Easy access to new heterocyclic systems: 1,4-Oxazine and substituted 1,4-oxazines

Article abstract of DOI:10.1021/jo070528n

(Chemical Equation Presented) In the course of our investigations on the synthesis of new nitrogen heterocyclic derivatives, we were interested in the synthesis and study of new 1,4-oxazine rings. To this aim, the desired bisvinylphosphate was prepared fr

Full text of DOI:10.1021/jo070528n

Easy Access to New Heterocyclic Systems:
1,4-Oxazine and Substituted 1,4-Oxazines
Elise Claveau, Isabelle Gillaizeau,* Je´rome Blu, Ame´lie Bruel, and Ge´rard Coudert*
ICOA, UMR 6005, UniVersite´ d’Orle´ans, BP 6759, 45067 Orle´ans cedex 2, France
isabelle.gillaizeau@uniV-orleans.fr; gerard.coudert@uniV-orleans.fr
ReceiVed March 14, 2007
In the course of our investigations on the synthesis of new nitrogen heterocyclic derivatives, we were
interested in the synthesis and study of new 1,4-oxazine rings. To this aim, the desired bisvinylphosphate
was prepared from N-Boc morpholine-3,5-dione and was then engaged in palladium-catalyzed reactions
(reduction, Suzuki, and Stille cross-coupling reactions). The 1,4-oxazine and its corresponding
3,5-disubstituted derivatives were obtained in fair to good yields and were then functionalized under
anionic conditions.
Introduction
Ever-growing knowledge in molecular cell biology and recent
progress in biomedical research have considerably increased the
number of known targets for therapeutic intervention. As a
result, imperative demand for making diverse small molecule
libraries available for biological screening has constituted a
powerful driving force for advanced synthetic organic chem-
istry.1 Identifying improved methods for heterocycle synthesis
and, essentially, giving access to new heterocyclic scaffolds are
of prime importance. In connection with our efforts to develop
synthetic routes to nitrogen-containing heterocyclic deriva-
tives,2,5 and particularly six-membered ones, we intended to
prepare the oxazine systems I or II (cf. Figure 1) and various
substituted derivatives of this kind (compounds III, IV, and
V). These compounds are valuable building blocks for the
synthesis of more complex derivatives. Although the importance
of benzo-fused 1,4-oxazines has been extensively documented,
principally as a result of pharmaceutical and medicinal research,3
to the best of our knowledge, there is one sole literature
precedent for the study of the original 1,4-oxazine heterocycle.4
FIGURE 1. Access to 1,4-oxazine (I) and mono-, tri-, and tetrasub-
stituted derivatives (III, IV, and V).
As part of our interest in using readily available enol phosphates
for the synthesis of new heterocyclic compounds,5,6 we wish to
report herein a full account of our investigations on 1,4-oxazine
derivatives. In previous reports,5 we have outlined the synthesis
of 2,6-disubstituted 1,4-dihydropyridines from imide derivatives
by way of Pd-catalyzed coupling reaction of the corresponding
bisvinylphosphates. In this study, we explored the possibility
of synthesizing 1,4-oxazine and its corresponding 3,5-disubsti-
tuted derivatives by the same method. We considered then
functionalizing these new scaffolds under anionic conditions
to get easy access to mono-, tri-, and tetrasubstituted 1,4-
oxazines with diversity on the side chains.
(1) (a) For diversity-oriented synthesis, see: Tan, D. S. Nat. Chem. Biol.
2005, 1, 74. (b) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed.
2004, 43, 46. (c) Schreiber, S. L. Science 2000, 287, 1964.
(2) (a) Lepifre, F.; Buon, C; Roger, P.-Y.; Bouyssou, P.; Coudert, G.
Tetrahedron Lett. 2004, 45, 8257. (b) Lepifre, F.; Clavier, S.; Bouyssou,
P.; Coudert, G. Tetrahedron 2001, 57, 6969. (c) Buon, C.; Chacun-Lefevre,
L.; Rabot, R.; Bouyssou, P.; Coudert, G. Tetrahedron 2000, 56, 605. (d)
Lepifre, F.; Buon, C.; Rabot, R.; Bouyssou, P.; Coudert, G. Tetrahedron
Lett. 1999, 40, 6373.
10.1021/jo070528n CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/17/2007
4832
J. Org. Chem. 2007, 72, 4832-4836

Easy Access to New Heterocyclic Systems
TABLE 1. Suzuki and Stille Coupling Reactions on
Bisvinylphosphate 3
SCHEME 1. Preparation of the Bisvinylphosphate 3
Results and Discussion
On the basis of our previous results,5 a synthesis of the desired
bisvinylphosphate 3 was envisaged starting from the N-Boc
morpholine-3,5-dione 2 (cf. Scheme 1). The latter was obtained
from commercially available morpholine 3,5-dione 1, otherwise
easily prepared by fusing diglycolic acid with ammonium
carbonate.7 Treatment of the N-Boc derivative 2 with KHMDS
(2.5 equiv) in the presence of HMPA (2.5 equiv) in THF at
-78 °C provided a bispotassium enolate, which was trapped
by reaction with diphenylchlorophosphate (2.2 equiv, THF, -78
°C). After workup and purification by silica gel chromatography,
the required bisvinylphosphate 3 was isolated in 64% yield.8
By using LiHMDS as a base under the same conditions,
compound 3 was isolated in 55% yield. It is noteworthy that
the use of LDA as a base for the formation of the bisenolate
(3) For a recent review on biologically active 1,4-benzoxazine derivatives,
see the following: (a) Achari, B.; Mandal, S. B.; Dutta, P. K.; Chowdhury,
C. Synlett 2004, 2449 and references therein. For some recent examples,
see also the following: (b) Rybczynski, P. J.; Zeck, R. E.; Dudash, J.;
Combs, D. W.; Burris, T. P.; Yang, M.; Osborne, M. C.; Chen, X.; Demarest,
K. T. J. Med. Chem. 2004, 47, 196. (c) Yang, W.; Wang, Y.; Ma, Z.; Golla,
R.; Stouch, T.; Seethala, R.; Johnson, S.; Zhou, R.; Gu¨ngo¨r, T.; Feyen, J.
H. M.; Dickson, J. K. Bioorg. Med. Chem. Lett. 2004, 14, 2327. (d) Thomas,
A.; Ross, R. A.; Saha, B.; Mahadevan, A.; Razdan, R. K.; Pertwee, R. G.
Eur. J. Pharmacol. 2004, 487, 213. (e) Caliendo, G.; Perissutti, E.;
Santagada, V.; Fiorino, F.; Severino, B.; Cirillo, D.; d’Emmanuele di Villa
Bianca, R.; Lippolis, L.; Pinto, A.; Sorrentino, R. Eur. J. Med. Chem. 2004,
39, 815. (f) Dougherty, K. J.; Bannatyne, B. A.; Jankowska, E.; Krutki, P.;
Maxwell, D. J. J. Neurosci. 2005, 25, 584. (g) Stefanic Anderluh, P.;
Anderluh, M.; Ilas, J.; Mravljak, J.; Sollner Dolenc, M.; Stegnar, M.; Kikelj,
D. J. Med. Chem. 2005, 48, 3110. (h) Lee, H. J.; Ban, J. Y.; Seong, Y. H.
Life Sci. 2005, 78, 294. (i) Xu, D.; Chiaroni, A.; Fleury, M.-B.; Largeron,
M. J. Org. Chem. 2006, 71, 6374.
a Reagents and conditions: 10 mol % of Pd(PPh3)4, 5 equiv of RSnBu3,
6 equiv of LiCl, THF, 2 h, reflux.10 b Reagents and conditions: (i) 10 mol
% of PdCl2(PPh3)2, THF, rt, 15 min; (ii) 5 equiv of RB(OH)2, 3 equiv of
Ba(OH)2‚8H2O, EtOH, reflux, 1 h.
(4) The sole literature precedent: Herbert, B. Arch. Pharm. 1982, 315,
684.
(5) (a) Mousset, D.; Gillaizeau, I.; Hassan, J.; Lepifre, F.; Bouyssou, P.;
Coudert, G. Tetrahedron Lett. 2005, 46, 3703. (b) Mousset, D.; Gillaizeau,
I.; Sabatie´, A.; Bouyssou, P.; Coudert, G. J. Org. Chem. 2006, 71, 5993.
(6) (a) Nicolaou, K. C.; Shi, G. Q.; Namoto, K.; Bernal, F. Chem.
Commun. 1998, 1757. (b) Nicolaou, K. C.; Shi, G. Q.; Gunzner, J. L.;
Ga¨rtner, P.; Yang, Z. J. Am. Chem. Soc. 1997, 119, 5467. (c) Huffman, M.
A.; Yasuda, N. Synlett 1999, 471. (d) Jiang, J. L.; Devita, R. J.; Doss, G.
A.; Goulet, M. T.; Wyvratt, M. J. J. Am. Chem. Soc. 1999, 121, 593. (e)
Moraes, D. N.; Barrientos-Astigarraga, R. E.; Castelani, P.; Comasseto, J.
V. Tetrahedron 2000, 56, 3327. (f) Coe, J. W. Org. Lett. 2000, 2, 4205. (g)
Wu, J.; Yang, Z. J. Org. Chem. 2001, 66, 7875. (h) Sasaki, M.; Ishikawa,
M.; Fuwa, H.; Tachibana, K. Tetrahedron 2002, 58, 1889. (i) Miller, J. A.
Tetrahedron Lett. 2002, 43, 7111. (j) Takakura, H.; Sasaki, M.; Honda, S.;
Tachibana, K. Org. Lett. 2002, 4, 2771. (k) Lo Galbo, F.; Occhiato, E. G.;
Guarna, A.; Faggi, C. J. Org. Chem. 2003, 68, 6360. (l) Liao, Y.; Hu, Y.
H.; Wu, H.; Zhu, Q.; Donovan, M.; Fathi, R.; Yang, Z. Curr. Med. Chem.
2003, 10, 2285. (m) Campbell, I. B.; Guo, J.; Jones, E.; Steel, P. G. Org.
Biomol. Chem. 2004, 2, 2725. (n) Larsen, U. S.; Martiny, L.; Begtrup, M.
Tetrahedron Lett. 2005, 46, 4261. (o) Other research in this field: Occhiato,
E.G.; Lo Galbo, F.; Guarna, A. J. Org. Chem. 2005, 70, 7324 and references
cited therein.
intermediate gave only very poor yields (10%), due to unreacted
starting material, even in the presence of HMPA.
In order to obtain symmetrical 3,5-disubstituted oxazines I,
the original bisvinylphosphate 3 was then subjected to Stille or
Suzuki coupling reactions. The Stille coupling reaction was
performed with tin reagents in the presence of catalytic Pd-
(PPh3)4 and anhydrous LiCl in refluxing THF for 2 h and
afforded the desired compounds 4a-c in fair to good yields.
The results of these coupling reactions are presented in Table
1 (entries 1-3). One of the attractive features of our approach
lies in its inherent versatility since a wide range of reactants
could be used. A Pd-catalyzed Suzuki-Miyaura coupling
reaction of the bisvinylphosphate 3 was also applied. By using
classical conditions, such as phenylboronic acid, PdCl2(PPh3)2
as a catalyst, aqueous Na2CO3 (2 M), a few drops of EtOH, in
(7) (a) Klose, J.; Reese, C. B.; Song, Q. Tetrahedron 1997, 53, 14411.
(b) Wolfe, J. F.; Rogers, T. G. J. Org. Chem. 1970, 35, 3600.
(8) The bisvinylphosphate 3 is stable for several months at 4 °C under
argon atmosphere.
J. Org. Chem, Vol. 72, No. 13, 2007 4833

Claveau et al.
TABLE 2. Preparation of Tri- and Tetrasubstituted Derivatives 6a-k and 7a-c
a Reagents and conditions: (i) 1.5 equiv of n-BuLi, THF, -78 °C, 45 min; (ii) 3 equiv of electrophile, -78 °C, 1 h. b Reagents and conditions: (i) 2
equiv of n-BuLi, THF, -78 °C, 45 min; (ii) 2 equiv of HMPA, -78 °C, 10 min; (iii) 5 equiv of electrophile, -78 °C, 3 h. c Reagents and conditions: (i)
1.5 equiv of n-BuLi, 1.2 equiv of HMPA, THF, -78 °C, 45 min; (ii) 3 equiv of electrophile, -78 °C, 1 h. d Reagents and conditions: (i) 3 equiv of
TBDMSCl, 6 equiv of imidazole, DMF, 40 °C, 20 h (91% yield); (ii) conditions described in a. e Reagents and conditions: (i) 3 equiv of TBDMSCl, 6 equiv
of imidazole, DMF, 50 °C, 14 h (78% yield); (ii) conditions described in a.
THF under reflux,5 the desired disubstituted oxazine 4d was
isolated but in 45% yield only. However, using a stronger base,
Ba(OH)2‚8H2O,9the expected bisphenyl compound 4d could be
isolated in high yield (86%). By applying these conditions in
the presence of typical aryl or heteroaryl boronic acids, the
corresponding 3,5-disubstituted oxazines 4d-g were then
isolated in good yields (cf. Table 1, entries 4-7).
The reductive cleavage of the vinyl phosphate group was also
investigated. We had previously shown that it was possible to
reduce the vinylphosphate moiety by adapting a procedure first
described by Cacchi.2b,11 Hence, treatment of bisvinylphosphate
3 with triethylammonium formate, palladium acetate, and
triphenylphosphine in THF led to the core heterocyclic system
5 in 70% yield (Scheme 2). To the best of our knowledge, so
far, there has been no description in the literature of 1,4-oxazine
5. This original derivative 5 might hopefully find some useful
application as a building block in organic and medicinal
chemistry.
In order to take advantage of these 1,4-oxazine scaffolds, we
next focused on studying their reactivity toward organometallic
reagents. On the basis of our previous results in the 1,4-
benzoxazine series,2c we investigated the functionalization of
these 1,4-oxazine derivatives by means of lithium anion species
derived from a hydrogen-metal interchange in the presence of
(9) (a) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207. (b)
Baudoin, O.; Gue´nard, D.; Gue´ritte, F. J. Org. Chem. 2000, 65, 9268.
(10) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033.
(11) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25, 4821.
4834 J. Org. Chem., Vol. 72, No. 13, 2007

Easy Access to New Heterocyclic Systems
TABLE 3. Functionalization of the 1,4-Oxazine 5a
SCHEME 2. Catalyzed Palladium Reduction of
Bisvinylphosphate 3
SCHEME 3. Wittig Reaction on Compound 6e
SCHEME 4. Sonogashira Reaction on Compound 6i
a Reagents and conditions: (i) 1.1 equiv of n-BuLi, THF, -78 °C, 5
min; (ii) 5 equiv of electrophile, -78 °C, 30 min.
alkylithium reagents. This methodology, which offers the
opportunity to easily introduce various substituents on these
compounds, should be particularly useful for the development
of libraries of biologically relevant 1,4-oxazine derivatives.
Hence, we decided first of all to introduce various substituents
at C-2 and/or C-6 on the 3,5-disubstituted 1,4-oxazines 4. The
first attempts were made on bisphenyl derivative 4d, chosen as
a model compound. The best results were obtained using n-BuLi
as a base at -78 °C for 45 min in the presence or absence of
HMPA.12 The 2-lithio derivatives were trapped by a range of
electrophiles (3-5 equiv), leading to the required trisubstituted
derivatives 6a-i in fair to good yields (cf. Table 2). Derivative
6e, bearing an aldehyde function at C-2, was successfully
submitted to a Wittig reaction (cf. Scheme 3), which provided
the conjugated diene 8 in good yield. The latter is, for instance,
a potential precursor in Diels-Alder reactions. Compounds 6a
and 6i obtained in satisfying yield are very useful compounds
in metal-catalyzed cross-coupling reactions. A Sonogashira
coupling reaction13 was also successfully realized on the iodo
compound 6i (cf. Scheme 4). Studies along this line are currently
underway in our laboratory. Interestingly, the same sequence
as above was effective with compounds 4f, disubstituted by a
benzofuranyl group, and 4c, disubstituted by a phenyl ethynyl
group, leading, respectively, to the trisubstituted derivatives 6j
and 6k in moderate yields.
As our goal was to introduce functional groups around the
1,4-oxazine ring for additional decoration, we then attempted
to introduce a fourth substituent. Following the same procedure
as above, tetrasubstituted compounds 7a-c were isolated in
moderate yields (cf. Table 2, entries 12-14). These results might
be explained by a lack of reactivity of trisubstituted derivatives.
However, it should be noted that in these cases the alcohol group
present on compounds 6c and 6k should first be protected, that
is, by a silyl group, in order to avoid side reactions.14 Moreover,
the preparation of tetrasubstituted derivatives, as a one-pot
procedure, directly from the disubstituted compounds 6 did not
increase the yields of the reaction. Similarly, nor did the use of
another base such as LDA.
Encouraged by these promising results, we turned then our
attention toward the preparation of the monosubstituted deriva-
tives 10 from the simple 1,4-oxazine ring 5 (cf. Table 3). In
fact, we expected the regioselective deprotonation of this
heterocyclic system at carbon C-3, in the R position to nitrogen
bearing an electron-withdrawing group, rather than at carbon
C-2. As a matter of fact, treatment of 1,4-oxazine 5 at -78 °C
with n-BuLi as a base afforded the 3-lithio derivative,15 which
was quenched with various electrophiles, leading to original
compounds 10a-d. For instance, 10a isolated in fair yield could
then be submitted to a palladium cross-coupling reaction and
thus offers an easy access to a range of 3-substituted oxazines.
According to the nature of the substituents previously introduced
at carbon C-3, its metalation directing potency could also be
used to set the deprotonation on carbon C-2 with a view to
finally obtaining 2,3-disubstituted oxazines. A lack of directing
effect, on the contrary, could allow deprotonation preferentially
at the C-5 carbon. Hence, introduction of new substituents at
this position led in this case to unsymmetrical 3,5-disubstituted
oxazines. Elaboration of these derivatives is further investigated
and their properties further studied.
(13) (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; Chapter
5. (b) Brandsma, L.; Vasilevsky, S. F.; Verkruijsse, H. D. Application of
Transition Metal Catalysts in Organic Synthesis; Springer-Verlag: Berlin,
Germany, 1998; Chapter 10. (c) Rossi, R.; Carpita, A.; Bellina, F. Org.
Prep. Proced. Int. 1995, 27, 127. (d) Sonogashira, K. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Pergamon: New York, 1991; Vol. 3,
Chapter 2.4.
(14) In the case of compounds 6c and 6k, only 1.5 equiv of n-BuLi
(instead of 2 equiv) was used in order to preclude the reaction of the base
directly on the 3,4,5-trimethoxyaldehyde. The obtained corresponding
alcohol is difficult to separate effectively from the desired trisubstituted
compound.
(15) The regioselective functionalization of the oxazine 5 at the C-3
position was confirmed by the following reaction. The analytical data of
compound 11 are depicted in the Experimental Section.
(12) Addition of HMPA, which stabilizes the formed anion, was in most
cases useful to improve the reaction’s yield.
J. Org. Chem, Vol. 72, No. 13, 2007 4835

Claveau et al.
was refluxed for 1 h. After cooling, the reaction mixture was filtered
through Celite and was washed with EtOAc. The organic phase
was washed with brine, dried over anhydrous MgSO4, and
concentrated. Flash chromatography (petroleum ether/EtOAc, 9:1)
afforded 4d (0.101 g, 86%) as white crystals: mp 125 °C; IR (KBr)
In conclusion, we have shown that the Suzuki and Stille
coupling reactions realized on bisvinylphosphate, derived from
N-Boc morpholine-3,5-dione, give an easy access to a new
family of heterocyclic compounds. These oxazinic derivatives
constitute ideal precursors for the elaboration of more complex
molecules likely to be of interest in medicinal chemistry. Finally,
our strategy allows access to various 1,4-oxazines with a high
level of diversity and with different functional groups that can
be used for further decoration of the scaffold. Studies are
currently in progress in our laboratory with a view to exploit
the potentiality furnished by this original heterocyclic system.
1
3088, 2977, 1718, 1653, 1306, 1122 cm-1; H NMR (CDCl3) δ
7.25-7.48 (m, 10H), 6.76 (s, 2H), 1.09 (s, 9H); 13C NMR (CDCl3)
δ 153.5 (s), 137.7 (s), 134.9 (s), 128.6 (d), 127.4 (d), 126.7 (s),
126.0 (s), 124.4 (d), 81.7 (s), 27.7 (q). HRMS (EI) m/z [M]+• calcd
for C21H21NO3: 335.1521; found 335.1534.
Preparation of the 4-(tert-Butoxycarbonyl)-[1,4]-oxazine (5).
To a solution of bisvinylphosphate 3 (3.235 g, 4.76 mmol) in DME
(20 mL), under argon, were added Pd(OAc)2 (0.009 g, 0.38 mmol)
and PPh3 (0.200 g, 0.76 mmol). The flask was evacuated and
backfilled with argon three times, and the mixture was stirred for
5 min. Then, this solution was cannulated dropwise, under argon,
into a degassed solution of formic acid (0.876 g, 19.04 mmol) and
triethylamine (2.890 g, 28.56 mmol) in DME (20 mL). The mixture
was refluxed for 40 min at 85 °C. After cooling, the reaction mixture
was filtered through Celite and was washed with EtOAc. The
organic phase was washed with brine, dried over anhydrous MgSO4,
and concentrated. Flash chromatography (petroleum ether) afforded
5 (0.611 g, 70%) as a colorless oil: IR (KBr) 2983, 1700, 1684,
Experimental Section
Only representative procedures and characterizations of the
products are described here. Full details can be found in the
Supporting Information.
Preparation of the 3,5-Bis{(phenyloxy)[bisphosphoryl]oxy}-
4-(tert-butoxycarbonyl)-[1,4]-oxazine (3). A solution of KHMDS
(1.159 g, 5.81 mmol) in THF (20 mL) was cooled to -78 °C under
argon. Subsequently, a solution of 2 (0.500 g, 2.32 mmol), distilled
diphenyl chlorophosphate (1.373 g, 5.11 mmol), and distilled
HMPA (1.041 g, 5.81 mmol) in THF (5 mL) was added dropwise
over 5 min. After 15 min at -78 °C, the reaction mixture was
diluted with Et2O (50 mL). Water (50 mL) was then added, and
the mixture was extracted with EtOAc. The organic phase was dried
over anhydrous MgSO4 and concentrated. Flash chromatography
(petroleum ether/EtOAc, 7:3 + 0.1% NEt3) afforded 3 (1.010 g,
64%) as a white solid: mp 86-87 °C; IR (KBr) 3101, 1734, 1487,
1
1653 cm-1; H NMR (CDCl3) δ 5.97 (dd, J ) 1.6 and 4.7 Hz,
1H), 5.82 (dd, J ) 1.9 and 5.3 Hz, 1H), 5.60 (d, J ) 5.0 Hz, 1H),
5.47 (d, J ) 5.0 Hz, 1H), 1.47 (s, 9H); 13C NMR (CDCl3) δ 148.2
(s), 130.3 (d), 128.9 (d), 109.3 (d), 108.7 (d), 81.6 (s), 28.4 (q).
HRMS (EI) m/z [M]+• calcd for C9H13NO3: 183.0895; found
183.0913.
General Procedure for the Preparation of the Trisubstituted
Derivatives. 4-(tert-Butoxycarbonyl)-3,5-diphenyl-2-trimethyl-
silanyl-[1,4]-oxazine (6b). A solution of 4-(tert-butoxycarbonyl)-
3,5-diphenyl-[1,4]-oxazine 4d (0.100 g, 0.30 mmol) in THF (7 mL)
was cooled to -78 °C under argon. Subsequently, n-butyllithium
(0.373 mL, 1.6 M in hexane, 0.60 mmol) was added dropwise, and
the reaction mixture was stirred for 45 min at -78 °C. Distilled
HMPA (0.107 g, 0.60 mmol) was then added. After stirring for 10
min at -78 °C, a solution of trimethylsilyl chloride (0.162 g, 1.49
mmol) in THF (1 mL), previously dried over molecular sieves (4
Å), was added dropwise. After 1 h at -78 °C, the reaction was
quenched by slow addition of water. The aqueous phase was then
extracted with EtOAc, and the organic phase was washed with brine.
The organic phase was dried over anhydrous MgSO4 and concen-
trated. Flash chromatography (petroleum ether/EtOAc, 95:5) af-
forded 6b (0.098 g, 81%) as a colorless oil: IR (NaCl) 2979, 1760,
1695, 1600, 1451, 1149 cm-1; 1H NMR (CDCl3) δ 7.16-7.39 (m,
10H), 6.74 (s, 1H), 0.99 (s, 9H), -0.10 (s, 9H); 13C NMR (CDCl3)
δ 153.1 (s), 151.8 (s), 139.4 (d), 136.9 (s), 136.5 (s), 135.0 (s),
129.5 (d), 128.5 (d), 128.0 (d), 127.5 (s), 127.1 (d), 124.1 (d), 81.3
(s), 27.9 (q), -0.9 (q). HRMS (EI) m/z [M]+• calcd for C24H29-
NO3Si: 407.19167; found 407.1928.
1
1305, 1187 cm-1; H NMR (CDCl3) δ 7.14-7.32 (m, 20H), 6.74
4
(d, JHP ) 3.1 Hz, 2H), 1.41 (s, 9H); 13C NMR (CDCl3) δ 152.8
(s), 150.4 (s), 150.3 (s), 131.9 (s), 131.8 (s), 130.5 (s), 130.4 (s),
129.9 (d), 129.7 (s), 125.8 (d), 120.2 (d), 120.1 (d), 84.3 (s), 27.9
23
(q). HRMS (TOF ES+) m/z [M + Na]+ calcd for C23H31NO11
NaP2: 702.1270; found 702.1329.
-
General Procedure (A) for Stille-Type Coupling Reactions.
(E,E)-4-(tert-Butoxycarbonyl)-3,5-diethenyl-[1,4]-oxazine (4a).
To a stirred solution of bisvinylphosphate 3 (0.150 g, 0.22 mmol)
in THF (1.7 mL), tributyl(vinyl)tin (0.350 g, 1.10 mmol) and LiCl
(0.056 g, 1.32 mmol) were added under argon. Then, the flask was
evacuated and backfilled with argon three times. Under argon, Pd-
(PPh3)4 (0.026 g, 0.02 mmol) was added, and the mixture was
refluxed for 2 h. After cooling, the reaction mixture was filtered
through Celite and was washed with EtOAc. The organic phase
was washed with brine, dried over anhydrous MgSO4, and
concentrated. Flash chromatography (petroleum ether/EtOAc, 95:
5) afforded 4a (0.026 g, 50%) as a colorless oil: IR (NaCl) 2964,
1
2370, 1700, 1260 cm-1; H NMR (CDCl3) δ 6.66 (s, 2H), 6.23
(dd, J ) 11.0 and 17.3 Hz, 2H), 5.34 (dd, J ) 1.0 and 17.0 Hz,
2H), 5.10 (dd, J ) 1.0 and 10.8 Hz, 2H), 1.44 (s, 9H). Slow
decomposition of 4a over several hours precluded satisfactory 13
C
Acknowledgment. We thank La Ligue Contre le Cancer
Comite´ du Loiret and La Fe´de´ration pour la Recherche Me´dicale
Comite´ d’Orle´ans for the financial support.
NMR and HRMS analysis.
General Procedure (B) for Suzuki-Miyaura-Type Coupling
Reactions. 4-(tert-Butoxycarbonyl)-3,5-diphenyl-[1,4]-oxazine
(4d). To a solution of bisvinylphosphate 3 (0.240 g, 0.35 mmol) in
THF (2.5 mL) under argon was added PdCl2(PPh3)2 (0.025 g, 0.04
mmol). The flask was evacuated and backfilled with argon three
times, and the mixture was stirred for 15 min. Then, phenylboronic
acid (0.215 g, 1.77 mmol), Ba(OH)2‚8H2O (0.334 g, 1.06 mmol),
H2O (0.7 mL), and few drops of EtOH were added. The mixture
Supporting Information Available: Detailed experimental
1
procedures, full characterization of new compounds, and H and
13C NMR spectra for compounds 1-10. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO070528N
4836 J. Org. Chem., Vol. 72, No. 13, 2007