at 0, 90, and 180° in φ. Unit-cell
parameters were determined from 60 data frames collected
at different sections of the Ewald sphere. No absorption
corrections were required.
No symmetry higher than triclinic was evident from the
diffraction data. Solution in P-1 yielded chemically reasonable
and computationally stable results of refinement. The struc-
tures were solved by direct methods, completed with difference
Fourier syntheses, and refined with full-matrix least-squares
procedures based on F2. All non-hydrogen atoms were refined
with anisotropic displacement parameters. All hydrogen atoms
were treated as idealized contributions. All scattering factors
and anomalous dispersion factors are contained in the SHEX-
TL 5.1 program library (Bruker AXS, 1997, Madison, WI).
3-Aza -1-oxo-3-p h en yl-N-p h en yl-9-vin ylb icyclo[4.4.0]-
d eca n -2-im in e (8a ) (R1 ) H, R2 ) H, X ) Y ) C6H5N): mp
) 122-123 °C; IR (CdN) 1627 cm-1
;
1H NMR (200 MHz,
CDCl3) δ 1.30-2.25 (m, 9H), 4.05 (d,1H, J ) 10.6 Hz), 4.55
(dd, 1H, J ) 10.6 and 2.9 Hz), 5.43 (d, 1H, J ) 5.09 Hz), 5.50
(d, 1H, J ) 1.47 Hz), 6.03 (dd, 1H, J ) 17.5 and 10.5 Hz),
6.88-7.50 (m,10H); 13C NMR (300 MHz, CDCl3) δ 20.90, 24.45,
25.67, 33.20, 38.25, 61.76, 68.44, 116.99, 121.67, 123.66,
126.68, 128.16, 130.23, 139.93, 143.95, 149.97 (CdN); MS (m/
e) 331 [M - 1]+, 332 [M]+. Anal. Calcd for C22H24N2O: C, 79.48;
H, 7.28; N, 8.43. Found C, 79.48; H, 7.17; N, 8.37.
3-Aza -1-oxo-3-(p-ch lor op h en yl)-N-(p-ch lor op h en yl)-9-
vin ylbicyclo[4.4.0]d eca n -2-im in e (8b) (R1 ) H, R2 ) H, X
) Y ) p-ClC6H4N): mp ) 142-143 °C; IR (CdN) 1622 cm-1
;
Ack n ow led gm en t. We are grateful to the Natural
Sciences and Engineering Research Council of Canada
for support of this research. We thank Dr. Glenn P. A.
Yap for the X-ray structure determinations.
1H NMR (200 MHz, CDCl3) δ 1.31-1.90 (m, 9H), 3.95 (dd, 1H,
J ) 10.8 and 1.4 Hz), 4.48 (dd, 1H, J ) 10.8 and 2.8 Hz), 5.41
(d, 1H, J ) 13.0 Hz), 5.46 (d, 1H, J ) 6.6 Hz), 6.00 (dd, 1H, J
) 17.2 and 10.8 Hz), 6.80 (d, 2H), 7.16 (d, 2H), 7.35 (m, 4H);
13C NMR (300 MHz, CDCl3) δ 20.78, 24.43, 25.57, 33.14, 38.07,
61.65, 68.37, 117.00, 124.73, 126.20, 128.08, 131.36, 131.94,
138.80, 143.88, 147.10, 149.44. (CdN); MS (m/e) 400 [M]+.
Anal. Calcd for C22H22Cl2N2O: C, 65.84; H, 5.53; N, 6.98.
Found C, 66.05; H, 5.60; N, 6.96.
Su p p or tin g In for m a tion Ava ila ble: The procedures for
1
the preparations, spectral data, and H and 13C NMR spectra
of 1c-e; spectral data of compounds 4c-g, 5c-k , 8c-j, and
1
9c-d ; H and 13C NMR spectra of compounds 4c, 4g, 5d , 5e,
8i, 8j, 9c. Text giving full details of the X-ray structures of 8a
and 8f including the experimental procedures, tables of crystal
data, structure refinements, coordination parameters, bond
lengths, bond angles, and anisotropic displacement param-
eters. This material is available free of charge via the Internet
at http://pubs.acs.org.
3-Aza -1-oxo-N-(p h en yl)-9-vin ylb icyclo[4.4.0]d eca n -2-
on e (9a ) (R1 ) H, R2 ) H, X ) C6H5N, Y ) O): mp ) 162-
163 °C; IR (CdO) 1683 cm-1 1H NMR (200 MHz, CDCl3) δ
;
1.54-2.30 (m, 9H), 4.41 (dd, 1H, J ) 11.22 and 1.46 Hz), 4.96
(dd, 1H, J ) 10.80 and 2.2 Hz), 5.76 (m, 2H), 6.31 (dd, 1H, J
) 17.3 and 10.7 Hz), 7.61-7.73 (m, 5H); 13C NMR (300 MHz,
CDCl3) δ 20.66, 24.22, 25.25, 32.75, 37.47, 62.78, 68.22, 116.71,
J O990430B