New persistent heteroarylmethyl radicals resulting from the intramolecular addition of aryloxymethyl radicals onto ketenimines. Synthesis of 2H-1,4-benzoxazines

Article abstract of DOI:10.1055/s-2004-822883

A novel method for producing aryloxymethyl radicals, based on the treatment of (phenylseleno)methyl aryl ethers with tris(trimethylsilyl)silane and AIBN is disclosed, as well as the intramolecular addition of such radicals onto C,C-disubstituted ketenimines. The persistent α-(2H-1,4-benzoxazin-3-yl) benzyl radicals resulting from such cyclization processes undergo cross-coupling with the 1-cyano-1-methylethyl radical arising from the thermal decomposition of AIBN to give 2H-1,4-benzoxazines. These radical cyclizations are controlled by the persistent radical effect. The crystal and molecular structure of benzoxazine 10a has been solved by X-ray analysis.

Full text of DOI:10.1055/s-2004-822883

LETTER
991
New Persistent Heteroarylmethyl Radicals Resulting from the Intramolecular
Addition of Aryloxymethyl Radicals onto Ketenimines. Synthesis of 2H-1,4-
Benzoxazines
Synthesis of
2
H
-1,4-B
a
enzoxazine
t
s
eo Alajarín,a Angel Vidal,*a María-Mar Ortín,a Delia Bautistab
a
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, 30100, Murcia, Spain
Fax +34(968)364149; E-mail: vidal@um.es
b
Servicio Universitario de Instrumentación Científica, Universidad de Murcia, Campus de Espinardo, 30100, Murcia, Spain
Received 16 February 2004
yl)(diphenyl)methyl 2 (R4 = Ph) and (indol-2-yl)(meth-
yl)(phenyl)methyl 2 (R4 = Me) radicals (Scheme 1).7
When the benzylic radicals 1 were generated following
xanthate based chemistry the resulting (indol-2-yl)methyl
Abstract: A novel method for producing aryloxymethyl radicals,
based on the treatment of (phenylseleno)methyl aryl ethers with
tris(trimethylsilyl)silane and AIBN is disclosed, as well as the in-
tramolecular addition of such radicals onto C,C-disubstituted keten-
imines. The persistent a-(2H-1,4-benzoxazin-3-yl)benzyl radicals radicals 2 underwent reduction or a redox process fol-
resulting from such cyclization processes undergo cross-coupling
lowed by other transformations of the resulting ions to
give 2-substituted indoles.7a,b Interestingly, when the
with the 1-cyano-1-methylethyl radical arising from the thermal
decomposition of AIBN to give 2H-1,4-benzoxazines. These radi-
benzylic radicals 1 were produced from benzyl phenyl se-
cal cyclizations are controlled by the persistent radical effect. The
lenides by treatment with tris(trimethylsilyl)silane in the
crystal and molecular structure of benzoxazine 10a has been solved
presence of AIBN these radical processes turned out to be
controlled by the Persistent Radical Effect (PRE),8 giving
rise to 3-(1H-indol-2-yl)propionitriles resulting from the
selective cross-coupling of the persistent radicals 2 and
the transient 1-cyano-1-methylethyl radical arising from
AIBN.7c
by X-ray analysis.
Key words: ketenimine, aryloxymethyl radical, cyclization, persis-
tent, 1,4-benzoxazines
Radicals are called persistent if their lifetimes exceed sig-
nificantly, in liquid solution and under similar conditions,
those of some reactive standard radicals.1 Carbon-cen-
tered radicals, when created under an appropriate environ-
ment, can be rendered persistent through intramolecular
steric protection. Triphenylmethyl radicals, and their sub-
stituted derivatives, are the prototype of persistent carbon-
centered radicals, in which the arrangement of the three
phenyl groups around the trivalent carbon atom sterically
slows down or inhibits their radical-radical reactions. The
preparation, properties and reactivity of this type of
persistent carbon-centered radicals are well known.2
However, to the best of our knowledge, analogous triaryl-
methyl radicals in which the radical center is connected
directly to an heteroaromatic ring are scarce. In this re-
spect, Mangini and Zarkadis have reported respectively
the formation of several thienylmethyl3 and pyridyl-
methyl4 radicals, in which the radical center is connected
to three carbon atoms; and Katritzky has described the
formation of diaryl(benzotriazol-1-yl)methyl radicals,5 in
which the radical center is connected to the nitrogen atom
of the benzotriazolyl substituent and two carbon atoms.
R1
R2
R1
R2
Ph
R4
N
N
C
Ph
H
R3
C
R4
R3
1
2
R4 = Ph, Me
Scheme 1 (Indol-2-yl)methyl radicals 2.
In the context of the generation of persistent tertiary car-
bon radicals bearing a nitrogenated heterocyclic ring at
the carbon-center radical, and following the study of new
organic processes controlled by the PRE, we present here-
in the intramolecular cyclization of the aryloxymethyl
radicals 3 bearing N-linked ketenimine units at ortho-po-
sition (Figure 1). This study required the development of
a new method for producing aryloxymethyl radicals like
3, and the cyclizations that follow up the generation of
such reactive species represent a novel protocol for the
synthesis of 2H-1,4-benzoxazines.
As part of our research work directed towards the study of
the chemical behaviour of ketenimines,6 we have recently
reported that the intramolecular addition of benzylic radi-
cals 1 onto the central carbon atom of C,C-disubstituted
ketenimine functions leads to persistent (indol-2-
R3
R2
R1
O
N
C
Ph
C
R4
3
SYNLETT 2004, No. 6, pp 0991–0994
0
6.
0
5.
2
0
0
4
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-822883; Art ID: G05004ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Aryloxymethyl radicals 3.

992
M. Alajarín et al.
LETTER
Ketenimines 8 shown in Scheme 3 were specifically de-
signed for generating such aryloxymethyl radicals 3
which could undergo intramolecular cyclization onto the
central carbon atom of the ketenimine function. Zard gen-
erated iminyl radicals R1R2C = N from O-(phenyl-
seleno)methyl oximes R1R2C = NOCH2SePh by the
action of tributyltin hydride/AIBN, via an intermediate
R1R2C = NOCH2 oxymethyl radical.9 Thus, inspired by
this conversion, we reasoned that the reaction of (phe-
nylseleno)methyl aryl ethers ArOCH2SePh with tributyl-
tin hydride/AIBN or tris(trimethylsilyl)silane/AIBN
should produce aryloxymethyl radicals. Aryloxymethyl
radicals have been already generated for useful purposes
in organic synthesis by decarboxylation of thiohydroxam-
ate esters,10 either through their photolysis in the presence
of 2-methylpropane-2-thiol or by treatment with tributyl-
tin hydride/AIBN, as well as by photoinduced electron
transfer reactions of a-silyl ethers11 and a-stannyl ethers,12
using methanol as solvent. These reported methods for the
formation of aryloxymethyl radicals are not compatible
with substrates 8 as all of them involve the use of a nu-
cleophilic solvent (methanol) or additive (2-methylpro-
pane-2-thiol) that could add to the ketenimine function.
R3
R3
R2
R1
OH
R2
O
Se-Ph
i)
NO2
R1
NO2
4
5
ii)
R3
R3
R2
O
Se-Ph
R2
R1
O
Se-Ph
iii)
R1
N PPh3
NH2
7
6
iv)
R3
R2
R1
O
N
Se-Ph
C
Ph
C
R4
8
Scheme 2 Reagents and conditions: (i) PhSeCH2Cl, K2CO3, DMF,
80 °C, 24 h; (ii) Fe, EtOH–HOAc, reflux, 3 h; (iii) PPh3, CCl4, Et3N,
MeCN, r.t., 12 h; (iv) Ph(R4)C=C=O, CH2Cl2, r.t., 30 min.
Ketenimines 8 were prepared in good overall yields (25–
58%) from commercially available 2-nitrophenols 4 in
four steps (Scheme 2). Alkylation of 4 with chloromethyl
phenyl selenide13 yielded the (phenylseleno)methyl aryl
ethers 5. Reduction of the nitro group in compounds 5 by
the iron-acetic acid system provided amines 6. Triphe-
nylphosphazenes 7 were prepared by treating acetonitrile
solutions of amines 6 with triphenylphosphane, carbon
tetrachloride and triethylamine. Aza-Wittig reaction14 of
the triphenylphosphazenes 7 with methyl phenyl ketene15
or diphenyl ketene16 gave ketenimines 8.
R3
R2
R1
O
N
Se-Ph
C
Ph
C
R4
8
i)
R3
R3
The radical cyclization of the C,C-disubstituted keten-
imines 8 was carried out by a three-portion addition of
a stoichiometric excess of tris(trimethylsilyl)silane (3
equiv) and AIBN (1.2 equiv) to a 0.015 M solution of the
ketenimines in boiling benzene.17 Pleasingly, under these
conditions ketenimines 8 were totally consumed and col-
umn chromatography of the final reaction mixtures al-
lowed the isolation of the 2H-1,4-benzoxazines 9 and 10,
R2
R1
O
N
R2
R1
O
N
CN
+
CH3
Ph
CH3
Ph R4
R4
CN
CH3
CH3
9
10
Scheme 3 Reagents and conditions: (i) Tris(trimethylsilyl)silane (3
in moderate to good combined yields (36–82%), see equiv), AIBN (1.2 equiv), benzene, reflux, 24 h.
Scheme 3 and Table 1.
The structural characterization of the benzoxazines 9 and
10 relies on their analytical and spectroscopic data.17 The
1H NMR and 13C NMR data of compounds 9 clearly show
the presence of the propionitrile chain at the C3 position
of the benzoxazine ring. The same structural fragment
was also present in the 3-(1H-indol-2-yl)propionitriles
previously prepared by us.7c An X-ray structure determi-
nation of benzoxazine 10a (R1 = R2 = R3 = H; R4 = C6H5)
was definitive for unequivocally establishing the structure
of compounds 10.18 A NOESY spectrum of compound
10g (R1 = Cl; R2 = R3 = H; R4 = CH3) showed crosspeaks
between the signals of the methyl group at the exocyclic
double bond (R4) and the two methyl groups of the tert-
alkyl substituent at the nitrogen atom, thus proving the
E-configuration of the exocyclic double bond in this com-
pound.
A reasonable mechanistic explanation for the conversion
8 → 9 + 10 is given in Scheme 4: the in situ formed
[(CH3)3Si]3Si radical should attack the selenium atom of
ketenimines 8 to give PhSeSi[Si(CH3)3]3 and the expected
aryloxymethyl radicals 3, which undergo cyclization to
the tertiary radicals 11a by intramolecular addition of the
radical moiety onto the central carbon atom of the keten-
imine function. Then (2H-1,4-benzoxazin-3-yl)methyl
radicals 11a undergo radical-radical cross coupling with
the 1-cyano-1-methylethyl radical arising from AIBN to
afford compounds 9. The unpaired electron of radicals
Synlett 2004, No. 6, 991–994 © Thieme Stuttgart · New York

LETTER
Synthesis of 2H-1,4-Benzoxazines
993
Table 1 2H-1,4-Benzoxazines 9 and 10
Compounds
R1
R2
R3
R4
9/10a
Yield of 9 and 10
(%)b
9a, 10a
9b, 10b
9c, 10c
9d, 10d
9e, 10e
9f, 10f
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
0.7:1
1:1
79
CH3
CH3O
H
74
1:1
36
C6H4
0.7:1
0.7:1
0.5:1
1.8:1
73
H
CH3
H
H
H
H
66
Cl
82
9g, 10g
Cl
H
78
a Determined in the final reaction mixture by 1H NMR analysis.
b Combined yield after the chromatographic purification.
11a can also reside on the nitrogen atom of the 1,4-benz- In conclusion, in this report we have described a new
oxazine substituent, as indicated by the canonical form method for producing aryloxymethyl radicals, and we
11b. The radical-radical coupling of 11b with the 1-cy- have shown how this type of oxymethyl radicals adds in-
ano-1-methylethyl radical present in the reaction medium tramolecularly onto ketenimines to afford new examples
explains the formation of compounds 10.
of persistent radicals, which in turn undergo cross-cou-
pling with the 1-cyano-1-methylethyl radical present in
the reaction medium to give finally substituted 2H-1,4-
benzoxazines. The Persistent Radical Effect apparently
controls these radical processes.
To the light of these results, the (2H-1,4-benzoxazin-3-
yl)methyl radicals 11a seem to be persistent tertiary meth-
yl radicals, and their canonical forms 11b could be classi-
fied as cyclic persistent nitrogen-centered radicals.19
Acknowledgment
R3
R3
This work was supported by the MCYT and FEDER (Project
BQU2001-0010), and Fundación Séneca-CARM (Project PI-1/
00749/FS/01). One of us (M.-M. O.) thanks the Fundación Séneca-
CARM for a fellowship.
R2
R1
O
N
Se-Ph
R2
R1
O
N
C
Ph
C
C
Ph
C
R4
R4
References
8
3
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R3
R3
R2
R1
O
R2
O
Ph
Ph
R1
N
N
R4
R4
11b
11a
CN
C
CH3
CH3
R3
R3
R2
R1
O
N
R2
R1
O
N
CN
+
Ph
CH3
CH3
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Ph R4
R4
CN
CH3
CH3
10
9
Scheme 4 Proposed mechanism for the conversion 8 → 9 + 10.
Synlett 2004, No. 6, 991–994 © Thieme Stuttgart · New York

994
M. Alajarín et al.
LETTER
(8) For a seminal paper in which the PRE was recognized see:
(a) Fischer, H. J. Am. Chem. Soc. 1986, 108, 3925. (b) For
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crude material was chromatographed on a silica gel column,
using hexanes/EtOAc (9:1) as eluent.
1,4-Benzoxazine 9f: Rf = 0.48; yield 27%; colorless prisms
(Et2O); mp 177–178 °C. IR (nujol): 2234, 1625, 1258, 1220,
1164, 1117, 1074, 1044, 964, 889, 827, 741, 707 cm–1. 1H
NMR (300 MHz, CDCl3): d = 1.23 (s, 3 H), 1.50 (s, 3 H),
3.39 (d, 1 H, J = 13.5 Hz), 4.28 (d, 1 H, J = 13.5 Hz), 6.79
(d, 1 H, J = 8.7 Hz), 7.11 (dd, 1 H, J = 8.7, 2.7 Hz), 7.41
(very broad s, 8 H), 7.61 (d, 1 H, J = 2.7 Hz), 7.91 (broad s,
2 H). 13C NMR (75 MHz, CDCl3): d = 25.3, 27.6, 37.3 (s),
63.6, 64.2 (s), 116.7, 127.2 (s), 127.4, 127.7 (s), 128.3,
128.5, 128.6, 128.9, 130.0, 131.1, 133.9 (s), 136.4 (s), 137.0
(s), 145.2 (s), 164.9 (s). MS: m/z (relative intensity) = 402 (3)
[M+ + 2], 400 (8) [M+], 332 (100). Anal. Calcd for
C25H21ClN2O: C, 74.90; H, 5.28; N, 6.99. Found: C, 74.77;
H, 5.21; N, 7.11.
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(Et2O); mp 143–144 °C. IR (nujol): 2233, 1624, 1600, 1579,
1494, 1299, 1261, 1236, 1198, 1128, 971, 870, 819, 763,
709, 668 cm–1. 1H NMR (300 MHz, CDCl3): d = 1.47 (s, 3
H), 1.51 (s, 3 H), 4.77 (d, 1 H, J = 11.7 Hz), 4.92 (d, 1 H,
J = 11.7 Hz), 6.82 (d, 1 H, J = 8.7 Hz), 6.99 (dd, 1 H, J = 8.7,
2.4 Hz), 7.08–7.11 (m, 2 H), 7.15 (d, 1 H, J = 2.4 Hz), 7.16–
7.19 (m, 2 H), 7.28–7.35 (m, 6 H). 13C NMR (75 MHz,
CDCl3): d = 27.8, 28.9, 56.8 (s), 65.2, 118.3, 121.8 (s),
123.4, 124.7, 125.1 (s), 128.1, 128.2, 128.4, 128.5, 129.8,
130.6, 132.4 (s), 139.5 (s), 140.2 (s), 142.8 (s), 147.5 (s).
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332 (100). Anal. Calcd for C25H21ClN2O: C, 74.90; H, 5.28;
N, 6.99. Found: C, 74.76; H, 5.18; N, 7.08.
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heated under nitrogen at reflux temperature and
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tris(trimethylsilyl)silane (0.56 g, 2.25 mmol) and AIBN
(0.098 g, 0.6 mmol) were added. Further additions of
tris(trimethylsilyl)silane and AIBN were made as follows: 1)
after 4 h since the first addition, tris(trimethylsilyl)silane
(0.19 g, 0.75 mmol) and AIBN (0.098 g, 0.6 mmol) and 2) 4
h later, tris(trimethylsilyl)silane (0.37 g, 1.5 mmol) and
AIBN (0.098 g, 0.6 mmol). After 16 h since the last addition
the solvent was removed under reduced pressure and the
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Synlett 2004, No. 6, 991–994 © Thieme Stuttgart · New York