Efficient, high-yield, one-pot protocol for the synthesis of 1,2,4-oxadiazine derivatives

Article abstract of DOI:10.1055/s-0029-1217326

1,2-Diaza-1,3-dienes easily react as Michael acceptors with arylamidoximes in a one-pot, high-yield heterocyclization process. Depending on the linear or cyclic structure of the ene mojety, 1,2,4-oxadiazin-5-ones or spiro cycloalkyl-1,2,4-oxadiazin-5-one

Full text of DOI:10.1055/s-0029-1217326

LETTER
1583
Efficient, High-Yield, One-Pot Protocol for the Synthesis of 1,2,4-Oxadiazine
Derivatives
S
ynthesis of 1,2,4-
r
O
xadiaz
a
ine
D
erivat
z
ives io A. Attanasi,a Livius Cotarca,b Gianfranco Favi,a Paolino Filippone,a Francesca R. Perrulli,a Stefania
Santeusanio*a
a
Istituto di Chimica Organica della Facoltà di Scienze e Tecnologie, Università degli Studi di Urbino ‘Carlo Bo’, Via I Maggetti 24,
61029 Urbino, Italy
Fax +39(0722)303441; E-mail: stefania.santeusanio@uniurb.it
ZaCh System S.p.A., Via Dovaro 2, 36045 Almisano di Lonigo (VI), Italy
b
Received 23 March 2009
Scheme 1, Table 1). In principle and according to our pre-
Abstract: 1,2-Diaza-1,3-dienes easily react as Michael acceptors
vious similar study,7 under basic conditions the amidine
function could provide different intramolecular ring clo-
sures: one at the ester function bonded at C4, the other at
the hydrazono function.
with arylamidoximes in a one-pot, high-yield heterocyclization pro-
cess. Depending on the linear or cyclic structure of the ene mojety,
1,2,4-oxadiazin-5-ones or spiro cycloalkyl-1,2,4-oxadiazin-5-one
derivatives can be directly obtained.
Key words: 1,2-diaza-1,3-dienes, arylamidoximes, nucleophilic
additions, cyclizations, spiro compounds
It was found that the treatment of 3a–j in THF with a
stoichiometric amount of NaH promoted regioselective
intramolecular cyclization at the ester function with loss
of an alcohol molecule affording 1,2,4-oxadiazin-5-one
derivatives 4a–j in moderate yields.
The development of general and simple synthetic path-
ways for the generation of new and original libraries of
heterocyclic compounds is currently one of the most im-
portant challenges in organic chemistry. A literature sur-
vey revealed that oxadiazine derivatives possess quite
interesting pharmacological properties1 and other biolog-
ical activities.2
OH
O
R3
N
N
+
R2O
N
R1
H2N
Ar
2a–c
1a–f
R2OH, r.t.
Although the use of amidoximes3 as building blocks in
1,2,4-oxadiazole synthesis from different substrates is
well documented,4 their use to produce 1,2,4-oxadiazine
derivatives is scarcely represented,5a–d especially by reac-
tion with activated a,b-unsaturated systems.5e
O
R3
N
NH
R2O
N
R1
O
Based on our experience concerning the construction of
useful heterocyclic scaffolds from 1,2-diaza-1,3-dienes,6
we wanted to approach a straightforward method for ac-
quiring the title compounds.
H2N
Ar
3a–j
83–99%
NaH
Conjugated heterodiene system enhances the electrophilic
character of the terminal carbon of 1,2-diaza-1,3-dienes
making it capable of undergoing nucleophilic attack.
Since arylamidoximes possess both a hydroxyimino and
an amino group at the same carbon atom, they appeared to
be the appropriate for the construction of oxadiazine ring.
O
N
R3
H
N
HN
N
R1
H
O
Ar
4a–j
78–89%
Initially, we investigated the reactivity between 1,2-diaza-
1,3-butadienes 1a–f and arylamidoximes 2a–c in non-
polar and polar solvents (toluene, THF, MeCN, DMF,
MeOH). In every case, the reaction was fast and proceed-
ed through a regioselective O-nucleophilic attack of the
amidoxime derivative at terminal carbon of the conjugat-
ed azo–ene system allowing to produce stable Michael
adducts 3a–j in nearly quantitative yields (83–99%;
Scheme 1
Based on these observations and with the aim of develop-
ing a one-pot protocol for these heterocyclic compounds,8
we decided to carry out the reactions between 1a–f and
2a–c, firstly in the appropriate alcohol until formation of
3a–j9 and then by adding NaH to promote the ring closure.
This tandem Michael addition–heterocyclization process,
followed by acidic workup, exclusively provided new
widely functionalized 1,2,4-oxadiazin-5-one derivatives
4a–j10 in excellent yields (78–89%; Table 1). To the best
of our knowledge, only one report exists for similar com-
SYNLETT 2009, No. 10, pp 1583–1586
x
x
.x
x
.2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217326; Art ID: D07909ST
© Georg Thieme Verlag Stuttgart · New York

1584
O. A. Attanasi et al.
LETTER
Table 1 Results of the Synthesis of Michael Adducts 3a–j and 1,2,4-Oxadiazin-5-one Derivatives 4a–j
Entry
1,2-Diaza-1,3-butadiene 1
Arylamidoxime 2
Michael adduct 3
1
R1
R2
R3
2
Ar
3
Yield (%)a
4
Yield (%)b
1
2
1a
1b
1c
1d
1e
1a
1b
1d
1e
1f
CO2Me
CO2t-Bu
4-O2NC6H4
CO2Et
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
2a
2a
2a
2b
2b
2c
2c
2c
2c
2c
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-t-BuC6H4
4-t-BuC6H4
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
92
95
90
83
97
99
83
98
93
95
4a
4b
4c
4d
4e
4f
4g
4h
4i
87
86
85
78
88
84
89
81
79
86
3
4
5
CO2Bn
CO2Me
CO2t-Bu
CO2Et
Me
Me
Me
Et
6
7
Ph
8
Ph
9
CO2Bn
CO2t-Bu
Me
Me
Ph
10
Ph
3j
4j
a Yield of pure isolated adduct.
b Yield of pure isolated product in one-pot procedure.
pounds, prepared by Santilli who used dimethyl acety-
lenedicarboxylate as activated unsaturated system.5e
O
OH
Ar
OEt
N
+
With optimized conditions in hand, a variety of cyclic
conjugated azoalkenes was used to establish the generali-
ty and efficiency of this protocol. Cycloalkenyl-1-di-
azenes 1g–j11 readily reacted with arylamidoximes 2b,c in
ethanol at room temperature to produce hydrazone deriv-
atives 3. These were not isolated but were immediately
treated with NaH to give the subsequent [4+2] hetero-
cyclization process (Scheme 2, Table 2). After evapora-
tion of the reaction solvent and subsequent acidic
workup,12 novel spirocycloalkyl-1,2,4-oxadiazin-5-one
derivatives 5a–d13 were obtained. In agreement with the
above previous results and in contrast with results with
similar reactive systems,14 internal nucleophilic attack by
means of the amidino function took place exclusively at
the ethoxycarbonyl group at C4 of cycloalkyldiazenes 1g–j.
(
)
n
N
N
H2N
R1
1g–j
n = 1, 2
2b,c
EtOH, r.t.
O
OEt
N
O
NH2
Ar
(
)
n
N
HN
R1
3
NaH
H
N
O
Ar
Table 2 Synthesis of Spiro Cycloalkenyl-1,2,4-Oxadiazine Deriva-
tives 5a–d
N
O
N
Entry Cycloalkenyl-1-diazene 1 Arylamidoxime 2 Spiro 5
( )
n
1
R1
n
2
Ar
5
Yield
(%)a
HN
5a–d
79–95%
R1
Scheme 2
11
12
13
14
1g CO2Me
1h CO2Me
1i CONHPh
1j CO2Bn
1
2
2
2
2b 4-t-BuC6H4 5a 79
2c
2c
2c
Ph
Ph
Ph
5b 95
5c 92
5d 85
diazin-5-one derivatives by coupling arylamidoximes
with 1,2-diaza-1,3-dienes as activated olefinic systems.
One of the most interesting features of the methodology
presented here is that there is no need to isolate Michael
adducts, therefore constituting a practical, high-yielding,
one-pot protocol for the formation of 1,2,4-oxadiazin-5-
one derivatives variously functionalized at C6 of the six-
membered heterocycle giving materials potentially useful
as plant hormones and herbicides.15
a Yield of pure isolated product in one-pot procedure.
In summary, we have reported an easy and efficient one-
pot synthesis of a set of widely functionalized 1,2,4-oxa-
Synlett 2009, No. 10, 1583–1586 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,2,4-Oxadiazine Derivatives
1585
(8) One-Pot Procedure for the Preparation of 1,2-Diaza-1,3-
butadiene Derivatives 4a–j
Acknowledgment
This work was supported by financial assistance from the Ministero
dell’Istruzione, dell’Università e della Ricerca (MIUR), and the
Università degli Studi di Urbino ‘Carlo Bo’.
1,2-Diazabuta-1,3-diene 1a–f (1 mmol), prepared and used
as a EE/EZ-isomer mixture,6a and arylamidoxime 2a–c (1
mmol) were dissolved in alcohol (8 mL) with magnetic
stirring, and the reaction mixture was allowed to stand at r.t.
until disappearance of the reagents and the formation of
Michael adduct 3a–j (0.33–4.0 h, monitored by SiO2 TLC).
A stoichiometric amount of NaH was added, and the crude
reaction mixture was allowed to stand at r.t. until the
complete disappearance of 3a–j was observed by TLC
analysis (0.5–8.0 h). After removal of the solvent in vacuo,
the residue was suspended in H2O, neutralized with 2 N HCl,
extracted with CH2Cl2, and the organic extracts dried. After
filtering, the organic solvent was evaporated, and the solid
residue was crystallized from the appropriate solvent.
(9) Data for Michael Adduct 3f
White powder from EtOAc–n-pentane, mp 99–100 °C
(dec.). IR (KBr): 3490, 3395, 2995, 1765, 1730, 1700, 1640,
1590, 1545 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 1.91
(s, 3 H, CH3), 3.67 (s, 6 H, 2 × OCH3), 4.98 (s, 1 H, CH),
6.29 (s, 2 H, NH2), 7.36–7.43 (m, 3 H, Ar), 7.61 (d, J = 8.0
Hz, 2 H, Ar), 10.15 (s, 1 H, NH). 13C NMR (100 MHz
DMSO-d6): d = 12.90, 51.86, 51.93, 84.33, 126.08, 128.20,
129.72, 132.07, 148.14, 152.82, 154.46, 169.25. MS: m/z
(%) = 322 [M+] (0.6), 291 (0.5), 263 (1), 249 (1), 136 (15),
115 (58), 83 (100). Anal. Calcd for C14H17N3O5: C, 54.72; H,
5.58; N, 13.67. Found: C, 54.73; H, 5.61; N, 13.62.
(10) Data for Methyl 2-[1-(5-Oxo-3-phenyl-5,6-dihydro-4H-
1,2,4-oxadiazin-6-yliden)ethyl]-1-hydrazinecarboxylate
(4f)
References and Notes
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Dickinson, K. E. J.; Hedberg, S. A.; Delaney, C. L.;
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Matthews, T. R. J. Med. Chem. 1977, 20, 134. (b) Khan,
K. M.; Rahat, S.; Choudhary, M. I.; Atta-ur-Rahman; Ghani,
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Acta 2002, 85, 559. (c) Arikan, N.; Sumengen, D.; Dulger,
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K. E.; Varella, E. A.; Nicolaides, D. N. Curr. Pharm. Des.
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(4) (a) Clapp, L. B. In Advances in Heterocyclic Chemistry,
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Tetrahedron Lett. 1999, 40, 8547. (c) Crestey, F.; Lebargi,
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Hagmann, W. K.; Hale, J. J. Tetrahedron Lett. 2007, 48,
2231. (e) Braga, A. L.; Lüdtke, D. S.; Alberto, E. E.;
Dorneller, L.; Severo Filho, W. A.; Corbellini, V. A.; Rosa,
D. M.; Schwab, R. S. Synthesis 2004, 1589. (f) Ispikoudi,
M.; Litinas, K. E.; Fylaktakidou, K. C. Heterocycles 2008,
75, 1321. (g) Hamze, A.; Hernandez, J. F.; Fulcrand, P.;
Martinez, J. J. Org: Chem. 2003, 68, 7316. (h) Zhou, T.;
Chen, Z.-C. Synth. Commun. 2002, 32, 887.
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Silicon Relat. Elem. 2007, 182, 299. (b) Srivastava, R. M.;
De Morais, L. P. F.; De Melo Souto, S. C.; Carpenter, G. B.;
De Carvalho, L. T. Tetrahedron Lett. 2006, 47, 3173.
(c) Hussein, A. Q. Heterocycles 1987, 26, 163. (d) Tabei,
K.; Kawashima, E.; Takada, T.; Kato, T. Chem. Pharm.
Bull. 1982, 30, 3987. (e) Santilli, A. A.; Scotese, A. C.
J. Heterocycl. Chem. 1979, 16, 213.
Pink powder from CH2Cl2–PE (40–60 °C), mp 148–149 °C
(dec.). IR (KBr): 3420, 3390, 3320, 2990, 1770, 1740, 1620,
1575 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 1.97 (s, 3 H,
CH3), 3.61 (s, 3 H, OCH3), 6.88 (br s, 1 H, NH), 7.52–7.63
(m, 3 H, Ar), 7.98 (d, J = 6.8 Hz, 2 H, Ar), 9.93 (br s, 1 H,
NH), 11.43 (br s, 1 H, NH). 13C NMR (100 MHz DMSO-d6):
d = 12.12, 51.81, 93.61, 127.25, 128.30, 128.85, 132.48,
152.38, 154.36, 160.94, 181.72. ESI-MS: m/z calcd for
C13H14N4O4: 290.1; found: 291 [M+1].
(11) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.;
Golobič, A.; Lillini, S.; Mantellini, F. Synlett 2006, 2735.
(12) Typical One-Pot Procedure for the Synthesis of
Spirocycloalkyl-1,2,4-oxadiazin-5-one Derivatives 5a–d
To a solution of arylamidoxime 2b,c (1 mmol) in EtOH (4
mL), 1-cycloalkenyl-1-diazene 1g–j (1 mmol), prepared as
previously reported and dissolved in EtOH (4 mL), was
added dropwise at r.t. with magnetic stirring. The reaction
mixture was allowed to stand at r.t. until the disappearance
of the reactants (0.5–6.0 h) and the formation of the pertinent
1,4-adduct 3. The crude reaction mixture was then treated
with NaH (1 equiv) until complete disappearance of the
intermediate was observed by TLC analysis (0.5–4.0 h).
After removal of the solvent in vacuo, the residue was
suspended in H2O, neutralized with 2 N HCl, extracted with
CH2Cl2, and the organic extracts dried. After filtering, the
organic solvent was evaporated and the solid residue was
crystallized from the appropriate solvent.
(6) (a) Attanasi, O. A.; De Crescentini, L.; Filippone, P.;
Mantellini, F.; Santeusanio, S. ARKIVOC 2002, (xi), 274;
and references cited therein. (b) Attanasi, O. A.;
De Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.;
Santeusanio, S. Synlett 2004, 549. (c) Attanasi, O. A.;
Carvoli, G.; Filippone, P.; Perrulli, F. R.; Santeusanio, S.;
Serri, A. M. Synlett 2004, 1643. (d) Attanasi, O. A.;
Baccolini, G.; Boga, C.; De Crescentini, L.; Filippone, P.;
Mantellini, F. J. Org. Chem. 2005, 70, 4033. (e) Attanasi,
O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Lillini,
S. P.; Mantellini, F.; Santeusanio, S. Synlett 2005, 1474.
(f) Palacios, F.; Aparicio, D.; López, Y.; de los Santos, J. M.
Tetrahedron 2005, 61, 2815. (g) Attanasi, O. A.; Abbiati,
G.; Rizzato, S.; Rossi, E.; Santeusanio, S. Tetrahedron 2007,
63, 11055. (h) Attanasi, O. A.; Davoli, P.; Favi, G.;
Filippone, P.; Forni, A.; Moscatelli, G.; Prati, F. Org. Lett.
2007, 9, 3461. (i) Attanasi, O. A.; Favi, G.; Filippone, P.;
Perrulli, F. R.; Santeusanio, S. Org. Lett. 2009, 11, 309.
(7) Attanasi, O. A.; Favi, G.; Filippone, P.; Giorgi, G.; Lillini,
S.; Mantellini, F.; Perrulli, F. R. Synlett 2006, 2731.
(13) Data for Methyl 2-{12-Oxo-9-phenyl-7-oxa-8,11-
diazaspiro[5.6]dodec-8-en-1-yliden}-1-hydrazine-
carboxylate (5b)
White powder from THF–n-pentane, mp 218–219 °C (dec.).
IR (Nujol): 3368, 3187, 1749, 1713, 1616 cm–1. 1H NMR
(400 MHz, DMSO-d6): d = 1.34–1.40 (m, 1 H, cy), 1.66–
1.99 (m, 5 H, cy), 2.19–2.27 (m, 1 H, cy), 2.90–2.94 (m, 1 H,
Synlett 2009, No. 10, 1583–1586 © Thieme Stuttgart · New York

1586
O. A. Attanasi et al.
LETTER
cy), 3.62 (s, 3 H, OCH3), 7.44–7.51 (m, 3 H, Ar), 7.65 (d,
J = 6.8 Hz, 2 H, Ar), 10.23 (s, 1 H, NH), 11.28 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 19.83, 22.97, 24.75,
31.24, 51.87, 79.43, 127.19, 128.47, 129.44, 131.03, 150.26,
153.64, 154.41, 167.10. ESI-MS: m/z calcd for C16H18N4O4:
330.1; found: 331 [M + 1].
(14) Attanasi, O. A.; Berretta, S.; De Crescentini, L.; Favi, G.;
Filippone, P.; Giorgi, G.; Lillini, S.; Mantellini, F.
Tetrahedron Lett. 2007, 48, 2449.
(15) Farge, D.; Leboul, J.; Goff, Y.; Poiget, G. DE 2640464,
1977.
Synlett 2009, No. 10, 1583–1586 © Thieme Stuttgart · New York

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