Synthesis of polyfluorodibenz[b,f][1,4]oxazepines by the cyclization of 2-[(polyfluorobenzylidene)amino]phenols

Article abstract of DOI:10.1016/S0022-1139(02)00033-7

Thermolysis of 2-[(polyfluorobenzylidene)amino]phenols in ethanol in the presence of triethylamine affords the corresponding fluorinated dibenz[b,f][1,4]oxazepines in moderate to high yields. The structures of 2-[(2,3,4,5,6-pentafluorobenzylidene)amino]ph

Full text of DOI:10.1016/S0022-1139(02)00033-7

Journal of Fluorine Chemistry 115 (2002) 91±99
Synthesis of poly¯uorodibenz[b, f ][1,4]oxazepines by the cyclization
of 2-[(poly¯uorobenzylidene)amino]phenols
Cara L. Allaway, Martina Daly, Mark Nieuwenhuyzen, Graham C. Saunders*
School of Chemistry, Queen's University Belfast, David Keir Building, Belfast BT9 5AG, UK
Received 22 November 2001; received in revised form 22 January 2002; accepted 24 January 2002
Abstract
Thermolysis of 2-[(poly¯uorobenzylidene)amino]phenols in ethanol in the presence of triethylamine affords the corresponding ¯uorinated
dibenz[b,f ][1,4]oxazepines in moderate to high yields. The structures of 2-[(2,3,4,5,6-penta¯uorobenzylidene)amino]phenol and 1,2,3,4-
tetra¯uorodibenzo[b,f ][1,4]oxazepine have been determined by single-crystal X-ray diffraction. # 2002 Elsevier Science B.V. All rights reserved.
Keywords: Dibenzoxazepine; Cyclisation; SNAr; Crystal structure
1. Introduction
2. Results and discussion
The penta¯uorinated compound 2-[(2,3,4,5,6-penta¯uoro-
benzylidene)amino]phenol, 1a, has been reported to undergo
cyclisation in DMF at 100 8Cto afford in high yield 1,2,3,4-
tetra¯uorodibenzo[b, f ][1,4]oxazepine, 2a (Scheme 1) [1]
by an intramolecular SNAr reaction [2±4]. Similarly, 2-
[(2,3,4,5,6-penta¯uorophenylimino)methyl]phenol, 3, cycli-
sed to 6,7,8,9-tetra¯uorodibenzo[b, f ][1,4]oxazepine, 4, in
DMF at 100 8Cin the presence of potassium ¯uoride [1].
Although this route might be expected to provide a
convenient and high yield route to other ¯uorinated
dibenz[b, f ][1,4]oxazepines and related heterocylces, it
has been limited to 1a, 3 and its para-methoxy-substituted
tetra¯uoro analogue [5]. We are interested in ¯uorinated
dibenz[b, f ][1,4]oxazepines and related ¯uorinated hetero-
cycles because of the well documented biological activity of
dibenz[b, f ][1,4]oxazepine [6±12], which might be expected
to be enhanced by the presence of ¯uorine atoms [13±15],
and also as precursors to more elaborate ¯uorinated com-
pounds [16,17].
The ¯uorinated aromatic imines 1a±d were prepared
readily in high yields from the respective ¯uorinated ben-
zaldehyde and 2-aminophenol by Schiff base condensation
in dichloromethane over anhydrous magnesium sulphate at
room temperature (Scheme 2). Imines 1a±d were charac-
terised by mass spectrometry, NMR and IR spectroscopies,
and elemental analysis. Imine 1a was structurally charac-
terised by single-crystal X-ray diffraction (Fig. 1). Crystal-
lographic data are given in Table 1 and selected bond
distances and angles are given in Table 2. The asymmetric
unit of 1a contains one molecule. The molecule is almost
planar with torsion angles across C(6)±C(7), C(7)±N(8) and
N(8)±C(9) of À172.9(2), 179.7(2) and À176.4(2)8, respec-
tively. The molecule possesses an intramolecular O±H Á Á Á N
hydrogen bond between the hydroxyl and the imine moieties
Ê
Ê
(H Á Á Á N 2:10ꢀ3† A, H Á Á Á N 2:631ꢀ2† A and an O±H Á Á Á N
angle of 122(2)8). The hydroxyl group also shows a weak
secondary intramolecular interaction with the closest
Ê
¯uorine atom (H Á Á Á F distance of 2.90 A). The molecules
Here, we report the syntheses of ¯uorinated dibenzoxaze-
pines by intramolecular cyclisation of 2-[(poly¯uorobenzyl-
idene)amino]phenols, attempts to prepare other ¯uorinated
heterocycles by a similar route and the structures of 1a and
2a.
of 1a are arranged as dimeric columns via O±H Á Á Á O
Ê
Ê
(H Á Á Á O 2:52ꢀ2† A, O Á Á Á O 2:865ꢀ3† A and an O±H Á Á Á O
angle of 107(2)8) and p Á Á Á p hydrogen bonding interactions
with H Á Á Á O and ring centre to ring centre distances of 2.51
Ê
and 3.64 A, respectively. The columns are arranged such that
the penta¯uorophenyl and the phenyl moieties alternate
within a column.
Thermolysis of 1a in re¯uxing ethanol for 96 h. produced
a mixture of products. The expected cyclic product 1,2,3,4-
tetra¯uorodibenzo[b,f ][1,4]oxazepine, 2a, was isolated as a
* Corresponding author. Tel.: ‡44-28-9027-4682;
fax: ‡44-28-9038-2117.
E-mail address: g.saunders@qub.ac.uk (G.C. Saunders).
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 0 3 3 - 7

92
C.L. Allaway et al. / Journal of Fluorine Chemistry 115 (2002) 91±99
Scheme 1.
Scheme 2.
Fig. 1. Molecular structure of 2-[(2,3,4,5,6-pentafluorobenzylidene)amino]phenol 1a with thermal ellipsoids at the 30% level.

C.L. Allaway et al. / Journal of Fluorine Chemistry 115 (2002) 91±99
93
Table 1
Crystallographic data for 2-[(2,3,4,5,6-pentafluorobenzylidene)amino]phenol, 1a, and 1,2,3,4-tetrafluorodibenzo[b,f][1,4]oxazepine, 2a
1a
2a
Formula
C13H6F5NO
C13H5F4NO
Formula weight
Crystal system
Space group
287.19
Triclinic
Å
P1
267.18
Monoclinic
P21/n
Ê
a (A)
Ê
b (A)
Ê
c (A)
6.3133(9)
7.1840(10)
12.2583(17)
81.888(2)
86.162(3)
86.896(3)
548.61(13)
2
7.4091(6)
21.5604(16)
13.3325(10)
a (8)
b (8)
g (8)
±
97.966(2)
±
Ê 3
V (A )
2109.2(3)
Z
8
Dc (g cmÀ3
)
1.739
0.43 Â 0.32 Â 0.11
0.169
1.683
0.42 Â 0.24 Â 0.19
0.156
Crystal size (mm)
m (mmÀ1
)
2y range (8)
Total reflections
Unique reflections (Rint
3 ! 58
3 ! 58
6390
2475 (0.0391)
1580
24369
4967 (0.0804)
2501
)
Observed reflections (I > 2s(I))
Parameters
205
R1 0.0469, wR2 0.1160
383
R1 0.0503, wR2 0.1048
Final R indices (I > 2s(I))
R indices (all data)
R1 0.0744, wR2 0.1303
R1 0.1145, wR2 0.1254
3
3
Weighting scheme
Ê À3
Goodness of fit on F2
w ˆ 1=‰s2ꢀF02† ‡ f0:0784ꢀF02 ‡ 2Fc2†=3g Š
w ˆ 1=‰s2ꢀF02† ‡ f0:0572ꢀF02 ‡ 2Fc2†=3g Š
Max., min. Dr (eA
)
0.32, À0.24
0.940
0.26, À0.27
0.881
Data completeness
0.87
0.92
Estimated standard deviations are given in parentheses. Data were collected at 153(2) K on a Bruker DXS SMART diffractometer with graphite
Ê
monochromator and Mo Ka radiation (l ˆ 0:71073 A).
pale yellow solid in ca. 50% yield by extraction with hexane,
leaving a red residue. Compound 2a was fully characterised
by elemental analysis, mass spectrometry and NMR and IR
spectroscopies. The 19F spectrum of 2a, recorded in d-
Table 2
Ê
Selected distances (A) and angles (8) for 2-[(2,3,4,5,6-pentafluorobenzy-
lidene)amino]phenol, 1a
chloroform, shows four resonances of equal intensity indi-
cative of four non-equivalent ¯uorine environments in the
range d À140 to À165, and the 1H NMR spectrum shows the
imine hydrogen atom resonance at d 8.57. These spectral
data are similar to those reported for 2a in acetone and THF
[1]. The identity of the red residue, which is insoluble in
chloroform, but completely soluble in acetone is unknown.
The 1H and 19F NMR spectra of the residue are simple and
similar to those of 2a, but slightly broadened in the 19F NMR
spectrum. Mass spectrometry revealed no simple low mole-
cular mass compound and the analytical data revealed a
signi®cantly lower proportion of carbon than for 2a. We
tentatively suggest that the residue may be a polymeric
compound formed by intermolecular reactions. The forma-
tion of compound 2a is presumably by an intramolecular
SNAr reaction whereby the phenolic oxygen, probably as
phenoxide, attacks an ortho-C±F bond, after isomerisation to
the cis-isomer [2±4]. The byproduct of this reaction would
be expected to be hydrogen ¯uoride. Although this was not
observed directly, the 19F NMR spectrum of the crude
product showed characteristic resonances at ca. d À136.8
and À150.0, which can be assigned to the anions SiF62À and
N(8)±C(7)
1.261(3)
1.463(3)
1.412(2)
1.361(2)
1.341(2)
1.385(3)
1.392(3)
C(7)±C(6)
N(8)±C(9)
O(10)±C(10)
Mean C±F
Mean C±C (C6F5)
Mean C±C (C6H4OH)
C(7)±N(8)±C(9)
N(8)±C(7)±C(6)
C(7)±C(6)±C(1)
C(7)±C(6)±C(5)
C(1)±C(6)±C(5)
N(8)±C(9)±C(10)
N(8)±C(9)±C(14)
C(10)±C(9)±C(14)
O(10)±C(10)±C(9)
F(1)±C(1)±C(6)
F(5)±C(5)±C(6)
122.50(17)
122.74(18)
119.46(17)
124.79(17)
115.76(17)
113.38(16)
127.48(17)
119.14(17)
119.15(17)
119.47(16)
121.15(16)
C(1)±C(6)±C(7)±N(8)
C(6)±C(7)±N(8)±C(9)
C(7)±C(8)±N(8)±C(10)
À172.9(2)
179.7(2)
À176.4(2)
Estimated standard deviations are given in parentheses.

94
C.L. Allaway et al. / Journal of Fluorine Chemistry 115 (2002) 91±99
Fig. 2. Molecular structures of the two molecules in the asymmetric unit of 1,2,3,4-tetrafluorodibenzo[b,f][1,4]oxazepine 2a with thermal ellipsoids at the
30% level.
BF4À, respectively. These anions are formed by the reaction
of HF with the borosilicate glass reaction vessel [18]. Further
con®rmation of the mechanism was obtained by addition of
a slight excess of triethylamine to the reaction, which greatly
reduced the time of the reaction to 3 h. and also the amount
of red by-product, to give 2a in ca. 80% yield.
The structure of 2a has been determined by single-crystal
X-ray diffraction (Fig. 2). Crystallographic data are given in
Table 1 and selected bond distance and angles are given in
Table 3. The asymmetric unit of 2a contains two indepen-
dent molecules A and B, which are enantiomers by virtue of
the buckling of the seven-membered ring. The angles
between the planes de®ned by C6H4 and C6F4, 145(1)
and 147(1)8 for A and B, respectively, are similar to that
of 1448 between the two C6H4 planes of the similar compound
2-chloro-11-(4-methylpiperazin-1-yl)dibenz[b,f ][1,4]ox-
azepine (loxapine) [19]. Although not con®rmed, the inter-
conversion of the enantiomers of 2a is presumably rapid in
solution, since interconversions of enantiomers of similar
compounds comprising seven-membered rings have been
found to have low activation energies (ca. 40 kJ molÀ1
)
Table 3
Ê
Selected bond distances (A) and angles (8) for 1,2,3,4-tetrafluorodiben-
zo[b,f][1,4]oxazepine, 2a
[20]. The bond distances and angles for A and B are identical
within experimental error. The molecules are arranged into
columns consisting of alternating A and B via p Á Á Á p stacking
Molecule A
Molecule B
Ê
(distances of 3.62 and 3.78 A). These columns are arranged
N±C(8)
1.287(3)
1.405(3)
1.472(3)
1.378(3)
1.398(3)
1.343(3)
1.379(3)
1.388(4)
1.276(3)
1.415(3)
1.477(3)
1.372(3)
1.407(3)
1.345(3)
1.379(3)
1.385(4)
in pairs resulting from formation of C±H Á Á Á N (bridging
N±C(10)
C(7)±C(8)
O(1)±C(2)
C±H to imine of an adjacent molecule) hydrogen bonded
Ê
Ê
dimers (H Á Á Á O 2:51ꢀ2† A, C Á Á Á N 3:504ꢀ3† A and an C±
H Á Á Á N angle of 169(1)8). As in 1a the columns are arranged
such that the tetra¯uorophenyl and the phenyl moieties
alternate within a column. The bond distances of the
seven-membered ring are identical within experimental error
with those of related dibenz[b,f ][1,4]oxazepines, such as
loxapine, the structure of which has been determined for
orthorhombic [19] and monoclinic polymorphs [21], and 2-
chloro-11-(piperazin-1-yl)dibenz[b,f ][1,4]oxazepine (amox-
apine) [21]. The angles are however signi®cantly different. In
particular, the N=C±C and C±O±C angles are ca. 3 and 48
more obtuse, respectively, than for the loxapine and amox-
apine. Presumably this is a consequence of the piperazinyl
substituent at the imine carbon atom of loxapine and amox-
apine.
O(1)±C(15)
Mean C±F
Mean C±C (C6F4)
Mean C±C (C6H4)
C(8)±N±C(10)
N±C(8)±C(7)
123.1(2)
129.1(2)
122.7(2)
120.1(2)
117.2(2)
117.0(2)
126.0(2)
116.9(2)
114.72(17)
121.4(2)
120.9(2)
123.3(2)
129.6(2)
122.7(2)
119.6(2)
117.5(2)
116.7(2)
125.8(2)
117.4(2)
115.60(17)
121.7(2)
121.1(2)
C(8)±C(7)±C(2)
C(8)±C(7)±C(6)
C(2)±C(7)±C(6)
N±C(10)±C(11)
N±C(10)±C(15)
C(11)±C(10)±C(15)
C(2)±O±C(15)
O±C(2)±C(7)
O±C(15)±C(10)
Estimated standard deviations are given in parentheses.

C.L. Allaway et al. / Journal of Fluorine Chemistry 115 (2002) 91±99
95
Scheme 3.
Using the same conditions as for the synthesis of 2a, the
¯uorinated 2-[(benzylidene)amino]phenols, 1b and 1c, gave
the respective poly¯uorodibenz[b, f ][1,4]oxazepines, 2b and
2c, in yields of ca. 65% (Scheme 2). The convenience of the
two-step syntheses of ¯uorinated dibenz[b, f ][1,4]oxazepines
suggested that this route may also offer advantages over
the four-step synthesis of the non-¯uorinated dibenz-
[b, f ][1,4]oxazepine, 2d which involves initial formation
of the ether linkage by the reaction of phenol with 2-chloro-
nitrobenzene, followed by reduction of the nitro group,
conversion to the formamide, and cyclisation to form the
seven-membered ring by a Bischler±Napieralski type reac-
tion [22]. However, attempts to prepare 2d by cyclisation
of 2-[(2-¯uorobenzylidene)amino]phenol, 1d, in ethanol
with excess triethylamine were unsuccessful, even after
prolonged re¯ux.
Attempts to prepare 6,7,8,9-tetra¯uorodibenzo[b,f ][1,4]-
oxazepine, 4, by cyclisation of 3 using the same conditions
as for the formation of 2a were unsuccessful, even after
prolonged re¯ux. Evidently this reaction is dependent on
the solvent. That 1a reacts readily and 3 does not is con-
sistent with an SNAr reaction. As expected, the electron-
withdrawing ±CH=N substituent enhances the susceptibility
of C6F5 to nucleophilic attack, whereas the electron-donating
±N=CH substituent has the opposite effect.
We were interested in investigating whether similar
¯uorinated compounds would undergo similar cyclisations.
Reduction of imine 1a with sodium borohydride yielded
2-(2,3,4,5,6-Penta¯uorobenzylamino)phenol, 5, in 79%
yield (Scheme 4). Attempts to prepare 1,2,3,4-tetra¯uoro-
10,11-dihydrodibenz[b, f ][1,4]oxazepine, 6, by cyclisation
of 5 were unsuccessful. Compound 6 has previously been
prepared by reduction of dibenz[b, f ][1,4]oxapeine, 2a [17].
In an attempt to prepare the thiophenol analogue of 1a,
penta¯uorobenzaldehyde was treated with 2-aminothiophe-
nol. The product, 7, comprised a mixture of two isomers
(Scheme 5). 2-[(2,3,4,5,6-Penta¯uorobenzylidene)amino]-
thiophenol, 7a, is the minor isomer and 2-(2,3,4,5,6-penta-
¯uorophenyl)-2,3-dihydrobenzothiazole, 7b, is the major
2-[(2,3,4,5,6-Penta¯uorophenylimino)methyl]phenol,
3
[1], was prepared similarly to 1a from salicylaldehyde
and penta¯uoroaniline (Scheme 3). Consistent with the less
nucleophilic nature of the nitrogen of penta¯uoroaniline in
comparison to aminophenol and the less electrophilic nature
of the carbonyl carbon of salicylaldehyde in comparison to
¯uorinated benzaldehydes, the reaction was slower than for
the formation of 1a, and 3 was obtained in a relatively low
yield even after heating for 14 h. Imine 3 was characterised
by elemental analysis and NMR and IR spectroscopies.
Crystals of 3 suitable for an X-ray diffraction study were
obtained from dichloromethane, and since 3 has been
reported to exhibit polymorphism [23], it was considered
worthwhile to perform a cell parameter determination of the
crystals we obtained. The crystallographic and structural
data are entirely consistent with the a2 polymorph [23].
1
isomer as determined by H NMR spectroscopy.
In an attempt to prepare a ¯uorinated aromatic imine
containing a benzyl alcohol functionality, penta¯uorobenzal-
dehyde was treated with 2-aminobenzyl alcohol (Scheme 5).
The product 8 was characterised spectroscopically as 2-(2,3,
4,5,6-penta¯uorophenyl)-1,4-dihydro-2H-benzo[d][1,3]oxaz-
ine. The 1H and 19F NMR spectra also contained resonances
which suggest that the imine isomer may also be present in
small amounts (<5%). The penta¯uorophenylhydrazone, 9,

96
C.L. Allaway et al. / Journal of Fluorine Chemistry 115 (2002) 91±99
Scheme 4.
Scheme 5.
was prepared from 2-hydroxyphenylhydrazine and penta-
¯uorobenzaldehyde as for the imine 1a (Scheme 3). None
of 7±9 underwent cyclisation on treatment with triethylamine
in re¯uxing ethanol.
be conveniently carried out in reluxing ethanol by the
addition of triethylamine. The reaction occurs by an intra-
molecular SNAr reaction and at least two ¯uorine atoms are
necessary on the benzylidene arene. The difference in
reactivity between 1a and 3 indicates that under these
conditions it is necessary for the electrophilic arene to
be a benzylidene and not a phenylimine. The lack of
reactivity of 9 further supports this conclusion. The lack
of reactivity of 5, 7 and 8 indicates also that the nucleophile
must be a phenoxide.
3. Conclusion
Cyclisation of 2-[(poly¯uorobenzylidene)amino]phe-
nols to give ¯uorinated dibenzo[b, f ][1,4]oxazepines can

C.L. Allaway et al. / Journal of Fluorine Chemistry 115 (2002) 91±99
97
4. Experimental
579and458.1HNMR:8.82(1H,s,HC=N),7.30(1H,dd,J8.1,
1.4), 7.19 (1H, m), 7.14 (1H, m), 6.97 (1H, dd, J 8.2, 1.3), 6.86
(1H, m). 19F NMR: À138.91 (2F, m), À143.06 (2F, m).
4.1. Instrumentation
The H, 13Cand 19F NMR spectra were recorded using
4.3.3. 2-[(2,6-Difluorobenzylidene)amino]phenol (1c)
Yield 46%. Analysis: calc. for C13H9F2NO: C, 66.95; H,
3.9; N, 6.0; found: C, 66.4; H, 3.55; N, 5.6%. HRMS:
1
Bruker DPX300 or DRX500 spectrometers in CDCl3 unless
1
stated otherwise. H (300.01 or 500.13 MHz) were refer-
‡
enced internally, using the residual protio solvent resonance,
relative to SiMe4 (d 0) and 19F (282.26 MHz) externally to
CFCl3 (d 0). All chemical shifts are quoted in d (ppm), using
the high frequency positive convention, and coupling con-
stants in Hz. Unless stated otherwise, NMR spectra were
recorded in CDCl3. IR spectra were recorded as KBr dics.
Mass spectra were recorded on a VG Autospec X-series
mass spectrometer. Elemental analyses were carried out by
A.S.E.P., The School of Chemistry, The Queen's University
of Belfast.
C13H9F2NO requires 233.06522; found: M 233.06434.
IR: nmax(KBr) (cmÀ1) 3323, 1623, 1603, 1588, 1565,
1470, 1382, 1291, 1249, 1197, 1149, 1009, 966, 927,
856, 793, 782, 739, 711, 645, 580, 530, 519, 506, 468
and 458. 1H NMR: 8.86 (1H, s, HC=N), 7.33 (2H, m),
7.16 (1H, t, J 7.2), 6.95 (3H, m), 6.87 (1H, m). 19F NMR:
À112.57 (2F, dm, J 7.0).
4.3.4. 2-[(2-Fluorobenzylidene)amino]phenol (1d)
Yield 71%. Analysis: calc. for C13H10FNO: C, 72.55; H,
4.5; N, 6.4; found: C, 72.2; H, 4.5; N, 6.4%. HRMS:
‡
4.2. Materials
C13H10FNO requires 215.07464; found: M 215.07416.
IR: nmax(KBr) (cmÀ1) 3426, 1619, 1586, 1573, 1488,
1455, 1384, 1361, 1280, 1249, 1215, 1202, 1174, 1152,
1091, 1030, 974, 934, 859, 851, 820, 776, 764, 754, 600,
575, 482 and 472. 1H NMR: 8.95 (1H, s, HC=N), 8.10 (1H,
td, J 7.6, 1.6), 7.41 (1H, m), 7.27 (1H, dd, J 8.0, 1.4), 7.13
(3H, m), 6.95 (1H, dd, J 8.2, 1.2), 6.85 (1H, m). 19F NMR:
À120.96 (1F, m).
The compounds C6H4(OH)NH2-1,2, C6H4(CH2OH)NH2-
1,2, C6H4(SH)NH2-1,2, C6H4(OH)CHO-1,2, C6F5CHO,
C6HF4CHO-2,3,5,6, C6H3F2CHO-2,6, C6H3FCHO-2,
C6F5NH2 and C6F5NHNH2 (Aldrich) were used as supplied.
4.3. Syntheses of 2-[(polyfluorobenzylidene)amino]
phenols
4.4. Syntheses of dibenzo[b,f][1,4]oxazepines
A solution of the appropriate poly¯uorobenzaldehyde and
a stoichiometric quantity of 2-aminophenol in CH2Cl2 over
anhydrous MgSO4 was left at room temperature for 24 h.
The solution was ®ltered and the solvent removed by rotary
evaporation affording the product.
4.4.1. 1,2,3,4-Tetrafluorodibenzo[b,f][1,4]oxazepine (2a)
A solution of 1a (0.152 g, 0.52 m mol) in ethanol
(50 cm3) was treated with an excess of NEt3 (ca. 1 cm3)
at re¯ux. After 3 h the solvent was removed by rotary
evaporation to yield an orange oil, which was extracted
several times with hexane. The extracts were combined and
the solvent removed by rotary evaporation to give 2a as a
yellow solid (0.108 g, 78%). Analysis: calc. for C13H5F4NO:
C, 58.4; H, 1.9; N, 5.2; found: C, 57.9; H, 2.3; N, 5.0%.
4.3.1. 2-[(2,3,4,5,6-Pentafluorobenzylidene)amino]
phenol (1a)
Yellow crystals, yield 74%. Analysis: calc. for
C13H6F5NO: C, 54.4; H, 2.1; N, 4.9; found: C, 54.3; H,
2.1; N, 5.1%. HRMS: C13H6F5NO requires 287.03646;
‡
HRMS: C13H5F4NO requires 267.03073; found: M
‡
found: M 287.03696. IR: nmax(KBr) (cmÀ1) 3368, 1650,
267.02969. IR nmax(KBr) (cmÀ1) 2965, 1644, 1608, 1517,
1494, 1473, 1449, 1400, 1305, 1263, 1216, 1180, 1127,
1032, 1012, 963, 921, 875, 852, 826, 770, 738, 683, 668,
642, 615, 575, 549 and 462. 1H NMR: 8.67 (1H, s, HC=N),
7.39 (1H, m), 7.28 (2H, m), 7.20 (1H, m). 19F NMR:
À144.30 (1F, m), À149.31 (1F, dd, J ꢁ 19:5, 19.5),
À1565.94 (1F, m), À160.91 (1F, m).
1619, 1597, 1584, 1525, 1495, 1481, 1420, 1387, 1369,
1291, 1247, 1212, 1176, 1150, 1130, 1027, 1013, 965, 953,
1
936, 819, 755, 745, 673, 653, 570 and 471. H NMR: 8.82
(1H, s, HC=N), 7.35 (1H, dd, J 8.0, 1.3, C6H4), 7.28 (1H, m,
C6H4), 7.04 (1H, dd, J 8.2, 1.2, C6H4), 6.93 (1H, m, C6H4).
19F NMR: À142.25 (2F, dm, J 15.7, Fortho), À149.76 (1F, t, J
20.8, Fpara), À161.60 (2F, m, Fmeta).
4.4.2. 1,2,4-Trifluorodibenzo[b,f][1,4]oxazepine (2b)
Yield 67%. HRMS: C13H6F3NO requires 249.04015;
4.3.2. 2-[(2,3,5,6-Tetrafluorobenzylidene)amino]
phenol (1b)
‡
found: M 249.04098. IR: nmax(KBr) (cmÀ1) 1627, 1606,
1591, 1495, 1473, 1441, 1372, 1287, 1265, 1253, 1214,
Yellow crystals, yield 77%. Analysis: calc. for
C13H7F4NO: C, 58.0; H, 2.6; N, 5.2; found: C, 57.3; H,
2.8; N, 5.1%. HRMS: C13H7F4NO requires 269.04638;
1177, 1120, 1099, 1031, 960, 924, 853, 804, 768, 739, 722,
1
649 and 555. H NMR [(CD3)2CO]: 8.66 (1H, s, HC=N),
‡
found M 269.04707. IR: nmax(KBr) (cmÀ1) 3358, 1645,
7.51 (1H, m), 7.24 (3H, m), 7.11 (1H, m). 19F NMR
[(CD3)2CO]: À135.58 (1F, dm, J 13.9), À140.37 (1F, dm,
J 20.8), À147.28 (1F, m).
1626, 1595, 1495, 1483, 1390, 1378, 1286, 1273, 1249,
1205, 1178, 1145, 1047, 939, 845, 808, 753, 745, 699, 656,

98
C.L. Allaway et al. / Journal of Fluorine Chemistry 115 (2002) 91±99
4.4.3. 1-Fluorodibenzo[b,f][1,4]oxazepine (2c)
Yield 66%. HRMS: C13H8FNO requires 213.05899;
to give 5 as a yellow-brown crystalline solid. Yield 0.49 g,
79%. Analysis: calc. for C13H8F5NO: C, 54.1; H, 2.35; N, 4.9;
‡
found: M 213.05788. IR: nmax(KBr) (cmÀ1) 1674, 1622,
1585, 1484, 1379, 1270, 1222, 1102, 1065, 1031, 980, 885,
found: C, 54.0; H, 2.8; N, 4.8%. HRMS: C13H8F5NO requires
289.05261; found: M 289.05298. IR: nmax(KBr) (cmÀ1
‡
)
828, 737, 707, 612 and 543. 1H NMR: 8.55 (1H, s, HC=N),
3328, 2708, 1658, 1602, 1522, 1504, 1460, 1447, 1417,
1356, 1325, 1300, 1278, 1247, 1185, 1157, 1120, 1113,
1060, 1043, 1021, 950, 929, 871, 854, 830, 764, 747, 731,
685, 600, 583, 562 and 462. 1H NMR: 6.86 (1H, m, C6H4),
6.78 (1H, m, C6H4), 6.69 (2H, m, C6H4), 4.93 (1H, br s, NH),
4.47 (2H, s, CH2). 19F NMR: À144.10 (2F, m, Fortho),
À155.43 (1F, t, J 20.7, Fpara), À162.28 (2F, m, Fmeta).
7.32 (2H, m), 7.15 (2H, m), 7.04 (1H, m), 6.86 (2H, m). 19
F
NMR: À115.81 (s).
4.5. Thermolysis of 2-[(2,3,4,5,6-
pentafluorobenzylidene)amino]phenol (1a)
A solution of 1 (0.350 g, 1.20 m mol) in ethanol (70 cm3)
was heated under re¯ux for 96 h. After cooling, the solvent
was removed by rotary evaporation to give a red solid, which
was extracted with hexane. Removal of the solvent from the
hexane extract yielded 2a as yellow crystals. Yield 0.160 g
(50%). The residue was obtained as 0.135 g of red solid,
which was washed with a small amount of chloroform and
dried in vacuo. (Found: C, 44.0; H, 2.20; N, 5.15); nmax(KBr)
(cmÀ1) 3254, 1636, 1580, 1535, 1497, 1473, 1449, 1395,
1315, 1293, 1262, 1225, 1156, 1105, 1019, 758, 599 and
473. 1H NMR [(CD3)2CO]: 8.93 (1H, s, HC=N), 7.60 (3H,
m, C6H4), 7.43 (1H, m, C6H4). 19F NMR [(CD3)2CO)]:
À144.70 (1F, m, C6F4-terminal), À151.08 (1F, dd, J ꢁ
23:4, 23.4, C6F4), À158.20 (1F, dd, J 20.7, 10.4, C6F4-
terminal), À162.20 (1F, dd, J ꢁ 20:7, 20.7, C6F4).
4.8. 2-[(2,3,4,5,6-Pentafluorobenzylidene)amino]-
thiophenol (7a) and 2-(2,3,4,5,6-pentafluorophenyl)-2,3-
dihydrobenzothiazole (7b)
A solution of 2-aminothiophenol (1.40 g, 0.011 mol) and
penta¯uorobenzaldehyde (2.27 g, 0.012 mol) in CH2Cl2
(70 cm3) over anhydrous MgSO4 (ca. 2 g) was left at room
temperature for 24 h. The solution was ®ltered and the
solvent removed by rotary evaporation affording 2.77 g of
a mixture of 7a and 7b.
Yield 83%. Analysis: calc. for C13H6F5NS: C, 51.5; H,
2.0; N, 4.6; found: C, 51.3; H, 1.9; N, 4.6%. HRMS:
‡
C13H6F5NS requires 303.14112; found: M 303.01405.
IR: nmax(KBr) (cmÀ1) 3402, 2963, 1652, 1618, 1572,
1523, 1498, 1462, 1419, 1378, 1316, 1262, 1153, 1137,
1054, 1014, 966, 861, 799, 760, 732, 697, 663, 563, 474 and
458. 7a 1H NMR: 8.53 (1H, s, HC=N), 8.11 (1H, dd, J 8.4,
4.6. 2-[(2,3,4,5,6-Pentafluorophenylimino)methyl]phenol
(3)
0.7, C6H4), 7.90 (1H, dd, J 8.5, 1.1, C6H4), 7.45 (2H, m). 19
F
A solution of penta¯uoroaniline (1.00 g, 5.46 m mol) and
salicylaldehyde (0.75 g, 6.14 m mol) in CH2Cl2 (100 cm3)
was re¯uxed over anhydrous MgSO4 (ca. 1 g) for 14 h. The
solution was ®ltered and the solvent removed by rotary
evaporation affording a yellow solid, which was washed
with hexane (100 cm3) to remove unreacted starting materi-
als and dried in vacuo to yield pale yellow crystals of 3. Yield
0.335 g, 21%. Analysis: calc. for C13H6F5NO: 54.4; H, 2.1;
N, 4.9; found: C, 54.1; H, 2.2; N, 4.9%. IR: nmax(KBr)
(cmÀ1) 1652, 1614, 1577, 1510, 1488, 1463, 1432, 1392,
1367, 1278, 1236, 1217, 1205, 1156, 1033, 979, 902, 790,
763, 722 and 468. 1H NMR: 8.75 (1H, s, HC=N), 7.37 (2H,
m, C6H4), 6.98 (1H, d, J 8.4, C6H4), 6.91 (1H, dd, J ꢁ 7:5,
7.5, C6H4). 19F NMR: À152.36 (2F, dd, J 20.7, 6.1, Fortho),
À158.58 (1F, t, J 20.9, Fpara), À162.75 (2F, m, Fmeta).
NMR: À138.82 (2F, m, Fortho), À150.56 (1F, t, J 20.5, Fpara),
À161.08 (2F, m, Fmeta). 7b 1H NMR: 6.97 (1H, dd, J 7.5, 2.3,
C6H4), 6.89 (1H, m, C6H4), 6.71 (1H, m, C6H4), 6.62 (1H, s,
NCHS), 6.59 (1H, dd, J 7.8, 0.8, C6H4), 4.23 (1H, br s, NH).
19F NMR: À142.21 (2F, dd, J 22.0, 7.0, Fortho), À154.49 (1F,
t, J 21.0, Fpara), À161.85 (2F, m, Fmeta).
4.9. 2-(2,3,4,5,6-Pentafluorophenyl)-1,4-dihydro-2H-
benzo[d][1,3]oxazine (8)
A solution of 2-aminobenzyl alcohol (0.58 g, 4.7 m mol)
and penta¯uorobenzaldehyde (0.93 g, 4.7 m mol) in CH2Cl2
(100 cm3) over anhydrous MgSO4 (ca. 2 g) was left at room
temperature for 24 h. The solution was ®ltered and the
concentrated to 20 cm3 by rotary evaporation. Addition of
hexane (20 cm3) gave cream crystals of 8, which were
washed with hexane and dried in vacuo. Yield 53%. Ana-
lysis: calc. for C14H8F5NO: C, 55.8; H, 2.7; N, 4.65; found:
4.7. Synthesis of 2-(2,3,4,5,6-
pentafluorobenzylamino)phenol (5)
C, 56.0; H, 2.6; N, 4.8%. HRMS: C14H8F5NO ‡ H requires
‡
Sodium borohydride (0.66 g, 17.5 m mol) was added in
small portions to 1a (0.62 g, 2.16 m mol) in methanol
(80 cm3) and the mixture left for 12 h. Water (10 cm3) was
added and the methanol removed by rotary evaporation. The
product was extracted into dichloromethane (2 Â 50 cm3).
The combined extracts were dried over magnesium sulphate
and ®ltered. The solvent was removed by rotary evaporation
302.06043; found: M 302.06091. IR: nmax(KBr) (cmÀ1
)
3368, 1650, 1619, 1597, 1585, 1526, 1496, 1481, 1420,
1388, 1369, 1292, 1316, 1247, 1212, 1176, 1150, 1130,
1028, 1013, 965, 954, 937, 875, 819, 755, 745, 673, 653,
635, 570 and 471. 1H NMR: 7.08 (1H, m, C6H4), 6.90 (2H,
m, C6H4), 6.73 (1H, d, J 7.9, C6H4), 5.84 (1H, s, NCHO),
5.11, 5.02 (2H, AB quartet, J 14.0, C6H4CH2O). 19F NMR:

C.L. Allaway et al. / Journal of Fluorine Chemistry 115 (2002) 91±99
99
Ê
À142.18 (2F, d, J 6.0, Fortho), À152.77 (1F, t, J 20.5, Fpara),
À161.40 (2F, m, Fmeta).
(monoclinic, P21/c, a ˆ 12:101, b ˆ 7:373, c ˆ 12:890 A
and b ˆ 95:898) [25].
4.10. 2-[N0-(2,3,4,5,6-
pentafluorobenzylidene)hydrazino]phenol (9)
Acknowledgements
Salicylaldehyde (0.21 g, 1.72 m mol) and penta¯uorohy-
drazine (0.35 g, 0.177 m mol) were treated as in 4.6 yielding
0.34 g of cream solid. Yield 66%. Analysis: calc.
C14H8F5N2O requires C, 51.7; H, 2.3; N, 9.3; found: C,
We thank Prof. D.R. Boyd and Dr. P. Stevenson for helpful
discussion.
51.5; H, 1.9; N, 9.1%. HRMS: C13H8F5N2O requires
302.04785; found: M 302.04781. IR: nmax(KBr) (cmÀ1
References
‡
)
3304, 1660, 1622, 1601, 1571, 1545, 1532, 1501, 1459,
1388, 1263, 1218, 1202, 1170, 1143, 1130, 1104, 1023, 972,
950, 801, 786, 759, 670, 575 and 472. 1H NMR: 10.35 (1H,
s), 7.97 (1H, s), 7.28 (1H, m, C6H4), 7.17 (1H, dd, J 7.7, 1.6,
C6H4), 6.99 (1H, d, J 8.2, C6H4), 6.91 (1H, m, C6H4). 19F
NMR: À157.51 (2F, d, J 20.0, Fortho), À162.82 (2F, dd, J
22.5, 20.0, Fmeta), À166.67 (1F, tm, J 22.5, Fpara).
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4.11. X-ray crystal structure determinations
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265.
Crystals of 1a, 2a and 3 were grown from dichloro-
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the SAINT-NT [24] software using j/o scans. Cell para-
meters for 3 were determined on a Siemens P3 diffract-
ometer with graphite monochromated Cu Ka radiation at
room temperature. Crystal stabilities for 1a and 2a were
monitored via recollection of the ®rst set of frames. There
were no signi®cant variations (<Æ1%). Cell parameters
were obtained from 1959 and 3183 accurately centred
re¯ections in the y range 2±288 for 1a and 2a, respectively.
The structures were solved using direct methods and
re®ned with the SHELXTL program package [25] and the
non-hydrogen atoms were re®ned with anisotropic thermal
parameters. Hydrogen-atom positions were located from
difference Fourier maps and then fully re®ned for 1a and
[9] B. Ballantyne, D.W. Swanston, Acta Pharmacol. Toxicol. 35 (1974)
412.
[10] P. Holland, Br. J. Dermatol. 90 (1974) 657.
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[13] J.W. Clayton Jr., Fluor. Chem. Rev. 1 (1967) 197.
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D.R. Russell, G.C. Saunders, J. Chem. Soc., Dalton Trans. (1996)
3215.
P
2
2a. The function minimised was ‰wꢀjF0j À jFcj †Š with
2
2
re¯ection weights wÀ1 ˆ ‰s2jF0j ‡ ꢀg1P† ‡ ꢀg2P†Š where
[19] T.J. Petcher, H.-P. Weber, J. Chem. Soc., Perkin Trans. II (1976)
1415.
 Â
[20] M. Nogradi, W.D. Ollis, I.O. Sutherland, J. Chem. Soc., Chem.
2
2
P ˆ ‰maxjF0j ‡ 2jFcj Š=3. C rystallographic data (excluding
structure factors) for the structures in this paper have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication nos. CCDC 174440 and
174441. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, (fax: ‡44-1223-336033 or e-mail: deposit@ccdc.-
cam.ac.uk).
Commun. (1970) 158.
[21] D.B. Cosulich, F.M. Lovell, Acta Cryst. B33 (1977) 1147.
[22] A.W.H. Wardrop, G.L. Sainsbury, J.M. Harrison, T.D. Inch, J. Chem.
Soc., Perkin Trans. I (1976) 1279.
[23] S.V. Lindeman, V.G. Adrianov, S.G. Kravcheni, V.M. Potapov, K.A.
Potekhin, Y.T. Struchkov, Zh. Strukt. Khim. 22 (1981) 123. (CSD
code BANGOM02).
[24] SAINT-NT, Program for Data Collection and Data Reduction,
Bruker-AXS, Madison, WI, 1998.
The cell parameters for 3 (monoclinic, P21/c, a ˆ
Ê
12:104(13), b ˆ 7:413(8), c ˆ 12:861(19) A and b ˆ
[25] G.M. Sheldrick, SHELXTL Version 5.0, A System for Structure
Solution and Refinement, Bruker-AXS, Madison, WI, 1998.
95:91(10)8) are entirely consistent with the a2 polymorph