An efficient approach to original substituted 2-arylidene-2H-[1,4]-oxazin- 3(4H)-ones via a tandem intramolecular P(O→C) migration/Horner-Wadsworth- Emmons olefination sequence

Article abstract of DOI:10.1055/s-0028-1087665

A useful tool for the synthesis of 2-arylidene-2H-[1,4]-oxazin-3(4H)-one derivatives is described. Starting from bisvinylphosphate intermediate, the key step is an intramolecular P(O→C) migration combined with a Horner-Wadsworth-Emmons olefination as a on

Full text of DOI:10.1055/s-0028-1087665

LETTER
263
An Efficient Approach to Original Substituted 2-Arylidene-2H-[1,4]-oxazin-
3(4H)-ones via a Tandem Intramolecular P(O→C) Migration/Horner–
Wadsworth–Emmons Olefination Sequence
Synthesis of
A
ry
l
lidene
i
-2
H
-[1
s
,4]-oxazin
e
-3(4
H
)-ones Claveau, Isabelle Gillaizeau,* Gérard Coudert*
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans, Rue de Chartres, B.P. 6759, 45067 Orléans, Cedex
2, France
Fax +33(2)38417281; E-mail: isabelle.gillaizeau@univ-orleans.fr; E-mail: gerard.coudert@univ-orleans.fr
Received 23 September 2008
Ar
Ar
Ar
Abstract: A useful tool for the synthesis of 2-arylidene-2H-[1,4]-
oxazin-3(4H)-one derivatives is described. Starting from bisvi-
nylphosphate intermediate, the key step is an intramolecular
P(O→C) migration combined with a Horner–Wadsworth–Emmons
olefination as a one-pot procedure.
O
O
N
P
O
R
N
P
I
O
N
P
II
O
III
Key words: vinylphosphate, Horner–Wadsworth–Emmons olefi-
nation, 1,3-phosphorus migration, oxazine, arylidene
Figure 1
been generated and diastereoselective variant has been
unveiled.7 This elegant rearrangement has given access to
phosphono ketones that had been inaccessible or difficult
to obtain by classical methods until then. Taking into ac-
count this result, we postulated that functionalized 2-
arylidene-2H-[1,4]-oxazin-3(4H)-one derivatives I could
be obtained via an intramolecular P(O→C) migration af-
ter basic treatment of the bisvinylphosphate 2 combined
The versatility and synthetic utility of the enol phosphate
function in organic synthesis have been largely demon-
strated in the recent literature.1 During the course of our
studies directed toward the synthesis of new nitrogen con-
taining derivatives, we intended to prepare 2-arylidene-
2H-[1,4]-oxazin-3(4H)-ones derivatives I (Figure 1).
While benzofused derivatives like 2-arylidene-2H-[1,4]-
benzoxazin-3(4H)-ones II2 or also arylidene-1,3-dihy-
droindol-2-ones III3 have been largely studied because of
their biological activities on the central nervous system or
their efficiency as kinase inhibitors, there has been, to the
best of our knowledge, no report on the synthesis of 2-
arylidene-2H-[1,4]-oxazin-3(4H)-one derivatives I. In ad-
dition, in recent years the synthesis of a-methylene-g-lac-
tams, isosteric analogues of the naturally occurring a-
methylene-g-lactones, has received considerable attention
as a consequence of the proven biological properties of
this motif.4 By using our previously described methodol-
ogy based on palladium-catalyzed cross-coupling reac-
tions of vinyl phosphate intermediates,5 we want to report
herein an efficient access to a variety of substituted 2-
arylidene-2H-[1,4]-oxazin-3(4H)-one derivatives I. The
latter might be not only of potential interest in terms of bi-
ological activity and of synthesis but also it would allow
access to new heterocyclic scaffolds.
successively with
a
Horner–Wadsworth–Emmons
olefination8 and a palladium cross-coupling reaction on
the remaining enol phosphate function.
In order to demonstrate the feasibility of this strategy and
to get the best yields, different approaches were tested.
First of all, we tried to isolate the intermediary phospho-
nate 3 before performing the Horner–Wadsworth–
Emmons olefination. To this aim and as previously report-
ed,5c treatment of the N-Boc derivative 1 with KHMDS
(2.5 equiv) in the presence of HMPA (2.5 equiv) in THF
at –78 °C provided a bispotassium enolate which was im-
mediately trapped by reaction with diphenylchlorophos-
phate (2.2 equiv, THF, –78 °C, 15 min). Without
isolation, this mixture was exposed to additional KHMDS
(1 equiv). After stirring for one hour at –78 °C, the bis-
vinylphosphate 2 rearranged through an intramolecular
migration of the diphenyl phosphoryl group from oxygen
to the a-carbon to provide the required a-phosphonolac-
tam 3.9 After purification by silica gel chromatography,
the a-phosphonolactam 310 was isolated in only 20% yield
together with 9% of the parent bisvinylphosphate 2. Even
if the conversion of vinylphosphate 2 into a-phosphono-
lactam 3 corresponds to a balanced reaction, a very clean
rearrangement was observed based upon the TLC control
of the mixture. So the low yield may be attributed to the
instability of the a-phosphonolactam 3.
A few years ago, Wiemer et al.6 demonstrated that enol
phosphates derived from five- and six-membered rings
undergo a 1,3-phosphorus migration to afford b-keto-
phosphonates upon deprotonation with LDA. Since
Wiemer’s initial report, the scope of this rearrangement
has been expanded to include cyclic enones, esters, lac-
tones, and lactams, some mechanistic information has
As this step suffers from problem of reproducibility, alter-
native bases were studied. No improvement was observed
when LiHMDS [(Scheme 1, (iii) conditions] was used as
SYNLETT 2009, No. 2, pp 0263–0267
Advanced online publication: 15.01.2009
DOI: 10.1055/s-0028-1087665; Art ID: D33908ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

264
E. Claveau et al.
LETTER
O
P
PhO
PhO
O
O
N
O
N
O
P
O
P
O
P
i
PhO
PhO
OPh
OPh
OPh
OPh
O
N
O
O
O
O
O
ii or iii or iv
Boc
Boc
Boc
1
2
3
Scheme 1 Reagents and conditions: (i) KHMDS (2.5 equiv), HMPA (2.5 equiv), THF, ClP(O)(OPh)2 (2.2 equiv), –78 °C, 15 min; (ii)
KHMDS (1 equiv), THF, –78 °C, 1 h, 3 (20% via not isolated 2), or (iii) LiHMDS (1 equiv), 3 (17% via not isolated 2), or (iv) n-BuLi (1 equiv),
3 (32% via isolated 2).
MeO
MeO
OMe
ii
O
N
i
iii
O
P
2
1
3
16% overall yield
OPh
OPh
O
O
Boc
4a
Scheme 2 Reagents and conditions: (i) KHMDS (2.5 equiv), HMPA (2.5 equiv), THF, ClP(O)(OPh)2 (2.2 equiv), –78 °C, 15 min (2 not iso-
lated); (ii) KHMDS (1 equiv), THF, –78 °C, 1 h (3 not isolated); (iii) 3,4,5-trimethoxybenzaldehyde (2 equiv), 1 h, 0 °C (16% overall yield).
a base even when changing the sequence of reagent addi- use of this intermediate in the Horner–Wadsworth–
tions, and varying the temperature for enolate formation. Emmons reaction was validated by addition of various al-
More encouraging results were obtained by using n-butyl- dehydes to the crude mixture to give the exo-alkylidene or
lithium [Scheme 1, (iv) conditions]. In this case, the 1,3- -arylidene derivatives 4a–e13 which were isolated, albeit
phosphorus migration reaction was tested directly from in fair or modest yields (Table 1). The slight instability of
the worked up bisvinylphosphate 2, obtained in 64% yield the alkylidene derivatives 4d and 4e could explain why
the from N-Boc morpholine-3,5-dione 1.11 The desired a- the yields were so moderate in this case (Table 1, entries
phosphonolactam 3 was then isolated in just 32% yield as 4 and 5). Unfortunately, no improvement was observed by
the only product.
performing the Horner–Wadsworth–Emmons olefination
as a separate step on the isolated a-phosphonolactam 3. In
fact, arylidenes 4 were thus obtained with comparable
yields. Accordingly, it appears that this is the limiting
step. In addition to the convenient tandem 1,3-phosphorus
migration–Horner–Wadsworth–Emmons olefination se-
quence, one of the attractive features of our approach lies
in its inherent versatility since a wide range of aldehydes
could be used. The remaining enol phosphate function
could eventually be subjected to various reactions.
To circumvent this problem and to improve the general
yield, we attempted to perform the Horner–Wadsworth–
Emmons olefination as a one-pot procedure without iso-
lating the intermediary phosphonate 3 (Scheme 2). Start-
ing from N-Boc morpholine-3,5-dione 1 and using
KHMDS as a base, after a complete conversion of the
vinylphosphate 2 into a-phosphonolactam 3 (TLC con-
trol), 3,4,5-trimethoxybenzaldehyde (2 equiv) was then
added at –78 °C to induce the Horner–Wadsworth–
Emmons olefination. The mixture was quickly warmed to In order to achieve our synthetic route to 2-arylidene-2H-
0 °C (1 h) and the desired exoarylidene derivative 4a was [1,4]-oxazin-3(4H)-one derivatives I, palladium-cata-
isolated as a single stereoisomer.12a The small coupling lyzed reactions were then investigated on enol phosphates
constant (J < 5 Hz) observed between the exocyclic vinyl 4. The Stille coupling reaction14 was performed with var-
proton and the carbon of the carbonyl (3JC–H = 3,5 Hz) ious tin reagents in the presence of catalytic Pd(PPh3)4 and
confirmed the (Z)-geometry of the introduced double anhydrous LiCl in refluxing THF. The desired original
bond.12 Unfortunately, this one-pot procedure was charac- compounds 5a–c15 were isolated in modest yields
terized by a low yield (16%).
(Table 2, entries 1–4). In addition, treatment of enol phos-
phate 4b with triethylammonium formate, palladium ace-
tate and triphenylphosphine5c in THF gave the basic
heterocyclic system 5e isolated in fair yield (48% yield,
Table 2, entry 5). It is noteworthy that by submitting vi-
nylphosphate 4 to classical basic Suzuki coupling condi-
tions [PhB(OH)2,PdCl2(PPh3)2, Na2CO3 2 M, THF], a
degradation reaction was observed.
To achieve the intramolecular P(O→C) migration and the
Horner–Wadsworth–Emmons olefination as a one-pot
procedure, we next examined the protocol using n-BuLi
as a base (Table 1). In this case, we started directly from
the isolated bisvinylphosphate 2, prepared as reported
above. Treatment of 2 with n-BuLi (1.2 equiv) at –78 °C
in THF for 10 minutes led to the formation of a-
phosphonolactam 3 via an 1,3-phosphorus migration. The
Synlett 2009, No. 2, 263–267 © Thieme Stuttgart · New York

LETTER
Synthesis of Arylidene-2H-[1,4]-oxazin-3(4H)-ones
265
Table 1 Rearrangement into a-Phosphonolactam 3 Combined with Horner–Wadsworth–Emmons Olefinations
O
P
Ar
Li+
–
PhO
PhO
O
O
O
n-BuLi
ArCHO (5 equiv)
0 °C, 2 h
O
P
O
O
O
(1,2 equiv)
OPh
OPh
PhO
PhO
OPh
OPh
OPh
OPh
P
P
P
O
N
O
O
N
O
THF, –78 °C
10 min
O
N
O
Boc
Boc
Boc
4
3
2
Entry
Aldehydes
Products 4
Yield (%)a
MeO
OMe
MeO
MeO
CHO
MeO
1
4a 42
O
N
O
OPh
OPh
OMe
P
O
O
Boc
CHO
2
3
4b 56
O
N
O
P
OPh
O
O
O
OPh
Boc
O
CHO
O
4c 35
O
P
OPh
OPh
O
O
N
O
Boc
O
4
5
MeCHO
4d 22
4e 36
OPh
OPh
P
O
N
O
Boc
O
N
O
MeCH2CHO
OPh
P
O
O
OPh
Boc
a Yields are calculated for the two-step reaction starting with bisvinylphosphate 2.
Because of their potential biological activity, the selected ing that the presence of different functional groups in
2-arylidene-2H-[1,4]-oxazin-3(4H)-one derivatives 5a–e many positions of these heterocycles makes such com-
were then tested on a variety of highly purified kinases pounds useful for further structural modifications and
(CK1, CDK5/p25, GSK-3a/b, DYRK1A)16,17 (Table 3). suitable as intermediates for more complex polycyclic
In the CDK inhibitors family, the most advanced mole- structures (via Diels–Alder cycloaddition for instance).
cule is the purine analogue [R-roscovitine (CYC-202)].18 Experiments designed to explore the potentiality offered
Unfortunately, in all cases the kinases tested were poorly by this original heterocyclic system are in progress and
or not inhibited (IC50 >10 mm).
will be described in due course.
To sum up, we have developed a new and easy method
that provides a useful tool for the synthesis of 2-arylidene-
2H-[1,4]-oxazin-3(4H)-one derivatives via an efficient
tandem 1,3-phosphorus migration/Horner–Wadsworth–
Emmons olefination sequence. In addition, it is worth not-
Acknowledgement
This research was supported by La Ligue Contre le Cancer (comité
du Loiret) and la FRM section Orléans. The authors thank Laurent
Synlett 2009, No. 2, 263–267 © Thieme Stuttgart · New York

266
E. Claveau et al.
LETTER
Table 3 Kinase Inhibition Values (IC50 in mm) for Compounds 5a–e
Table 2 Preparation of Functionalized 2-Arylidene-2H-[1,4]-ox-
azin-3(4H)-one 5a–e via Palladium-Catalyzed Reaction
Compounds
5a–e
CK1
>10
CDK5/p25
>10
GSK-3a/b DYRK1A
Ar
Ar
O
O
>10
130
>10
3.1
O
Pd(0)
OPh
OPh
P
(R)-roscovitine
0.45
0.16
Stille
or reduction
O
N
O
O
N
R
Boc
4
Boc
5
Meijer and Olivier Lozach (Cell Cycle Group UMR 7150 &
UPS2682 Roscoff, France) for the biological tests on kinases.
Entry Enol phos- Product
Yield (%)
phate 4
References and Notes
MeO
MeO
OMe
(1) (a) Lichtenthaler, F. W. Chem. Rev. 1961, 61, 607.
(b) Ebran, J.-P.; Hansen, A. L.; Gøgsig, T. M.; Skrydstrup,
T. J. Am. Chem. Soc. 2007, 129, 6931. (c) Sasaki, M.;
Fuwa, H.; Ebine, M. Org. Lett. 2008, 10, 2275.
O
1a
4a
5a 59
(d) Dugovic, B.; Reissig, H.-U. Synlett 2008, 769.
(2) (a) Gezginci, H.; Salman, S.; Okyar, A.; Baktir, G. Farmaco
1997, 52, 255. (b) Croce, P. D.; Ferraccioli, R.; La Rosa, C.
Heterocycles 1995, 40, 349. (c) Turk, C. F.; Krapcho, J.;
Michel, I. M.; Weinryb, I. J. Med. Chem. 1977, 20, 729.
(3) (a) Yu, H.; Wang, Z.; Zhang, L.; Zhang, J.; Huang, Q.
Bioorg. Med. Chem. Lett. 2007, 17, 2126. (b) Sun, L.; Tran,
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R.; Zhou, Y.; Waltz, K.; McMahon, G.; Tang, C. J. Med.
Chem. 2000, 43, 2655. (c) Stopeck, A.; Sheldon, M.;
Vahedian, M.; Cropp, G.; Gosalia, R.; Hannah, A. Clin.
Cancer Res. 2002, 8, 2798. (d) Andreani, A.; Burnelli, S.;
Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.;
Rambaldi, M.; Varoli, L.; Landi, L.; Prata, C.; Berridge,
M. V.; Grasso, C.; Fiebig, H.-H.; Kelter, G.; Burger, A. M.;
Kunkel, M. W. J. Med. Chem. 2008, 51, 4563.
O
N
O
Boc
O
O
2a
4b
5b 27
O
N
O
Boc
O
(4) (a) Belaud, C.; Roussakis, C.; Letourneux, Y.; Alami, N.;
Villiéras, J. Synth. Commun. 1985, 15, 1233. (b) Kornet,
M. J. J. Pharm. Sci. 1979, 68, 350. (c) Ikuta, H.; Shirota, S.;
Kobayashi, Y.; Yamagishi, K.; Yamada, K.; Yamatsu, I.;
Katayama, K. J. Med. Chem. 1987, 30, 1995. (d) Kim, S.
Y.; Lee, J. Bioorg. Med. Chem. 2004, 12, 2639. (e) Janecki,
T.; Błaszczyk, E.; Studzian, K.; Janecka, A.; Krajewska, U.;
Różalski, M. J. Med. Chem. 2005, 48, 3516. (f) Krawczyk,
H.; Albrecht, L.; Wojciechowski, J.; Wolf, W. M.;
Krajewska, U.; Różalski, M. Tetrahedron 2008, 64, 6307.
(5) (a) Mousset, D.; Gillaizeau, I.; Sabatié, A.; Bouyssou, P.;
Coudert, G. J. Org. Chem. 2006, 71, 5993. (b) Mousset, D.;
Gillaizeau, I.; Hassan, J.; Lepifre, F.; Bouyssou, P.; Coudert,
G. Tetrahedron Lett. 2005, 46, 3703. (c) Claveau, E.;
Gillaizeau, I.; Blu, J.; Bruel, A.; Coudert, G. J. Org. Chem.
2007, 72, 4832. (d) Cottineau, B.; Gillaizeau, I.; Farard, J.;
Auclair, M.-L.; Coudert, G. Synlett 2007, 1925.
3a
4a
5b
4b
4c
4b
5c 21
5d 39
5e 48
O
O
N
Ph
Boc
O
O
O
N
O
Boc
O
(e) Chaignaud, M.; Gillaizeau, I.; Ouhamou, N.; Coudert, G.
Tetrahedron 2008, 64, 805.
(6) (a) Hammond, G. B.; Calogeropoulou, T.; Wiemer, D. F.
Tetrahedron Lett. 1986, 27, 4265. (b) Calogeropoulou, T.;
Hammond, G. B.; Wiemer, D. F. J. Org. Chem. 1987, 52,
4185.
(7) Du, Y.; Wiemer, D. F. J. Org. Chem. 2002, 67, 5709; and
references cited therein.
(8) Baker, T. J.; Wiemer, D. F. J. Org. Chem. 1998, 63, 2613.
(9) a-Phosphonolactams analogous to 3 (Scheme 1) have been
prepared previously, in a number of different ways, and used
O
O
N
Boc
a Conditions: Pd(PPh3)4 (10 mol%), RSnBu3 (2.5 equiv), LiCl (3
equiv), THF, 2–3 h, reflux.
b Conditions: HCOOH (4 equiv), Et3N (6 equiv), Pd(OAc)2 (0.08
equiv), Ph3P (0.16 equiv), DME, reflux, 30 min.
Synlett 2009, No. 2, 263–267 © Thieme Stuttgart · New York

LETTER
in olefination processes. For recent representative examples,
Synthesis of Arylidene-2H-[1,4]-oxazin-3(4H)-ones
267
MgSO4, and concentrated. Flash chromatog-raphy (PE–
see: (a) Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem.
2003, 3798. (b) Gois, P. M. P.; Afonso, C. A. M.
Tetrahedron Lett. 2003, 44, 6571. (c) Bower, J. F.; Svenda,
J.; Williams, A. J.; Charmant, J. P. H.; Lawrence, R. M.;
Szeto, P.; Gallagher, T. Org. Lett. 2004, 6, 4727. (d) Sudau,
A.; Münch, W.; Bats, J.-W.; Nubbemeyer, U. Eur. J. Org.
Chem. 2002, 3315.
EtOAc, 8:2) afforded 4a (0.193 g, 42%) as a yellow oil. IR
(NaCl): 2926, 1693, 1446, 1240, 1043 cm–1. 1H NMR (250
MHz, CDCl3): d = 7.20–7.41 (m, 20 H), 6.90 (s, 2 H), 6.71
(d, 4JHP = 3.3 Hz, 1 H), 6.66 (s, 1 H), 3.87 (s, 3 H), 3.85 (s, 6
H), 1.50 (s, 9 H). 13C NMR (62.5 MHz, CDCl3): d = 156.2(s),
152.6 (s), 150.1 (s, JC,P = 7.4 Hz), 146.7 (s), 139.1 (s), 138.7
(s), 130.4 (s, JC,P = 7.6 Hz), 130.1(d), 127.1(s), 126.1(d),
124.5 (d), 121.4 (d, JC,P = 4.9 Hz), 120.0 (d, JC,P = 4.9 Hz),
108.0(d), 86.2 (s), 60.9 (q), 56.1 (q), 27.6(q). MS (IS): m/
z = 626.5 [M + H]+, 648.5 [M + Na]+.
(10) The 1,3-phosphorus migration reaction was easily followed
by TLC.
Synthesis of 4-(tert-Butoxycarbonyl)-2-(diphenoxy-
phosphoryl)-5-(diphenoxyphosphoryloxy)-3-oxo-2,3-
dihydro-4H-[1,4]-oxazine (3)
(14) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033.
(15) General Procedure for Stille-Type Coupling Reactions –
Synthesis of (2Z)-4-(tert-Butoxycarbonyl)-2-(3,4,5-
trimethoxybenzylidene)-5-{benzo[b][1,4]dioxin-2-yl}-
2,3-dihydro-3-oxo-[1,4]-oxazine (5a)
A solution of KHMDS (13.94 mL, 0.5 M in toluene, 6.97
mmol) in THF (20 mL) was cooled to –78 °C under argon.
Subsequently, a solution of 1 (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 (15 mL) was
added dropwise over 5 min. After 15 min at –78 °C,
KHMDS was added (4.65 mL, 2.32 mmol). After an
additional hour at –78 °C, the reaction mixture was diluted
with Et2O (85 mL). Water (125 mL) was then added, and the
mixture was extracted with EtOAc. The organic phase was
washed with brine, dried over anhyd MgSO4, and
concentrated. Flash chromatography (PE–EtOAc, 7:3)
afforded 3 (0.315 g, 20%) as a pale yellow oil; Rf = 0.56
(PE–EtOAc, 6:4). IR (NaCl): 3068, 2988, 2930, 1790, 1489,
1206 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.07–7.26 (m,
20 H), 6.65 (d, 4JHP = 2.8 Hz, 1 H), 4.92 (d, 2JHP = 16.0 Hz,
1 H), 1.42 (s, 9 H). 13C NMR (62.5 MHz, CDCl3): d = 160.1
(s, JC,P = 4.5 Hz), 150.5 (s, JC,P = 7.5 Hz), 150.4 (s, JC,P = 6.5
Hz), 150.3 (s, JC,P = 7.6 Hz), 150.0 (s, JC,P = 9.6 Hz), 146.3
(s), 132.5 (s, JC,P = 8.9 Hz), 130.4 (d), 130.3 (d), 126.4 (d),
126.2(d), 122.9 (d, JC,P = 5.1 Hz), 121.1 (d), 121.0(d), 120.4
(d, JC,P = 2.1 Hz), 120.3 (d, JC,P = 2.1 Hz), 87.0(s), 74.8 (d,
JC,P = 160.1 Hz), 28.0(q). MS (IS): m/z = 680.5 [M + H]+,
702.0 [M + Na]+.
To a stirred solution of enol phosphate 4a (0.517 g, 0.83
mmol) in THF (16 mL), {benzo[b][1,4]dioxin-2-yl}tributyl-
stannane (0.874 g, 2.07 mmol) and LiCl (0.105 g, 2.48
mmol) were added under argon. Then, the flask was
evacuated and backfilled with argon three times. Under
argon, Pd(PPh3)4 (0.096 g, 0.08 mmol) was added, and the
mixture was heated at reflux during 150 min. After cooling,
the reaction mixture was diluted with EtOAc. The organic
phase was washed with brine, dried over anhyd MgSO4, and
concentrated. Flash chromatography (PE–EtOAc, 9:1 then
8:2) afforded 5a (0.247 g, 59%) as a yellow solid; mp 151–
152 °C. IR (NaCl): 2978, 2942, 2836, 1759, 1702, 1493,
1246 cm–1. 1H NMR (250 MHz, CDCl3) d = 6.95 (s, 1 H),
6.89 (s, 1 H), 6.83–6.87 (m, 2 H), 6.63–6.70 (m, 3 H), 6.20
(s, 1 H), 3.88 (s, 3 H), 3.87 (s, 6 H), 1.55 (s, 9 H). 13C NMR
(62.5 MHz, CDCl3): d = 156.1(s), 153.1(s), 148.0(s), 141.7
(s), 141.6(s), 140.2 (s), 139.1(s), 130.0(s), 128.5 (s),
128.0(d), 125.2 (d), 124.6 (d), 124.5 (d), 116.4 (d), 115.6 (d),
113.3 (s), 107.8 (d), 85.8 (s), 61.0(q), 56.2(q), 27.8 (q). ESI-
HRMS: m/z calcd for C27H27NO923Na [M +Na]+: 532.15835;
found: 532.1582.
(11) As previously reported, the synthesis of bisvinylphosphate 2
Compound 5b: yellow solid; mp 140–141 °C. HRMS (EI):
m/z calcd for C19H13NO4 [M – C4H8 – CO2]+: 319.08446;
found: 319.0838.
from N-Boc morpholine-3,5-dione 1 was optimal by using
KHMDS as a base (cf. ref. 5c
)
(12) (a) Yu, J. S.; Wiemer, D. F. J. Org. Chem. 2007, 72, 6263.
(b) Vögeli, U.; Von Philipsborn, W.; Nagarajan, K.; Nair,
M. D. Helv. Chim. Acta 1978, 61, 607. (c) Cabiddu, S.;
Floris, C.; Melis, S.; Sotgiu, F.; Cerioni, G. J. Heterocycl.
Chem. 1986, 23, 1815.
(13) General Procedure for the Wiemer Rearrangement
Followed by the Horner–Wadsworth–Emmons Reaction
– Synthesis of (6Z)-4-(tert-Butoxycarbonyl)-6-(3,4,5-
trimethoxybenzylidene)-5,6-dihydro-5-oxo-4H-[1,4]-
oxazin-3-yl Diphenyl Phosphate (4a)
Compound 5c: yellow oil. HRMS (EI): m/z calcd for
C17H11NO5 [M – C4H8 – CO2]+: 309.06372; found:
309.0642.
Compound 5d: yellow oil. HRMS (EI): m/z calcd for
C19H13NO2 [M – C4H8 – CO2]+: 287.09463; found:
287.0969.
Compound 5e: yellow oil. HRMS (EI): m/z calcd for
C16H17NO4 [M]+: 287.11576; found: 287.1166.
(16) Minireview: Soos, T. J.; Meijer, L.; Nelson, P. J. Drug News
Perspect. 2006, 19, 325.
A solution of the bisvinylphosphate 25c (0.500 g, 0.74 mmol)
in THF (7.5 mL) was cooled to –78 °C under argon.
Subsequently, n-BuLi (0.552 mL, 1.6 M in hexane, 0.88
mmol) was added dropwise, and the reaction mixture was
stirred for 10 min at –78 °C. A solution of 3,4,5-trimethoxy-
benzaldehyde (0.722 g, 3.68 mmol) in THF (2 mL),
previously dried over MS 4 Å, was then added dropwise.
After 15 min at –78 °C and 150 min at 0 °C, the reaction
mixture was diluted with Et2O (10 mL). Water (10 mL) was
then added, and the mixture was extracted with EtOAc. The
organic phase was washed with brine, dried over anhyd
(17) Kinase activities assay were performed as reported in ref. 15
and 17
.
(18) (a) Bach, S.; Knockaert, M.; Reinhardt, J.; Lozach, O.;
Schmitt, S.; Baratte, B. J. Biol. Chem. 2005, 280, 31208.
(b) Bettayeb, K.; Tirado, O. M.; Marionneau-Lambert, S.;
Ferandin, Y.; Lozach, O.; Morris, J. C.; Mateo-Lozano, S.;
Drueckes, P.; Schächtele, C.; Kubbutat, M.; Liger, F.;
Marquet, B.; Joseph, B.; Echalier, A.; Endicott, J.; Notario,
V.; Meijer, L. Cancer Res. 2007, 67, 8325. (c) Reinhardt,
J.; Ferandin, Y.; Meijer, L. Protein Expr. Purif. 2007, 54,
101.
Synlett 2009, No. 2, 263–267 © Thieme Stuttgart · New York

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