Synthesis of cyanodibenzo[1,4]dioxines and their derivatives by cyano-activated fluoro displacement reactions

Article abstract of DOI:10.1039/b008508l

A new group of cyanodibenzo[1,4]dioxines have been synthesized by cyano-activated fluoro displacement reactions between cyanodifluorobenzenes and catechols in DMF at 130°C in the presence of potassium carbonate. This route is exemplified by the synthesis of cyanodibenzo[1,4]dioxines from several substituted catechols. The reactions are virtually quantitative. Cyanodibenzo[1,4]dioxines were hydrolysed with potassium hydroxide in ethylene glycol or converted into amide derivatives to yield additional substituted dibenzo[1,4]dioxines. Cyanodibenzo[1,4]-dioxines are fluorescent and excitation and emission data are presented. Improved syntheses of 4,5-diphenyl-veratrole and 3,6-dimethylcatechol, the latter involving reduction of a phenolic Mannich base at atmospheric pressure, have been elaborated.

Full text of DOI:10.1039/b008508l

View Article Online / Journal Homepage / Table of Contents for this issue
Synthesis of cyanodibenzo[1,4]dioxines and their derivatives by
cyano-activated Ñuoro displacement reactions¤
Geo†rey C. Eastmond,*a Jerzy Paprotny,a Alexander Steinera and Linda Swansonb
a Department of Chemistry, University of L iverpool, L iverpool, UK L 69 7ZD.
E-mail: eastm=liv.ac.uk
b Department of Chemistry, University of L ancaster, L ancaster, UK L A1 4Y A
Received (in Cambridge) 19th October 2000, Accepted 23rd December 2000
First published as an Advance Article on the web 21st February 2001
A new group of cyanodibenzo[1,4]dioxines have been synthesized by cyano-activated Ñuoro displacement reactions
between cyanodiÑuorobenzenes and catechols in DMF at 130 ¡C in the presence of potassium carbonate. This
route is exempliÐed by the synthesis of cyanodibenzo[1,4]dioxines from several substituted catechols. The reactions
are virtually quantitative. Cyanodibenzo[1,4]dioxines were hydrolysed with potassium hydroxide in ethylene glycol
or converted into amide derivatives to yield additional substituted dibenzo[1,4]dioxines. Cyanodibenzo[1,4]-
dioxines are Ñuorescent and excitation and emission data are presented. Improved syntheses of 4,5-diphenyl-
veratrole and 3,6-dimethylcatechol, the latter involving reduction of a phenolic Mannich base at atmospheric
pressure, have been elaborated.
It was against this background that we recently reported,
brieÑy, the facile, quantitative synthesis of a new family of sub-
Introduction
Hazardous chlorine-substituted dibenzo[1,4]dioxines apart,
there is current interest in the efficient synthesis of substituted
dibenzo[1,4]dioxines, some derivatives of which, e.g.
dibenzo[1,4]dioxine-1-carboxamide, have potentially useful
biomedical properties, such as signiÐcant in vivo anti-tumor
activity.1 Dibenzo[1,4]dioxine-1- and -2-carboxylic acid were
Ðrst prepared in 1943 and 1936,2,3 respectively, but the bio-
logical activity of certain dibenzo[1,4]dioxines1,4,5 has recent-
ly generated interest in an efficient synthetic route to the
relatively unexplored substituted dibenzo[1,4]dioxines, espe-
cially dibenzo[1,4]dioxine-1-carboxylic acid, and their deriv-
atives.4,6,7
Lee and Denny reviewed routes to substituted dibenzodiox-
ines and favored reaction between catechol (or substituted
catechols) and activated 1,2-dichlorobenzenes or 1-chloro-2-
nitrobenzenes as the most useful route to provide the com-
pounds in high overall yields.6 Unsubstituted dibenzo[1,4]-
dioxine was obtained in good yield by treating catechol with
potassium metal in dry HMPA (a carcinogenic solvent), to
form the dianion at 20 ¡C, and then with chloro-2-nitro-
benzene at 110 ¡C (71% yield) or with 1,2-dinitrobenzene
(87%) but in negligible yields on reaction with 1,2-diÑuoro- or
1,2-dichloro-benzene. Ester activation was used to produce
substituted dioxines as precursors to dibenzo[1,4]dioxine-1-
and -2-carboxylic acids, wherein isopropyl esters of 1- and 2-
substituted acids were produced in 15È60% yields. More
recently Hellberg and Pelcman employed copper-mediated
aryl ether synthesis, with 2,3-dihydroxynaphthalene, to
prepare dibenzo[1,4]dioxines having naphthalene substit-
uents, in yields of about 20%.8 Most previous syntheses of
dibenzo[1,4]dioxines involving nucleophilic displacement
reactions have employed nitro-activation and displacement of
chloride or nitro groups and yields have generally been
modest. Cyano-activation and Ñuoro displacement have not
been used widely, if at all.
stituted dibenzo[1,4]dioxines, namely, cyanodibenzo[1,4]-
dioxines,9 which can be hydrolysed to carboxy-substituted
dibenzo[1,4]dioxines and, subsequently, converted into other
derivatives. The cyanodibenzo[1,4]-dioxines were prepared
via a simple reaction (Scheme 1) between a catechol (1) and
2,3- or 3,4-diÑuorobenzonitrile (2, 3) in DMF at 130 ¡C in the
presence of potassium carbonate. This process involves both
the facile cyano-activated ortho- or para-Ñuoro displacement
reaction and then, presumably, the subsequent and less-facile
meta-Ñuoro displacement reaction, accelerated as an intramol-
ecular cyclization reaction. We had previously demonstrated
that intermolecular cyano-activated ortho- and para-Ñuoro
displacement reactions between catechol and 1-cyano-2-
Ñuorobenzonitrile or 1-cyano-4-Ñuorobenzonitrile proceeded
readily under the same reaction conditions at 130 ¡C but meta-
Ñuoro displacement from 1-cyano-3-Ñuorobenzonitrile
required an elevated temperature of 170 ¡C.10,11
In this paper we exemplify the procedure used and describe,
in more detail, the synthesis and characterization of a larger
family of cyanodibenzo[1,4]dioxines and carboxydibenzo-
[1,4]dioxines derived therefrom. We also illustrate the
further functionalization of the dibenzo[1,4]dioxines by con-
version into other potentially useful derivatives. In addition, we
make comparisons between the cyano-activated and related
nitro-activated Ñuoro displacement reactions. Character-
ization data for the compounds, including Ñuorescence data,
are reported as ESI.
Results and discussion
In our preliminary study it was demonstrated that catechol
(1a) and the catechol derivative 2,3-dihydroxynaphthalene (1b)
will undergo a double Ñuoro displacement reaction with 2,3-
or 3,4-diÑuorobenzonitrile (2, 3) to yield
a 1- or 2-
cyanodibenzo[1,4]dioxine (6, 7), respectively.9 Equivalent
reactions between a series of catechol derivatives and the same
diÑuorobenzonitriles have now been investigated, i.e. in each
reagent hydroxyl groups or Ñuoro substituents are ortho to
each other. Substituted catechols were chosen such that, in
most cases, only a single cyanodibenzo[1,4]dioxine regio-
¤ Electronic supplementary information (ESI) available: NMR and
Ñuorescence spectral data for compounds 6 and 7, crystal structures of
6a, 11 and 16. See http://www.rsc.org/suppdata/nj/b0/b008508l/
DOI: 10.1039/b008508l
New J. Chem., 2001, 25, 379È384
379
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2001

View Article Online
Scheme 1
isomer could be formed. 4,5-Dimethylcatechol (1c) was pre-
pared according to a literature procedure.12 In addition, 3,6-
dimethylcatechol (1d) was synthesized by reduction of 3-
methyl-6-morpholinomethylcatechol. The reduction of phe-
nolic Mannich bases is usually performed under high
pressures of hydrogen.13 However, it was demonstrated that
the bases can be reduced at atmospheric pressure in reÑuxing
methanol by using ammonium formate with Pd/C catalysis
(Scheme 2).
To extend the synthesis to other cyanodibenzo[1,4]dioxines
for which only one regioisomer is possible, 4,5-
diphenylcatechol (1e) was synthesized and an improved prep-
aration of this substance was developed. Previous workers
prepared 4,5-diphenylcatechol by a dienoneÈphenol rearrange-
ment.14 In contrast, the use of a Suzuki coupling reaction
between 4,5-dibromoveratrole and phenylboronic acid was
investigated (Scheme 3). This led to 4,5-diphenylveratrole in
85% yield and this was demethoxylated to 4,5-
diphenylcatechol in 99% yield.
Fluoro displacement reactions between both compounds 2
and 3 and several catechol derivatives (1a–1e) were investi-
gated. In all cases the reactions were performed in DMF at
130 ¡C in the presence of potassium carbonate; these reaction
conditions were identical to those used previously in order to
synthesize bis(ether dinitrile)s, such as 1,2-bis(4-amino-
phenoxy)benzene from 1a and 4-Ñuorobenzonitrile.11 As can
be seen from the data presented, in all cases cyanodibenzo-
[1,4]dioxines were formed in high yields, in almost all cases in
excess of 90% and usually virtually quantitative; 2-cyano-7,8-
dimethyldibenzo[1,4]dioxine was formed in 80% yield. The
products were readily puriÐed to yield materials with sharp
melting points and further characterized by elemental analysis,
FTIR and 1H and 13C NMR. In addition, the identity of 1-
cyanodibenzo[1,4]dioxine (6a) was conÐrmed by single crystal
X-ray di†raction (see ESI¤). It crystallizes in monoclinic space
group C2/c with two molecules in the asymmetric unit. Both
crystallographically independent molecules are planar within
a deviation of only 0.02 A. The molecules are arranged in a
herringbone pattern which is commonly observed in crystal
structures of condensed aromatic systems.15
In addition to using symmetrical catechol derivatives, which
can only lead to a single regioisomeric cyanodibenzo[1,4]-
dioxine, reactions were also performed with a small number of
unsymmetrical catechols which could lead to two regio-
isomers. Thus 3-methylcatechol (1f) and 3,5-di-tert-butyl-
catechol (1h) were treated with 3, and alizarin (1,2-
dihydroxyanthraquinone) (1j) with
cyanodibenzo[1,4]dioxines.
2
to synthesize
Compounds 1f and 1h both gave high yields of 2-
cyanodibenzo[1,4]dioxines. Gas chromatography of the pro-
ducts demonstrated, in each case, the presence of two
products, presumably the two possible regioisomers, 2-cyano-
6-methyldibenzo[1,4]dioxine 7f and 2-cyano-9-methyl-
dibenzo[1,4]dioxine 7g from the catechol 1f and 2-cyano-6,8-
di-tert-butyldibenzo[1,4]dioxine 7h and 2-cyano-7,9-di-tert-
butyldibenzo[1,4]dioxine 7i from 1h, in equal quantities. Thus
the Ñuoro displacement reactions showed little or no regiosel-
ectivity due to the position of substituents on the catechol. No
attempt was made to separate or characterize the individual
isomers. A corresponding Ñuoro displacement reaction was
performed with alizarin primarily to demonstrate the potential
scope of the reaction; Sutherland et al.16 described the synthe-
sis of the corresponding unsubstituted benzo[b]anthracen-9,
10-diono[1,2-e][1,4]dioxine and there is potentially greater
interest in substituted dibenzo[1,4]dioxines. Reaction
between compounds 1j and 2 gave a violet powder, when dry,
Scheme 2
Scheme 3
380
New J. Chem., 2001, 25, 379È384

View Article Online
from which only compound 6j was isolated in modest yield
(28%) as a bright yellow crystalline solid; no attempt was
made to investigate the formation of regioisomers or to iden-
tify other products. Compound 6j was Ñuorescent and its Ñuo-
rescence could be switched on and o† by reduction and
oxidation, respectively.
In general, the nitro-activated nucleophilic displacement
reactions are not as clean as the nitrile activated processes and
we have not pursued these reactions further.
In view of the interest in functionalized dibenzo[1,4]-
dioxines, we converted the cyanodibenzo[1,4]dioxines into a
variety of other dibenzo[1,4]dioxine derivatives. We investi-
gated the hydrolysis of the cyanodibenzo[1,4]dioxines. Pre-
viously we had demonstrated that nitrile groups in
bis(cyanophenoxy)benzenes are readily hydrolysed by reÑux-
ing with methanolic potassium hydroxide.11 Cyanodibenzo-
[1,4]dioxines proved to be more resistant to hydrolysis but we
demonstrated that they could be hydrolysed readily at higher
temperatures. Thus, on reÑuxing with potassium hydroxide in
ethylene glycol complete hydrolysis (evolution of ammonia)
was achieved in about 15 min. High yields (in excess of 95%)
of the corresponding carboxydibenzo[1,4]dioxines 8 and 9
were obtained in this way (Scheme 1).
Interest has been expressed in amides of dibenzo[1,4]-
dioxines.1 We therefore considered the direct conversion of
cyanodibenzo[1,4]dioxines into amides; indirect conversion
via the carboxydibenzo[1,4]dioxine should be trivial. Despite
the relative difficulty in hydrolysing cyanodibenzo[1,4]-
dioxines to carboxydibenzo[1,4]dioxines, partial hydrolysis to
the dibenzo[1,4]dioxinecarboxylic acid amides proved easy.
Radziszewski, in 1885, Ðrst described the conversion of a
nitrile into an amide by reaction with hydrogen peroxide
under alkaline conditions;18 this reaction became a standard
route for synthesis of amides from nitriles and subsequently
many variations of this procedure have been reported.19 We
adapted the Radziszewski reaction to cyanodibenzo[1,4]-
dioxines. For the conversion of compound 7a a 1 : 1 acetoneÈ
ethanol mixture was found to be a suitable solvent system.
Reaction was performed in sodium hydroxide solution (6 M).
Hydrogen peroxide (30%) was added to the reaction mixture
which was heated to 60 ¡C for 4 h. The product, dibenzo[1,4]-
dioxine-2-carboxamide (12), was isolated by acidifying the
reaction mixture with hydrochloric acid. Volatiles were then
removed and the product was diluted with acetonitrile,
warmed to about 80 ¡C and Ðltered while warm. The yield of
the crude product, which was readily puriÐed by rec-
rystallization from acetonitrile, was 93%.
We presume that, in the Ðrst step of Scheme 1, the more-
facile ortho- or para-cyano-activated Ñuorine is displaced Ðrst
to form intermediates 4 and 5, respectively. Then, rather than
undergoing a second intermolecular Ñuoro displacement reac-
tion between the remaining hydroxyl on the catechol and
another molecule of diÑuorobenzonitrile (Scheme 1, path B),
an accelerated rapid intramolecular Ñuoro displacement reac-
tion involving ring closure proceeds preferentially to give the
cyano-substituted dibenzo[1,4]dioxine (Scheme 1, path A).
In synthetic organic chemistry, nitro-activated nucleophilic
displacement reactions are more widely used than their cyano-
activated equivalents. It is therefore relevant to compare the
two processes in the current context. While synthesizing
bis(ether dinitrile)s by treating diols with Ñuorobenzonitriles
we had demonstrated that, in addition to the ortho- and para-
cyano-activated Ñuoro displacements, which proceed readily
in DMF at 130 ¡C, it was also possible to perform meta-Ñuoro
displacement at 170 ¡C.11 In contrast, while nitro-activated
ortho- and para-Ñuoro displacement reactions would also
proceed readily at 130 ¡C the corresponding meta-Ñuoro dis-
placement would not proceed even at 170 ¡C.17 Thus it was
possible to take advantage of this fact and to prepare 1,2-
bis(4-amino-2-Ñuorophenoxy)benzene (10a) by treating two
molar equivalents of compound 3 with 1 molar equivalent of
catechol 1a and reduction of the dinitro compound so formed;
we did not attempt to prepare the equivalent bis(ether
dinitrile) because of anticipated complications over com-
petition between, say, para- and meta-Ñuoro displacement
which could lead to a mixture of products.
In an attempt to increase the Ñuorine content of dinitro
compounds, as precursors to bis(ether amine)s, by treating 2
molar equivalents of the nitrile 3 with 1 molar equivalent of
3-Ñuorocatechol (to form 10b), it was found that the reaction
was not clean but gave dark products. The only crystalline
compound successfully isolated from the reaction mixture
proved to be a Ñuoronitrodibenzo[1,4]dioxine (11). It was as a
result of this Ðnding that the reactions between catechols and
diÑuorobenzonitriles were undertaken. Two Ñuoronitro-
dibenzo[1,4]dioxine isomers were possible from the above
reaction, viz. 6-Ñuoro-2-nitrodibenzo[1,4]dioxine (11b) and 9-
Ñuoro-2-nitrodibenzo[1,4]dioxine (11a). The overall product
gave good elemental analysis for Ñuoronitrodibenzo[1,4]
dioxine. GC/MS showed the presence of two products, in
approximately equal proportions, both of which gave molecu-
lar ions corresponding to Ñuoronitrodibenzo[1,4]dioxines.
Crystal structure analysis on the crystalline product obtained
from MeCN also shows the existence of two isomers as indi-
cated by statistical disorder of Ñuorine atoms at the 1 and 4
positions (see ESI¤). ReÐnement of the occupancy factors of
both domains gives a ratio of 85 : 15 for isomers 9-Ñuoro-2-
nitro- and 6-Ñuoro-2-nitro-dibenzo[1,4]dioxine in the crystal.
Although a value of 15% for one domain seems to be rather
low to be accounted for in the reÐnement, the R value
dropped from 0.071 to 0.037 by introducing split F and H
positions in the reÐnement. In contrast to compound 6a the
dibenzodioxine core is slightly bent along the OÈO vector to
175.7¡.
For a second example we adapted the Ritter reaction which
can be used to convert nitriles into alkyl-substituted second-
ary amides with oleÐns, or oleÐns generated in situ, in the
presence of sulfuric acid.20 To demonstrate the applicability of
the Ritter reaction to cyanodibenzo[1,4]dioxines, compound
7a was suspended in acetic acid and ButOH added at 40È
50 ¡C. This was followed by a small amount of concentrated
sulfuric acid which caused the reaction mixture to become
clear. The solution was stirred at 40 ¡C for 2 h. On cooling to
about 0 ¡C the crystalline product dibenzo[1,4]dioxine-2-(N-
tert-butyl)carboxamide (13) was then isolated in 80% yield.
Experimental
General
IR spectra were determined from KBr discs on a Perkin-
Elmer FT-IR spectrometer Paragon 1000, NMR spectra on a
Bruker AMX-400 spectrometer. Accurate masses were mea-
sured using a VG analytical 7070E spectrometer and masses
of molecular ions on a TR10 spectrometer. Melting points
were determined with a Mettler hot stage attached to a polar-
izing microscope, using a heating rate of 1 ¡C min~1. 13C
NMR assignments and crystal structures of compounds 6a, 11
and 16 are in the ESI¤.
New J. Chem., 2001, 25, 379È384
381

View Article Online
Crystallography
56.05, 113.67, 126.25, 127.87, 129.95, 133.03, 141.43 and 148.19.
Calc. for C
H
O : C, 82.73, H, 6.24. Found: C, 82.73; H,
20 18
2
Crystal data were collected on a Stoe-IPDS di†ractometer at
293 K using Mo-Ka radiation (j \ 0.710 73 A). Full-matrix
least square reÐnements on F2 using all data (SHELX 97).21
6a: C H NO , M \ 209.20, monoclinic, space group C2/c,
6.30%. The crystal structure was determined (see ESI¤).
(ii) To 4,5-diphenylveratrole (1.75 g, 6 mmol) in CH Cl
2
2
(100 mL) under N at [78 ¡C boron tribromide (6 mL) in
2
CH Cl (60 mL) was added dropwise. The reaction mixture
13
7
2
2
2
a \ 27.732(6), b \ 7.833(2), c \ 19.416(4) A, b \ 106.80(3)¡,
was then added gradually in small portions to water (15 mL).
The water was changed four times when its pH reached 6.5È
7.0. The CH Cl layer was dried and solvent removed to yield
the crude catechol (1e) (1.57 g, 99%). The product was puriÐed
either by sublimation (250 ¡C, 0.5 Torr) or by recrystallization
from acetoneÈhexane (35 : 65) to give a sample of mp 146È
V \ 4038(2)
A
Ž
3,
Z \ 16,
k(Mo-Ka) \ 0.094
mm~1,
R1[I [ 2p(I)] \ 0.046, wR2 (all data) \ 0.112, 10 366 mea-
2
2
sured and 2555 independent reÑections, R \ 0.136. 11:
int
C
H FNO , M \ 247.18, monoclinic, space group P2 /c,
12
6
4
1
a \ 10.641(2), b \ 5.9763(7), c \ 16.382(2) A, b \ 102.50(2)¡,
V \ 1017.1(2)
AŽ 3, Z \ 4, k(Mo-Ka) \ 0.135 mm~1,
146.8 ¡C (lit.14 142È143 ¡C). Calc. for C
H
O : C, 82.42; H,
18 14
2
R1[I [ 2p(I)] \ 0.037, wR2 (all data) \ 0.109, 7413 measured
5.37. Found: C, 81.97, H, 5.34%. HRMS: calc. for C
H
O
18 14
2
and 1919 independent reÑections, R \ 0.027. The F atom in
m/z 262.099 37, found 262.099 22.
int
11 is disordered on two positions (see Discussion for details).
16:
C
H
O , M \ 290.38, orthorhombic, space group
Preparation of cyanodibenzo[1,4]dioxines: general procedure
In a three-necked Ñask equipped with a magnetic stirring bar,
20 18
2
P2 2 2 , a \ 8.6688(13), b \ 9.4019(10), c \ 19.222(2) A,
1 1 1
V \ 1566.7(3)
AŽ 3, Z \ 4, k(Mo-Ka) \ 0.078 mm~1,
N
inlet, DeanÈStark trap and thermometer were placed the
R1[I [ 2p(I)] \ 0.041, wR2 (all data) \ 0.074, 8441 measured
2
catechol (10 mmol) (or as detailed below), the diÑuoronitrile (2
or 3) (10 mmol), DMF (30 mL) and toluene (10 mL, or suffi-
cient to achieve a reÑux temperature of 125È130 ¡C). Under a
and 1981 independent reÑections, R \ 0.038.
int
CCDC reference number 440/255. See http://www.rsc.org/
suppdata/nj/b0/b008508l/ for crystallographic Ðles in .cif
format.
stream of N anhydrous potassium carbonate (30 mmol) was
2
added. The mixture was reÑuxed under N for 4È5 h (not
2
optimized). Some toluene was distilled o† and the reaction
Preparation of catechols
mixture cooled to about 80 ¡C and poured with vigorous stir-
ring into an iceÈwater mixture. The white, or o†-white,
product was Ðltered o†, washed thoroughly with water and air
dried. The cyanodibenzo[1,4]dioxines could be puriÐed by
recrystallization from MeOH or, better, from MeCNÈwater
(9 : 1). Analytical samples were best produced by sublimation
at 200 ¡C and 0.5 Torr.
3,4-Dimethylphenol,
catechol, 2,3-dihydroxynaphthalene and alizarin were avail-
able from commercial sources and used as supplied.
3,5-di-tert-butylcatechol,
3-methyl-
4,5-Dimethylcatechol (1c). This compound was prepared
(67.5%) from 3,4-dimethylphenol by oxidation with FremyÏs
salt in bu†ered (KH PO ), according to the procedure of
Teuber and co-workers.12 The intermediate ortho-quinone
was not isolated but taken into chloroform and reduced with
sodium dithionite. The compound had mp 86È87 ¡C (lit.12 87È
88 ¡C).
1-Cyanodibenzo[1,4]dioxine (6a). This compound was pre-
pared (99%) according to the general procedure from catechol
(1a) (20 mmol) and the nitrile 2; mp 91.7È92.0 ¡C (after
sublimation); IR (KBr): 2227, 1499, 1452, 1301 and 746 cm~1;
2
4
1H NMR (CDCl ): d 6.81 (m, 1H), 6.92 (dd, 1H, J \ 8.1, 7.7),
3
6.93 (m, 3H), 7.00 (dd, 1H, J \ 8.1, 1.6) and 7.11 (dd, 1H,
3,6-Dimethylcatechol (1d). (i) 3-Methyl-6-morpholino-
methylcatechol (14) was synthesized (71%) from 3-
methylcatechol according to the procedure of Cram and
co-workers.13 (ii) To the catechol 14 (2.23 g, 10 mmol) in
MeOH (25 mL), 10% Pd/C (2.4 g) wetted with methanol was
added, followed by powdered ammonium formate (2.6 g). The
mixture was heated under reÑux for 30 h then the catalyst was
Ðltered o† and washed twice with warm MeOH. The MeOH
was removed on a rotary evaporator and the residue dissolved
in CH Cl (50 mL). The solution was washed with HCl (1 M)
J \ 7.7, 1.6 Hz). Calc. for C H NO : C, 74.64; H, 3.37; N,
13
7
2
6.69%. Found: C, 74.63; H, 3.35; N, 6.72%. HRMS: calc. for
C
H NO m/z 209.047 67, found 209.047 80.
13
7
2
2-Cyanodibenzo[1,4]dioxine (7a). This compound was pre-
pared (quant.) from catechol (1a) (20 mmol) and the nitrile 3;
mp 159È159 ¡C (after sublimation); IR (KBr): 2220, 1494,
1417, 1311 and 760 cm~1; 1H NMR (CDCl ): d 6.82 (m, 2H),
3
6.84 (d, 1H, J \ 8.35), 6.92 (m, 2H), 7.03 (d, 1H, J \ 1.9) and
7.16 (dd, 1H, J \ 8.35, 1.9 Hz). Calc. for C H NO : C, 74.64;
2
2
13
7
2
then with a saturated aq. solution of NaCl. The product was
isolated by evaporation of the solvent to yield the catechol 1d
(1.01 g, 73%) which readily sublimed under vacuum to give
snow-white needles, mp 99.8 ¡C (lit.22 98.5È99.5 ¡C). Calc. for
C H O : C, 69.54; H, 7.29. Found: C, 69.38; H, 7.32%.
H, 3.37; N, 6.69%. Found: C, 74.41; H, 3.24; N, 6.61%.
HRMS: calc. for C H NO m/z 209.047 67, found 209.047 60.
13
7
2
1-Cyanobenzo[b]naphtho[2,3-e] [1,4]dioxine (6b). This was
prepared (91%) from 2,3-dihydroxynaphthalene (1b) (10
mmol) and the nitrile 2; mp 195.7È196.0 ¡C (from MeCN); IR
(KBr): 2229, 1513, 1461, 1292 and 750 cm~1; 1H NMR
8
10 2
4,5-Diphenylcatechol (1e). (i) To 4,5-dibromoveratrole (15)
(2.96 g, 10 mmol) in toluene (20 mL) under N was added 2 M
aq. sodium carbonate (15 mL), followed by phenylboronic
(CDCl ): d 6.98 (dd, 1H, J \ 8.2, 7.7), 7.11 (dd, 1H, J \ 8.2,
2
3
1.5), 7.18 (dd, 1H, J \ 7.7, 1.5 Hz), 7.23 (s, 1H), 7.36 (m, 2H),
acid (2.6 g, 21.4 mmol) and tetrakis(triphenylphosphine)-
palladium(0) (0.43 mmol). The reaction mixture was heated
under reÑux for 13 h then cooled to rt, 30% aq. H O (0.7
mL) added and the product extracted with diethyl ether (120
mL). The ether layer was washed with water, saturated aq.
sodium hydrogencarbonate and water and then dried and
evaporated to give 4,5-diphenylveratrole (16) (2.45 g, 85%).
Analytical samples were obtained by crystallization from any
of cyclohexane, MeOH, EtOH or CH Cl or by sublimation
7.37 (s, 1H) and 7.64 (m, 2H). Calc. for C H NO : C, 78.75;
17
9
2
H, 3.49; N, 5.40%. Found: C, 78.76; H, 3.43; N, 5.39%.
HRMS: calc. for
259.063 87.
C
H NO m/z 259.063 32, found:
2
2
17
9
2
2-Cyanobenzo[b]naphtho[2,3-e] [1,4]dioxine (7b). This was
prepared (97%) from 2,3-dihydroxynaphthalene (1b) (10
mmol) and the nitrile 3; mp 240.2È240.4 ¡C (from MeCN); IR:
2224, 1504, 1469, 1301 and 753 cm~1; 1H NMR (CDCl ): d
2
2
3
under high vacuum; mp 145.5È146.5 ¡C (lit.23 140È142 ¡C); 1H
6.99 (dd, 1H, J \ 8.35, 0.3), 7.20 (dd, 1H, J \ 1.9, 0.3), 7.25 (dd,
NMR (CDCl ) d 3.93 (s, 6H), 6.94 (s, 2H), 7.13 (dd, 4H,
1H, J \ 8.35, 1.9 Hz), 7.27 (m, 2H), 7.37 (m, 2H) and 7.55 (m,
3
J \ 9.0, 2.0 Hz) and 7.16È7.21 (m, 6H); 13C NMR (CDCl ) d
2H). Calc. for C H NO : C, 78.75; H, 3.49; N, 5.40%.
3
17
9
2
382
New J. Chem., 2001, 25, 379È384

View Article Online
Found: C, 78.68; H, 3.46; N, 5.42%. HRMS: calc. for
H NO m/z 259.063 32, found 259.063 87.
Found: C, 75.48; H, 4.07; N, 6.33%. The mixture was not
characterized further.
C
17
9
2
1-Cyano-7,8-dimethyldibenzo[1,4]dioxine (6c). This was
2-Cyano-6,8-di-tert-butyldibenzo[1,4]dioxine (7h) and 2-
cyano-7,9-di-tert-butyldibenzo[1,4]dioxine (7i). These com-
pounds were prepared (quant.) as a 1 : 1 mixture (by GC/MS)
from 3,5-di-tert-butylcatechol (1h) (10 mmol) and the nitrile 3;
prepared (80%) from 4,5-dimethylcatechol (1c) (10 mmol) and
the nitrile 2; mp 178È179 ¡C (after sublimation); IR (KBr):
2229, 1507, 1472, 1322 and 719 cm~1; 1H NMR (CDCl ): d
3
2.15 (s, 6H), 6.62 (m, 1H), 6.75 (m, 2H), 6.91 (dd, 1H, J \ 8.2,
mp 92È104 ¡C (after distillation). Calc. for C
H
NO : C,
21 23
2
7.8), 7.00 (dd, 1H, J \ 8.2, 1.6) and 7.12 (dd, 1H, J \ 7.8, 1.6
78.47; H, 7.21; N, 4.35%. Found: C, 78.80; H, 7.24; N, 4.37%.
The compounds were not characterized further.
Hz). Calc. for C
Found: C, 75.98; H, 4.65; N, 5.91%. HMRS: calc. for
H
NO : C, 75.93; H, 4.67; N, 5.90%.
15 11
2
C
H
NO m/z 237.078 98, found: 237.079 03.
1-Cyanonaphtho[2,3,-a]dibenzo[1,4]dioxine-8,13-dione (6j).
This was prepared (28%) from alizarine (1j) (6 mmol) and the
nitrile 2 at 130 ¡C (from toluene); mp above 300 ¡C. IR (KBr):
2237, 1673 and 1467 cm~1. Calc. for C H NO : C, 74.33; H,
15 11
2
2-Cyano-7,8-dimethyldibenzo[1,4]dioxine (7c). This was
prepared (67%) from 4,5-dimethylcatechol (1c) (10 mmol) and
the nitrile 3; mp 215.8È216.4 ¡C (after sublimation); IR (KBr):
21
9
4
2.67; N, 4.12%. Found: C, 74.52; H, 2.66; N, 4.09%. HRMS:
2224, 1504, 1460, 1327 and 796 cm~1. 1H NMR (CDCl ): d
calc. for C H NO m/z 339.053 16, found 339.053 13.
3
21
9
4
2.15 (s, 6H), 6.62 (s, 1H), 6.63 (s, 1H), 6.86 (d, 1H, J \ 8.3), 7.07
(d, 1H, J \ 1.9) and 7.18 (dd 1H, J \ 8.3, 1.9 Hz). Calc. for
Preparation of dibenzo[1,4]dioxinecarboxylic acids: general
procedure (5 mmol scale)
C
H
NO : C, 75.93; H, 4.67; N 5.90%. Found: C, 75.80;
15 11
2
H, 4.67; N, 5.90%. HRMS: calc. for C
237.078 98, found: 237.079 03.
H
NO m/z
15 11
2
Potassium hydroxide (1.5 g) was dissolved in water (1.5 mL)
and 1,2-ethanediol (10 mL). The cyanodibenzo[1,4]dioxine (5
mmol) was added and the reaction mixture heated under
reÑux for 30 min (ammonia evolution ceased after 15 min),
cooled and diluted with water followed by acidiÐcation with
hydrochloric acid. The carboxylic acid was Ðltered o†, washed
with water until neutral and, while wet, crystallized from
acetic acid. With smaller quantities the product is more effi-
ciently obtained by extraction of the acidiÐed mixture with
1-Cyano-6,9-dimethyldibenzo[1,4]dioxine (6d). This was
prepared (93%) from 3,6-dimethylcatechol (1d) (5 mmol) and
the nitrile 2; mp 185È186 ¡C (after sublimation); IR (KBr):
2214, 1464, 1425, 1302 and 777 cm~1; 1H NMR (CDCl ): d
3
2.17 (s, 3H), 2.23 (s, 3H), 6.66 (s, 2H), 6.90 (dd, 1H, J \ 8.1,
7.8), 7.02 (dd, 1H, J \ 8.1, 1.5) and 7.10 (dd, 1H, J \ 7.8, 1.5
Hz). Calc. for C
H
NO : C, 75.93; H, 4.67; N, 5.90%.
15 11
2
Et O. Analytical samples were obtained by sublimation at
Found: C, 75.88; H, 4.67; N, 5.95%. HRMS: calc. for
2
150 ¡C and 0.5 Torr.
C
H
NO m/z 237.078 98, found: 237.079 03.
15 11
2
2-Cyano-6,9-dimethyldibenzo[1,4]dioxine (7d). This was
Dibenzo[1,4]dioxine-1-carboxylic acid (8a). This acid was
prepared (quant.) from 1-cyanodibenzo[1,4]dioxine (6a) (0.7 g,
3.35 mmol); mp 212È213 ¡C (after sublimation) (lit.1 205È
207 ¡C;24 212È215 ¡C). Calc. for C H O : C, 68.42; H,
prepared (92%) from 3,6-dimethylcatechol (1d) (5 mmol) and
the nitrile 3; mp 174È176 ¡C (after sublimation); IR (KBr):
2224, 1504, 1464, 1307 and 792 cm~1; 1H NMR (CDCl ): d
3
13
8 4
2.15 (s, 3H), 2.16 (s, 3H), 6.64 (s, 2H), 6.86 (d, H(1)), 7.07 (d,
3.53%. Found: C, 68.33; H, 3.34%. HRMS: calc. m/z
J
\ 1.93, H(3)) and 7.16 (dd, J \ 8.35 Hz, H(4)). Calc.
228.042 27, found 228.042 44.
1, 3
for C
3, 4
H
NO : C, 75.93; H, 4.67; N, 5.90%. Found: C,
15 11
2
75.84; H, 4.67; N, 5.90%. HRMS: calc. for C
237.078 98, found 237.079 03. A violet dye was also isolated
but not identiÐed.
H
NO m/z
Dibenzo[1,4]dioxine-2-carboxylic acid (9a). This acid was
prepared (96%) from 2-cyanodibenzo[1,4]dioxine (7a) (5
mmol); mp 245È247 ¡C (from HOAc), 240 ¡C when sealed in a
capillary (lit.24 245.5È247 ¡C;25 239È241 ¡C). Calc. for
15 11
2
1-Cyano-7,8-diphenyldibenzo[1,4]dioxine (6e). This was pre-
pared (99%) from 4,5-diphenylcatechol (1e) (1 mmol) and the
nitrile 2; mp 179È180 ¡C (after sublimation); IR (KBr): 2234,
C
H O : C, 68.42; H, 3.53%. Found: C, 68.35; H, 3.38%.
13
8 4
HRMS: calc. m/z 228.042 27, found: 228.042 22.
1499, 1400, 1278 and 772 cm~1; 1H NMR (CDCl ): d 6.91 (s,
Benzo[b]naphtho[2,3-e] [1,4]dioxine-1-carboxylic
acid
3
1H), 6.95 (dd, 1H, J \ 8.1, 7.8), 7.02 (dd, 1H, J \ 8.1, 1.6), 7.06
(8b). The acid was prepared (78%) from 1-cyanobenzo[b]-
naphtho[2,3-e][1,4]dioxine (6b) (2 mmol); mp 270.8È271.3 ¡C
(s, 1H), 7.07 (m, 4H), 7.16 (dd, 1H, J \ 7.8, 1.6 Hz) and 7.19
(m, 6H). Calc. for C
Found: C, 82.97; H, 4.15; N, 3.86%. HRMS: calc. for
H
NO : C, 83.08; H, 4.18; N, 3.87%.
(after sublimation). Calc. for C
H
O : C, 73.37; H, 3.62%.
25 15
2
17 10
4
Found: C, 73.40; H, 3.58%. HRMS: calc. for C
278.057 92, found 278.058 15.
H
O m/z
17 10
4
C
H
NO m/z 361.110 29, found 361.110 07.
25 15
2
2-Cyano-7,8-diphenyldibenzo[1,4]dioxine (7e). This was pre-
Preparation of dibenzo[1,4]dioxinecarboxamides
pared (94%) from 4,5-diphenylcatechol (1e) (1 mmol) and the
nitrile 3; mp 249È249.6 ¡C (from toluene). IR (KBr): 2214,
1499, 1479, 1332 and 750 cm~1; 1H NMR (CDCl ): d 6.94 (d,
Dibenzo[1,4]dioxine-2-carboxamide (12). 2-Cyanodibenzo-
[1,4]dioxine (7a) (1.04 g, 5 mmol) was dissolved in 1 : 1
acetoneÈEtOH (50 mL). Aq. NaOH (6 M, 0.6 mL) was added
followed by aq. H O (30%, 3 mL) and the reaction mixture
3
1H, J \ 7.4), 6.94 (s, 1H), 6.95 (s, 1H), 7.07 (m, 4H), 7.15 (d,
1H, J \ 1.8), 7.20 (m, 6H) and 7.24 (dd, 1H, J \ 7.4, 1.8 Hz).
Calc. for C
H
NO : C, 83.08; H, 4.18; N, 3.87%. Found:
25 15
2
2 2
C, 82.85; H, 4.15; N, 3.87%. HRMS: calc. for C
m/z 361.110 29, found 361.109 36.
H
NO
heated to 60 ¡C for 4 h. The mixture was then acidiÐed (HCl)
and the volatiles were removed by evaporation. The residue
was diluted with MeCN (100 mL), warmed to about 80 ¡C and
Ðltered while warm. The amide (12) crystallized from the Ðl-
trate as Ðne needles (0.73 g) after which further solvent evapo-
ration yielded an additional 0.20 g. The Ðltrate from the Ðrst
hot Ðltration was washed with water and dried to yield a
further 0.12 g of less pure amide, giving a total of 1.05 g (93%).
Analytical samples were obtained by recrystallization from
25 15
2
2-Cyano-6-methyldibenzo[1,4]dioxine (7f) and 2-cyano-9-
methyldibenzo[1.4]dioxine (7g). These compounds were pre-
pared (99%) as
a
1 : 1 mixture (by GC/MS) from
3-methylcatechol (1f) (20 mmol) and the nitrile 3; mp 130È
138 ¡C (from MeOH); IR (KBr): 2222, 1505, 1471 and 1301
cm~1. Calc. for C H NO : C, 75.32, H, 4.06, N, 6.27%.
14
9
2
New J. Chem., 2001, 25, 379È384
383

View Article Online
3
4
5
6
7
M. Tomita, J. Pharm. Soc. Jpn., 1936, 56, 814; M. Tomita, J.
Pharm. Soc. Jpn., 1937, 57, 609.
MeCN; mp 231.7È232.5 ¡C; IR (KBr): 3416, 3188, 1659, 1496,
1314 and 730 cm~1. Calc. for C H NO : C, 68.71; H, 3.99;
13
9
3
N. Ruiz, C. Boun, M. D. Pukol, G. Guillaumet and G. Coudert,
Synth. Commun., 1996, 26, 2057.
N, 6.16%. Found: C, 69.00; H, 3.96; N, 6.18%. HRMS: calc.
for C H NO m/z 227.058 23, found: 227.058 32.
H. H. Lee, B. D. Palmer, M. Boyd, B. C. Baguley and W. A.
Denny, J. Med. Chem., 1992, 35, 258.
H. H. Lee and W. A. Denny, J. Chem. Soc., Perkin T rans. 1, 1990,
1071.
C. Chowdhury, G. Chowdhury, S. Guha, A. K. Mukherjee and
N. G. Kunda, J. Org. Chem., 1998, 63, 1863.
J. Hellberg and M. E. Pelcman, T etrahedron L ett., 1994, 35, 1769.
G. C. Eastmond and J. Paprotny, Chem. L ett., 1999, 479.
13
9
3
Dibenzo[1,4]dioxine-2-(N-tert-butyl)carboxamide (13). 2-
Cyanodibenzo[1,4]dioxine (7a) (0.152 g, 0.727 mmol) was sus-
pended in HOAc (5 mL) at 40È50 ¡C and ButOH (1 g) added,
then conc. H SO (1 g) when the suspension became clear.
8
9
2
4
The solution was stirred at 40 ¡C for 2 h. After cooling to
room temperature, no crystals formed until ice was added
when the solid product was Ðltered o†, washed with water,
10 G. C. Eastmond and J. Paprotny, US Pat., 5,834,620, 1998.
11 G. C. Eastmond and J. Paprotny, J. Mater. Chem., 1997, 7, 1321.
12 H.-J. Teuber and W. Rau, Chem. Ber., 1953, 86, 1036; H.-J.
Teuber and G. Staiger, Chem. Ber., 1955, 88, 802.
13 R. C. Helgeson, T. R. L. Tarnowski, J. M. Timko and D. J. Cram,
J. Am. Chem. Soc., 1977, 99, 6411; T. W. Bell, G. M. Lein, H.
Nakamura and D. J. Cram, J. Org. Chem., 1983, 48, 4728.
14 A. A. Frimer, V. Marks, M. Sprecher and P. Gilinski-Sharon, J.
Org. Chem., 1994, 59, 1831.
saturated aq. NaHCO and water. The wet product was rec-
3
rystallized to give dibenzo[1,4]dioxine-2-(N-tert-butyl)carbox-
amide (13) (0.16 g, 80%), mp 201.6È202.6 ¡C (from MeOH); IR
(KBr): 1639, 1494, 1362, 1212, 1311 and 741 cm~1. Calc. for
C
H
NO : C, 72.06; H, 6.04; N, 4.94%. Found: C, 71.80;
17 17
3
H, 6.14; N, 4.80%. HRMS: calc. for C
283.120 85, found 283.121 25.
H
NO m/z
17 17
3
15 G. R. Desiraju, Chem. Commun., 1997, 1475.
16 R. G. Sutherland, A. Piorko, C. C. Lee, S.H. Simonsen and V. M.
Lynch, J. Heterocycl. Chem., 1988, 25, 1911.
17 G. C. Eastmond and J. Paprotny, Synthesis, 1998, 894.
18 B. Radziszewski, Ber. Dtsch. Chem. Ges., 1885, 18, 355.
19 J. V. Murray and J. B. Cloke, J. Am. Chem. Soc., 1934, 56, 2749
and references cited therein.
20 J. J. Ritter and P. P. Minieri, J. Am. Chem. Soc., 1948, 70, 4045;
J. J. Ritter and J. Kalish, J. Am. Chem. Soc., 4048; H. Plaut and
J. J. Ritter, J. Am. Chem. Soc., 1951, 73, 4076.
21 G. M. Sheldrick, SHELX 97, Program for crystal structure reÐne-
ment, University of Gottingen, Germany, 1997.
Acknowledgements
The authors wish to thank the EPSRC for Ðnancial support
and acknowledge the help given by Mr S. Apter (elemental
analysis, FTIR), Mr A. Mills and Ms M. McCarron (GC and
MS), Dr P. Leonard who recorded NMR spectra and assigned
the 1H spectra and Mr J. Bickley (X-ray di†raction).
22 D. J. Fields, J. B. Miller and D. D. Reynolds, J. Org. Chem., 1964,
2640.
23 R. J. Bushby and C. Hardy, J. Chem. Soc., Perkin T rans. 1, 1986,
721.
24 R. C. Cambie, S. J. Janssen, P. S. Rutledge and P. D. Woodgate,
J. Organomet. Chem., 1991, 420, 387.
25 G. Vasiliu and I. Baciu, An. Univ. Bucuresti, Ser. Stiint. Nat.,
1996, 15, 125; G. Vasiliu and I. Bacill, Chem. Abstr., 1968, 68,
59509.
References
1
B. D. Palmer, G. W. Rewcastle, G. J. Atwell, B. C. Baguley and
W. A. Denny, J. Med. Chem., 1988, 31, 707.
H. Gilman and C. G. Stuckwisch, J. Am. Chem. Soc., 1943, 65,
1461.
2
384
New J. Chem., 2001, 25, 379È384