The carbazole connection: Unusual products from the diazotization of anthranilic acids

Full text of DOI:10.1021/jo960949x

6748
J . Org. Chem. 1996, 61, 6748-6750
Th e Ca r ba zole Con n ection : Un u su a l
P r od u cts fr om th e Dia zotiza tion of
An th r a n ilic Acid s
Xiaoxin Qiao, Douglas M. Ho, and Robert A. Pascal, J r.*
Department of Chemistry, Princeton University,
Princeton, New J ersey 08544
Received May 22, 1996
We have described the efficient synthesis of octaphen-
ylnaphthalene by the diazotization of 3,4,5,6-tetraphen-
ylanthranilic acid (1) in the presence of tetraphenylcy-
clopentadienone.1 Since then, in an attempt to prepare
even more sterically encumbered naphthalenes, we dia-
zotized 1 in the presence of 2,5-bis(1-naphthyl)-3,4-
diphenylcyclopentadienone,2 but very little of the desired
dinaphthylhexaphenylnaphthalene was detected, and
this compound has not been isolated in pure form.
Instead, recrystallization of a nonpolar chromatographic
fraction from this reaction gave a small quantity of a
quite unusual product: 1,2,3,4,5,6,7,8-octaphenylcarba-
zole (2). This unexpected observation led us to examine
the diazotization of compound 1 in the absence of a diene.
When 1 was added slowly to a solution of isoamyl nitrite
(2 equiv) in 1,2-dichloroethane at reflux, numerous
products were formed, but from this mixture compound
2 was obtained as a crystalline solid in 5% yield. We
also searched for octaphenylbiphenylene (3), since ben-
zyne can dimerize to biphenylene in the absence of
suitable dienes;3-5 however, no trace of 3 was ever
observed, even though many fractions from this and other
reactions of 1 were screened by mass spectrometry.
F igu r e 1. Molecular structure of octaphenylcarbazole (2).
Thermal ellipsoids have been drawn at the 50% probability
level, and all hydrogen atoms but that of the amine have been
omitted for clarity.
in the carbazole nucleus the C(5)-C(6)-C(7)-C(8) tor-
sion angle is 23.3° (the crystallographic numbering
scheme is used). This distortion is due chiefly to repul-
sion between the C(5) and C(8) phenyls, which are tightly
stacked (the distance between the ipso carbon atoms of
these phenyls is 3.16 Å), so much so that the carbazole-
phenyl bonds are bent out of the mean planes of the
phenyl rings by approximately 7.3° and 11.2°, respec-
tively. Compound 2 possesses approximate C2 symmetry,
but its 13C NMR spectrum contains only 22 lines,
consistent with time-averaged C2v symmetry, which
suggests that 2 is conformationally flexible.
Does the diazotization of ordinary anthranilic acid (4)
yield carbazole? When compound 4 was added to a
solution of isoamyl nitrite (2 equiv) in hot dichloroethane,
GC and GC-MS analysis of an organic extract of the
reaction mixture revealed the presence of 13% biphen-
ylene (6) and 2% carbazole (5) as well as many other
products.7 We know of no report of the formation of
carbazole under these conditions; however, there are two
reports of carbazole derivatives from similar reactions,
but not of carbazole itself. Ghosh et al.8 observed the
formation of N-[(2-halophenyl)amino]carbazoles 7 from
the decomposition of benzenediazonium 2-carboxylate
hydrohalides in the presence of propylene oxide, and
Miwa et al.9 proposed structure 8 for a compound isolated
after decomposition of benzenediazonium 2-carboxylate
in acetone. No compounds with parent ions correspond-
ing to 7 or 8 were observed in the GC-MS analyses of
our reaction mixtures, but Ghosh et al. had noted that
compound 7 “decomposed readily in the gas chromato-
graph” to give carbazole.8 For this reason, our organic
extract was fractionated by preparative TLC. Both
biphenylene and carbazole were isolated, and their
X-ray crystallographic analysis conclusively estab-
lished the structure of 2,6 which is illustrated in Figure
1. Compound 2 is a crowded molecule, and intramolecu-
lar steric repulsions distort it from planarity; for example,
(1) Qiao, X.; Padula, M. A.; Ho, D. M.; Vogelaar, N. J .; Schutt, C.
E.; Pascal, R. A., J r. J . Am. Chem. Soc. 1996, 118, 741-745.
(2) Ogliaruso, M. A.; Romanelli, M. G.; Becker, E. I. Chem. Rev.
1965, 65, 261-367.
(7) Other compounds observed included phenyl benzoate (3%),
2-nitrodiphenylamine (4%), acridone (20%), and N,O-diphenylanthra-
nilate (23%). The identities of all but the last of these are based upon
chromatographic and mass spectral comparisons of the reaction
products with authentic standards; the structure of N,O-diphenylan-
thranilate is proposed on the basis of its mass spectral fragmentation
pattern.
(8) Ghosh, R.; Sheinin, E. B.; Bell, C. L.; Bauer, L. J . Heterocycl.
Chem. 1975, 12, 203-206.
(9) Miwa, T.; Kato, M.; Tamano, T. Tetrahedron Lett. 1968, 2743-
2745.
(3) Wittig, G. Angew. Chem. 1957, 69, 245-251.
(4) Berry, R. S.; Spokes, G. N.; Stiles, M. J . Am. Chem. Soc. 1962,
84, 3570-3577.
(5) Logullo, F. M.; Seitz, A. H.; Friedman, L.; Abrams, G. D.; Ertl,
H.; Yates, P. Organic Syntheses; Wiley: New York, 1973; Collect Vol.
V, pp 54-59.
(6) The authors have deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
S0022-3263(96)00949-8 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 19, 1996 6749
identities were confirmed by comparison with authentic
standards, but no trace of compound 7 was observed.
However, a parallel experiment provided strong evi-
dence that 7 or its derivatives are intermediates in these
reactions. In order to better define the role of arynes, if
any, in the formation of carbazoles, 2-amino-4-fluoroben-
zoic acid (9) was diazotized under similar conditions,
since the presence of intermediates such as fluorobenzyne
would lead to the formation of more than one isomer of
the expected difluorocarbazole. GC-MS analysis of the
organic extract of this reaction mixture showed a trace
of difluorobiphenylene and 4% difluorocarbazole, but
when the reaction mixture was fractionated by prepara-
tive TLC, the only band found to give the difluorocarba-
zole mass spectrum (in GC-MS analysis) was much less
polar than ordinary carbazole. Indeed, this compound
proved to be a mixture of isomers 10sfluorinated analogs
of Ghosh et al.’s compound 7.
In conclusion, carbazoles are formed in the diazotiza-
tion reactions of anthranilic acids (at least when halogens
are available), and arynes and N-[(2-halophenyl)amino]-
carbazoles are likely intermediates. A detailed mecha-
nism for this process is not obvious, nor are the factors
governing whether a particular (phenylamino)carbazole
will decompose to the corresponding carbazole. However,
dodecaphenyl-7, the presumed precursor of 2, if formed
must be extremely crowded, so that homolysis of the
N-N bond should be facile. Given that the carbazoles
are only minor products in these complex diazotization
reactions, further mechanistic studies may be difficult,
and we gladly leave further consideration of this problem
to the interested reader.
Exp er im en ta l Section
Compound 10 was isolated by preparative TLC, and
it appears homogeneous by TLC analysis in several
solvent systems. This material does decompose upon
GC-MS analysis to give difluorocarbazole, but a direct
inlet mass spectrum shows only 10, and an exact mass
determination confirmed the molecular formula of C18H10-
ClF3N2. The 1,2-dichloroethane solvent must be the
source of the chlorine in 10, and this was supported by
repeating the diazotization of 9 in 1,2-dibromoethane;
direct inlet mass spectral analysis of the carbazole
product of this reaction gave a parent ion at m/ z 390
that contained one bromine atom and no chlorine,
consistent with a molecular formula of C18H10BrF3N2. 1H
NMR analysis clearly indicates the presence of more than
one isomer of 10, and its 19F NMR spectrum shows 10
resonances (two of them nearly superimposed) in ratios
suggesting the presence of two isomers (63% and 18%)
with three inequivalent fluorine atoms and two isomers
(15% and 4%) with two types of fluorine atoms in a 2:1
ratio. This situation can result only if at least two
m-fluorobenzynes (or other “symmetric” intermediates)
are involved in the formation of 10. If one assumes that
the two nitrogens arise from a single diazonium group,
then the four observed isomers are most likely com-
pounds 10a -d .10
1,2,3,4,5,6,7,8-Oct a p h en ylca r b a zole (2). A solution of
isoamyl nitrite (0.150 mL, 1.12 mmol) in 1,2-dichloroethane (10
mL) was heated to reflux under argon. A solution of 3,4,5,6-
tetraphenylanthranilic acid1 (246 mg, 0.56 mmol) in 1,2-dichlo-
roethane (30 mL) was added dropwise to the reaction flask over
2 h, and heating was continued for 3 h. Ethanol (8 mL) and 1%
NaOH (32 mL) were added to quench the reaction, and the
resulting mixture was extracted with CHCl3 (100 mL). The
organic extract was washed with saturated NaHCO3 (2 × 50
mL) and water (2 × 50 mL), dried over MgSO4, and concentrated
to dryness. The residue was chromatographed on a silica gel
column (solvent, 3:1 hexanes-CHCl3), and the fractions contain-
ing 2 were further subjected to preparative TLC (silica gel GF;
solvent, 1:1 hexanes-benzene) to give pure compound 2 as a
colorless solid (10 mg, 4.6%): mp 300-303 °C dec; 1H NMR (500
MHz, CDCl3) δ 6.46 (d, J ) 7 Hz, 4H), 6.58 (m, 8H), 6.67 (m,
2H), 6.75 (m, 6H), 6.84 (m, 10H), 7.14 (m, 2H), 7.20 (m, 4H),
7.27 (m, 4H), 8.04 (s, 1H, NH); 13C NMR (125 MHz, CDCl3) δ
120.9, 122.7, 124.6, 124.7, 125.2, 126.0, 126.5, 126.8, 126.9, 128.2,
130.4, 130.5, 131.6, 131.9, 134.3, 136.7, 137.4, 138.3, 139.0, 140.5,
140.9, 141.0 (22 of 22 expected resonances); IR (KBr) νmax 3452
(NH), 3078, 3052, 3021, 1596, 1493, 1441, 1379, 1068, 793, 751,
694 cm-1; MS m/ z 775 (M+, 100), 698 (M - C6H5, 9), 697 (M -
C6H6, 9); exact mass 775.3241, calcd for C60H41N 775.3239.
Crystals of 2‚3CH2Cl2, suitable for X-ray analysis, were obtained
by recrystallization from CH2Cl2-CH3OH.
Rea ction of 2-Am in o-4-flu or oben zoic Acid w ith Isoa m yl
Nitr ite. A solution of isoamyl nitrite (0.878 mL, 6.54 mmol) in
1,2-dichloroethane (50 mL) was heated to reflux under argon.
A solution of 2-amino-4-fluorobenzoic acid (507 mg, 3.27 mmol)
in 1,2-dichoroethane (50 mL) was added dropwise over 1 h, and
heating was continued for 10 h. Ethanol (20 mL) and 1% NaOH
(60 mL) were added to quench the reaction, and the mixture
was extracted with CHCl3 (200 mL). The extract was washed
(10) Four isomers will result if one of the carbazole rings of 10 is
derived from a diazonium-containing fragment, which must have the
fluorine atom and diazonium group meta to each other, but only three
isomers would be formed if the chlorofluoroaniline is derived from the
diazonium-containing fragment. Of course, it may be that more than
one pathway exists for the formation of 10.

6750 J . Org. Chem., Vol. 61, No. 19, 1996
Notes
with saturated NaHCO3 (3 × 50 mL) and water (2 × 50 mL),
dried over MgSO4, and concentrated to dryness. The resulting
residue (59 mg) was fractionated by preparative TLC (silica gel
GF; solvent, 1:1 hexanes-benzene). The mixture of isomers 10
was obtained from a band of Rf 0.80, and this material was
further purified by preparative TLC (silica gel GF; solvent,
hexanes; Rf 0.18) to give 10 as a colorless solid (0.5 mg): 1H
NMR (270 MHz, CDCl3) δ 5.87 (m, 0.8 H), 6.10 (m, 0.2 H), 6.58
(m, 0.8 H), 6.71 (m, 0.2 H), 7.04-7.24 (m, 5 H), 7.36 (m, 1 H),
7.71 (m, 0.8 H), 7.96 (m, 1.2 H); 19F NMR (470 MHz, CDCl3,
CFCl3 reference) δ -112.68 (m, 0.81 F; isomers 10a and 10b,
carbazole F), -113.16 (m, 0.63 F; 10a , carbazole F), -113.27
(m, 0.18 F; 10b, carbazole F), -114.74 (m, 0.30 F; 10c, carbazole
F2), -114.84 (m, 0.08 F; 10d , carbazole F2), -121.43 (m, 0.04 F;
10d , phenyl F), -121.62 (m, 0.18 F; 10b, phenyl F), -122.82
(m, 0.63 F; 10a , phenyl F), -123.05 (m, 0.15 F; 10c, phenyl F);
MS m/ z 346 (M+, 25), 311 (M - Cl, 6), 202 (C12H6F2N, 100);
exact mass 346.0490, calcd for C18H10F335ClN2 346.0485.
Ack n ow led gm en t. This work was supported by
National Science Foundation Grant CHE-9408295, which
is gratefully acknowledged. We thank Dr. Istvan Pel-
czer for recording the 19F NMR spectrum of 10.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
1
NMR, 13C NMR, and mass spectra of compound 2 and the H
NMR, 19F NMR, and mass spectra of 10 (6 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O960949X