Synthesis and reactions of 3-halomethyl-substituted oxazine N-oxides

Article abstract of DOI:10.1016/j.tetlet.2009.12.066

A series of 3-halomethyl-5,6-dihydro-1,2-oxazine N-oxides (halogen = Cl, Br, I) is prepared from 4-phenyl-3,6,6-trimethyl-5,6-dihydro-4H-oxazine N-oxide by means of a silylation/halogenation sequence. The obtained halogenated N-oxides undergo reactions typical of cyclic six-membered nitronates including 1,3-dipolar cycloaddition, addition of nucleophiles, and substitution of the halogen by C-, S-, and N-nucleophiles.

Full text of DOI:10.1016/j.tetlet.2009.12.066

Tetrahedron Letters 51 (2010) 1038–1040
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and reactions of 3-halomethyl-substituted oxazine N-oxides
a
a
Andrey A. Mikhaylov a,b, Alexander D. Dilman a, , Roman A. Kunetsky , Yulia A. Khomutova ,
*
Marina I. Struchkova a, Alexander A. Korlyukov c, Sema L. Ioffe a, , Vladimir A. Tartakovsky
a
*
a N. D. Zelinsky Institute of Organic Chemistry, Leninsky prosp. 47, 119991 Moscow, Russian Federation
b Higher Chemical College of the Russian Academy of Sciences, Miusskaya sq. 9, 125047 Moscow, Russian Federation
c A. N. Nesmeyanov Institute of Organoelement Compounds, 119991 Vavilova str. 28, Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-halomethyl-5,6-dihydro-1,2-oxazine N-oxides (halogen = Cl, Br, I) is prepared from 4-phe-
nyl-3,6,6-trimethyl-5,6-dihydro-4H-oxazine N-oxide by means of a silylation/halogenation sequence.
The obtained halogenated N-oxides undergo reactions typical of cyclic six-membered nitronates includ-
ing 1,3-dipolar cycloaddition, addition of nucleophiles, and substitution of the halogen by C-, S-, and N-
nucleophiles.
Received 10 November 2009
Revised 3 December 2009
Accepted 11 December 2009
Available online 21 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Nitronates
5,6-dihydro-1,2-Oxazine-N-oxides
Halogenation
R
O
R
O
R
O
X
R
O
Nitronates A constitute an interesting class of nitro derivatives,
and in recent years there has been a significant development of the
chemistry of these compounds1 (Scheme 1). Alkyl nitronates (A,
Y = Alk) undergo various transformations such as dipolar cycload-
dition,1,2 nucleophilic addition,3 reduction,4 and silylation reac-
tions,5 while silyl nitronates (A, Y = SiR3) have been employed in
a number of catalytic asymmetric processes.6 It was demonstrated
that cyclic alkyl nitronates can serve as key intermediates in the
synthesis of natural products,1c,2 medicinal substances,7 and vari-
ous functionalized molecules.8
X
X
Y
N
N
N
TMS
TMS
O
O
O
A
A1
A2
X
X = Hal
N
N
O
O
O
A3
A4
Despite significant advances in the field of nitro group deriva-
tives, nitronates bearing a halogen atom have remained virtually
unexplored. Recently, we demonstrated that halo-substituted silyl
nitronates A1 exhibit specific properties, allowing for their applica-
tion in the synthesis of cyclic five-membered nitronates.9 Nitro-
nates A2 were proposed as short-lived intermediates in the
oxidative transformation of nitro alkanes into conjugated nitro al-
kenes, and their instability is associated with facile elimination of
halosilane (TMS-X).10 As for cyclic nitronates, compounds A3 are
known,11 while nitronates A4 have not been described.
Scheme 1.
silyl triflate afforded N-(silyloxy)enamine 3 in high yield, according
to a modified literature procedure.5
Given that enamines 3 exhibit nucleophilic reactivity towards
carbocationic electrophiles,5 we decided to study their behavior
with different halogenating reagents.12,13 The results are presented
in Table 1.
The reaction of enamine 3 with N-chloro- and N-bromosuccin-
imide proceeded cleanly to afford chloro- and bromonitronates
4a and b in almost quantitative yield after column chromatogra-
phy.14 Alternatively, we used elemental halogens in combination
with a source of acetate, which can trap the reactive halosilane
arising after halogenation of 3. Though tetrabutylammonium acte-
tate was successfully employed, the use of triethylamine together
with acetic acid was more convenient, since in this case, ammo-
nium by-products were removed upon work-up to furnish bromo-
and iodonitronates 4b and c in good purity. Fluorination using sev-
Herein we report the synthesis of 3-halomethyl-substituted
cyclic six-membered nitronates (5,6-dihydro-1,2-oxazine N-oxi-
des, A4) by means of functionalization of the 3-methyl group of
nitronate 2, and provide preliminary results on the investigation
of their chemistry.
Nitronate 2 was readily obtained from isobutylene, benzalde-
hyde, and nitroethane5a (Scheme 2). Silylation of 2 with trimethyl-
* Corresponding authors. Fax: +7 499 1355328.
E-mail addresses: adil25@mail.ru (A.D. Dilman), iof@ioc.ac.ru (S.L. Ioffe).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.066

A. A. Mikhaylov et al. / Tetrahedron Letters 51 (2010) 1038–1040
1039
Ph
Ph
O
O
Ph
TMSOTf, Et3N
N
N
CH2Cl2, —78 ºC, 3 h
O
O
OTMS
97%
NO2
2
3
Scheme 2.
atom and C@N bond can be considered as syn-clinal with the tor-
sion angle I(1)C(5)C(1)N(1) equal to 77.5(2)°. Other parameters,
such as the C@N and N–O bond lengths and the distorted half-chair
conformation with a displaced C(4) atom were similar to those
characteristics for previously reported cyclic nitronates.1a,5a
Nitronates 4 undergo typical reactions of a halomethyl group,
as well as those of a nitronate fragment. Thus, we demonstrated
that the halogen can be displaced by different heteroatom- and
carbon-centered nucleophiles, thereby providing the opportunity
for a facile access to functionalized cyclic nitronates. Reactions
of iodo-nitronate 4c with the potassium salts of phthalimide, p-
tolylthiol, and dimethyl malonate proceeded cleanly in DMF lead-
ing to the products of nucleophilic substitution 5 in high yields
(Table 2).
Table 1
Halogenation of enamine 3
Ph
Ph
halogenating
reagent
X
N
N
CH2Cl2
O
OTMS
O
O
3
4
Entry
X
Conditionsa
Product
Yieldb (%)
1
2
3
4
5
6
7
Cl
Br
Br
Br
I
NCS, À78 °C?rt
4a
4b
4b
4b
4c
4c
4c
96
93
83
90
76
81
60
NBS, À78 °C?rt
Br2, Bu4NOAc, À78 °C
Br2, Et3N/AcOH, À94 °C?À30 °C
I2, Bu4NOAc, À78 °C?rt
I2, Et3N/AcOH, À94 °C?À30 °C
ICl, À78 °C?rt
I
I
For nitronates 4, dipolar cycloaddition1,2 and Lewis acid-medi-
ated nucleophilic addition to the C@N bond3 were also studied.
Nitronate 4c reacted with excess methyl acrylate under reflux con-
ditions affording bicyclic product 6 as a mixture of two diastereo-
isomers in a ratio of 7.3:1 (Scheme 3).
a
After raising the temperature, the mixture was stirred for 10–30 min; see
Supplementary data for details.
b
Isolated yield.
A significant difference in the reactivity of bromo and iodo
derivatives was observed in the reactions of nitronates with silyl
ketene acetal 7. Thus, the reaction of bromo-nitronate 4b with 7
in the presence of TBS-triflate gave the expected product 9a in high
yield (Scheme 4). On the other hand, under similar conditions,
iodo-nitronate 4c smoothly furnished, after chromatography, a
mixture of enamine 10 and oxime 11 (the product of rearrange-
ment of enamine 10).15 Both these reactions proceed through the
initial generation of iminium species 8, observed by low tempera-
ture NMR measurements, by mixing nitronates 4b and c with tert-
butyldimethylsilyl triflate (TBSOTf). While bromo-substituted cat-
ion 8b undergoes conventional nucleophilic addition, iodinated
species 8c can serve as a source of positive iodine on reaction with
the silyl ketene acetal.
eral reagents (Selectfluor, PhIF2, and XeF2) was unsuccessful, and in
all cases, either decomposition or rearrangement of enamine 3 into
3-oxymethyl-1,2-oxazine was observed.15
The crystal structure of iodo-nitronate 4c was studied by X-ray
diffraction analysis (Fig. 1).16 The relative positions of the iodine
In summary, a series of halogenated cyclic six-membered nitro-
nates has been prepared starting from 3-methyl-substituted nitro-
nate 2 by means of a silylation/halogenation sequence. These
compounds were found to undergo nucleophilic substitution of
the halogen leading to new functionalized oxazine-N-oxides. The
Table 2
Nucleophilic substitution reactions of 4c
Ph
Ph
Nu
K
I
Nu
N
N
DMF
O
O
O
O
4c
5
NuÀ
Conditions
Product
Yielda (%)
PhthalNÀ
0 °C?rt, 1 h
5a
5b
5c
82
87
88
p-MeC6H4SÀb
(MeO2C)2CHÀb
À40?0 °C, 1 h
Figure 1. The molecular structure of 4c. Non-hydrogen atoms are presented by
thermal ellipsoids at 50% probability. Selected bond lengths and angles (Å and °):
I(1)–C(5) 2.182(2), O(1)–N(1) 1.411(3), O(2)–N(1) 1.259(2), N(1)–C(1) 1.307(3),
C(1)N(1)O(1) 122.35(19), N(1)C(1)C(5) 115.6(2), C(1)C(5)I(1) 111.13(16),
C(4)O(1)N(1)C(1) 26.9(3), C(1)C(2)C(3)C(4)–41.6(3).
À40?0 °C, 30 min
a
Isolated yield.
Generated from Nu–H using t-BuOK.
b

1040
A. A. Mikhaylov et al. / Tetrahedron Letters 51 (2010) 1038–1040
Ph
Ph
O
Ph
I
I
CO2Me
, 1.5 h
I
CO2Me
+
CO2Me
N
N
N
O
O
O
O
Δ
O
4c
6
82%, 7.3:1
Scheme 3.
Ph
O
CO2Me
Br
OTBS
OMe
95%
Ph
O
N
TBSOTf
2,6-lutidine
Ph
X=Br
X=I
OTBS
X
7
9a
X
N
Ph
Ph OTBS
CH2Cl2, _78 ºC
O
N
O
OTBS
4b,c
+
TfO
8b,c
N
N
TBS = t-BuMe2Si
O
OTBS
O
10
11
88%, 6.5:1
Scheme 4.
7. Sukhorukov, A. Yu.; Lesiv, A. V.; Khomutova, Y. A.; Ioffe, S. L.; Tartakovsky, V. A.
Synthesis 2009, 1999–2008.
nitronate fragment of the halo-nitronates took part in nucleophilic
addition and 1,3-dipolar cycloaddition reactions.
8. Cyclic six-membered nitronates were converted into functionalized oxazines,
which were used in the synthesis of amino acids, pyrrolidines, and furans, see:
(a) Sukhorukov, A. Y.; Klenov, M. S.; Ivashkin, P. E.; Lesiv, A. V.; Khomutova, Y.
A.; Ioffe, S. L. Synthesis 2007, 97–107; (b) Ivashkin, P. E.; Sukhorukov, A. Y.;
Eliseev, O. L.; Lesiv, A. V.; Khomutova, Y. A.; Ioffe, S. L. Synthesis 2007, 3461–
3468; (c) Sukhorukov, A. Y.; Lesiv, A. V.; Khomutova, Y. A.; Ioffe, S. L.;
Nelyubina, Y. V. Synthesis 2008, 1205–1220; (d) Sukhorukov, A. Y.; Lesiv, A. V.;
Eliseev, O. L.; Khomutova, Y. A.; Ioffe, S. L.; Borissova, A. O. Eur. J. Org. Chem.
2008, 4025–4034; (e) Sukhorukov, A. Y.; Lesiv, A. V.; Khomutova, Y. A.; Ioffe, S.
L. Synthesis 2009, 741–754; (f) Sukhorukov, A. Y.; Lesiv, A. V.; Eliseev, O. L.;
Khomutova, Y. A.; Ioffe, S. L. Synthesis 2009, 2570–2578.
9. (a) Kunetsky, R. A.; Dilman, A. D.; Ioffe, S. L.; Struchkova, M. I.; Strelenko, Y. A.;
Tartakovsky, V. A. Org. Lett. 2003, 5, 4907–4909; (b) Kunetsky, R. A.; Dilman, A.
D.; Struchkova, M. I.; Belyakov, P. A.; Tartakovsky, V. A.; Ioffe, S. L. Synthesis
2006, 2265–2270.
10. (a) Kunetsky, R. A.; Dilman, A. D.; Struchkova, M. I.; Tartakovsky, V. A.; Ioffe, S.
L. Tetrahedron Lett. 2005, 46, 5203–5205; (b) Ioffe, S. L.; Makarenkova, L. M.;
Strelenko, Yu. A.; Tartakovsky, V. A. Zh. Org. Khim. 1995, 31, 1208–1212.
11. Denmark, S. E.; Guagnano, V.; Dixon, J. A.; Stolle, A. J. Org. Chem. 1997, 62,
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Acknowledgements
This work was supported by the Russian Academy of Sciences
(Programs 1 and 18), the Russian Foundation for Basic Research
(Project 05-03-32733), the Russian Science Support Foundation,
and the Federal program ‘Scientific and educational personnel of
innovative Russia’ (Project 02.740.11.0258). We are grateful to
Mr. A. Levykin and Mr. I. Krylov for experimental contributions.
Supplementary data
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.066.
12. Earlier
we demonstrated
that
N,N-bis(silyloxy)enamines
undergo
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16. The crystal of 4c (C13H16INO2) was monoclinic at 100 K, space group P21/n,
a = 8.2376(9), b = 22.788(3), c = 7.2234(7) Å, b = 91.046(2)°, V = 1355.7(3) Å3,
Z = 4, M = 345.17, dcalcd = 1.691 g cmÀ3 ) = 2.353 cmÀ1, F(000) = 680.
, l (Mo Ka
18,025 reflections were collected using a Smart APEX II diffractometer, 4140
reflections were unique. R1 = 0.0346 was calculated against F2 for 3409
reflections with I >2r(I). Crystallographic data (excluding structure factors)
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have been deposited with the Cambridge Crystallographic Data Centre
(CCDC 753679) and are available free of charge at CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [Fax: +44(0) 1223 336033 or e-mail: deposit@
ccdc.cam.ca.uk].