Acid-promoted competing pathways in the oxidative polymerization of 5,6- dihydroxyindoles and related compounds: Straightforward cyclotrimerization routes to diindolocarbazole derivatives

Article abstract of DOI:10.1021/jo980875k

Oxidation of 5,6-dihydroxyindole (1a) in acidic aqueous media led to isomeric hexahydroxydiindolocarbazoles, isolated as the acetyl derivatives 5a (29%) and 6a (19%). When the reaction is stopped in the very early stages, small amounts of the indolylindoline 17 and the open trimer 18 can be isolated. Similar oxidation of the N-methyl (1b) and O,O-dimethyl (1c) derivatives of 1a, as well as of 5-methoxyindole (9b), 6-hydroxyindole (14a), and 6-benzyloxyindole (14b), afforded the corresponding diindolocarbazoles 5b and 6b, and 6c, 10, 16, and the related tetramer 15 in up to 70% overall yield, whereas 5,6-diacetoxyindole (1d), 5-hydroxyindole (9a), and indole failed to give cyclotrimerization products. Formation of diindolocarbazoles could be explained by a mechanism in which the electron-donating substituents propitiate an array of acid-induced couplings and subsequent dehydrogenation steps driven by the energetically favorable closure of the fused aromatic framework.

Full text of DOI:10.1021/jo980875k

7002
J . Org. Chem. 1998, 63, 7002-7008
Acid -P r om oted Com p etin g P a th w a ys in th e Oxid a tive
P olym er iza tion of 5,6-Dih yd r oxyin d oles a n d Rela ted Com p ou n d s:
Str a igh tfor w a r d Cyclotr im er iza tion Rou tes to Diin d oloca r ba zole
Der iva tives
Paola Manini, Marco d’Ischia, Mario Milosa, and Giuseppe Prota*,†
Department of Organic and Biological Chemistry, University of Naples Federico II,
Via Mezzocannone 16, I-80134 Naples, Italy
Received May 7, 1998
Oxidation of 5,6-dihydroxyindole (1a ) in acidic aqueous media led to isomeric hexahydroxydi-
indolocarbazoles, isolated as the acetyl derivatives 5a (29%) and 6a (19%). When the reaction is
stopped in the very early stages, small amounts of the indolylindoline 17 and the open trimer 18
can be isolated. Similar oxidation of the N-methyl (1b) and O,O-dimethyl (1c) derivatives of 1a ,
as well as of 5-methoxyindole (9b), 6-hydroxyindole (14a ), and 6-benzyloxyindole (14b), afforded
the corresponding diindolocarbazoles 5b and 6b, 5c and 6c, 10, 16, and the related tetramer 15 in
up to 70% overall yield, whereas 5,6-diacetoxyindole (1d ), 5-hydroxyindole (9a ), and indole failed
to give cyclotrimerization products. Formation of diindolocarbazoles could be explained by a
mechanism in which the electron-donating substituents propitiate an array of acid-induced couplings
and subsequent dehydrogenation steps driven by the energetically favorable closure of the fused
aromatic framework.
In tr od u ction
dihydroxyindoles, knowledge in this area until a decade
ago was very scanty and fragmentary because of the
discouraging chemistry of these compounds, which yield
on oxidation intractable mixtures of polymers via bewil-
dering arrays of oligomer intermediates.
A major breakthrough came in the 1980s, when the
first isolation and structural characterization of a dimer
of 1a by an improved methodology6 set the stage for a
series of studies which opened up unprecedented vistas
into the oxidation chemistry of 5,6-dihydroxyindoles7 as
well as of 4-, 5-, 6-, and 7-hydroxyindoles.8
The structural anatomy of the isolated oligomers
disclosed different patterns of reactivity dictated by the
position of the hydroxyl group on the indole ring. In
particular, the mode of coupling of 1a and related 5,6-
dihydroxyindoles reflected an unanticipated propensity
to couple through 2,2′-, 2,4′-, and 2,7′-linkages, as high-
lighted by the structures of the main dimers 2-4 isolated
from oxidation of 1a and 1b. Such a mode of coupling
stems from the peculiar dioxygenation pattern pertaining
to the 5,6-dihydroxyindole system, which directs signifi-
cant electron density on the 2-position of the indole
ring,7 favoring attack to the 4- and 7-positions of tran-
sient 5,6-indolequinone intermediates generated in the
process.
Because of the technological and commercial impor-
tance of indigo dyes,1 whose history stretches back into
antiquity, studies of the oxidation chemistry of hydroxy-
indoles have traditionally been concentrated on the
3-hydroxylated members of the series, the indoxyls,
leaving behind the scenes their congeners with one or
more hydroxyl groups on the benzene moiety. The latter
compounds, nevertheless, are currently attracting in-
creasing interest in view of their occurrence as the core
structural moiety in a number of compounds of outstand-
ing biomedical and industrial relevance, including neu-
rotransmitters and hormones,2 antitumor agents,3 alka-
loids, antibiotics, and enzyme cofactors.4
A prominent position, in this scenario, is occupied by
5,6-dihydroxyindole (1a ) and its 2-carboxylic acid, which
represent the key monomer intermediates in the biosyn-
thesis of melanins, the primary pigments of skin, hair,
and eyes in man and nonhuman mammals.5 Despite
pressing motivations for studies of the oxidation of 5,6-
† Phone: +39-81-7041249. Fax: +39-81-5521217. E-mail: prota@
cds.unina.it.
(1) Waring, D. R. In Comprehensive Heterocyclic Chemistry; Katritsky,
A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 1, pp
317-318.
(2) Sundberg, R. J . The Chemistry of Indoles; Academic Press: New
York, 1970; pp 341-392.
(3) (a) Auclair, C.; Vosin, E.; Banoun, H.; Paoletti, C.; Bernadou, J .;
Meunier, B. J . Med. Chem. 1984, 27, 1161-1166. (b) Kansal, V. K.;
Funakoshi, S.; Mangeney, P.; Gillet, B.; Guittet, E.; Lallemand, J . Y.;
Potier, P. Tetrahedron 1985, 41, 5107-5120. (c) Kansal, V. K.;
Sundaramoorthi, R.; Das, B. C.; Potier, P. Tetrahedron Lett. 1985, 26,
4933-4936.
In a reexamination of the oxidation chemistry of 1a ,
we have now found that the typical mode of polymeriza-
tion is inhibited at acidic pH, under which conditions a
complex and entirely different pattern of products is
(6) Napolitano, A.; Corradini, M. G.; Prota, G. Tetrahedron Lett.
1985, 26, 2805-2808.
(4) (a) Bell, M. R.; J ohnson, J . R.; Wildi, B. S.; Woodward, R. B. J .
Am. Chem. Soc. 1958, 80, 1001. (b) Stapleford, K. S. J . In Rodd’s
Chemistry of Carbon Compounds; Coffey, S., Ed.; Elsevier: Amster-
dam, 1977; Vol. 4B, pp 63-163. (c) McIntire, W. S.; Wemer, D. E.;
Christoserdov, A.; Lidstrom, M. E. Science 1991, 252, 817-824.
(5) (a) Prota, G. Melanins and Melanogenesis; Academic Press: San
Diego, 1992. (b) Prota, G. Fortschr. Chem. Organ. Naturst. 1995, 64,
93-148.
(7) For a recent review, see: (a) d’Ischia, M.; Napolitano, A.; Prota,
G. Gazz. Chim. Ital. 1996, 126, 783-789. Other leading references:
(b) Corradini, M. G.; Napolitano, A.; Prota, G. Tetrahedron 1986, 42,
2083-2088. (c) d’Ischia, M.; Napolitano, A.; Tsiakas, K.; Prota, G.
Tetrahedron 1990, 46, 5789-5796.
(8) (a) Napolitano, A.; d’Ischia, M.; Prota, G. Tetrahedron 1988, 44,
7265-7270. (b) Napolitano, A.; d’Ischia, M.; Prota, G.; Schultz, T. M.;
Wolfram, L. J . Tetrahedron 1989, 45, 6749-6760.
S0022-3263(98)00875-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/12/1998

Oxidative Polymerization of 5,6-Dihydroxyindoles
J . Org. Chem., Vol. 63, No. 20, 1998 7003
hexahydroxydiindolocarbazoles to suffer degradation to
intractable materials in air or in the presence of oxidants.
The yields of 5a and 6a vs 2a and 3a obtained by
oxidation of 1a with various oxidizing systems and at
different pH values are reported in Table 1. The forma-
tion of 5a and 6a increased with decreasing pH, whereas
formation of 2a and 3a was virtually suppressed at pHs
lower than 6. At pH 6, overall formation of 5a and 6a
plus 2a and 3a was very poor after 20 min of oxidation,
on account of a slow polymerization of 1a affording dark
melanin-like pigments without significant accumulation
of intermediate oligomers. At pH 1.4 the material
balance was one of the best ever obtained by oxidation
of 1a . In all cases examined, the remainder of the
oxidation mixtures was accounted for by polar, chromato-
graphically ill-defined species difficult to separate.
With ammonium persulfate, 5a was prevailing over the
whole acidic pH range, with the ratio of 5a :6a being
maximum at the lowest pH examined, i.e., 1.4. A similar
product distribution was found with Fe2+/H2O2 (Fenton
reagent), whereas with cerium(IV) ammonium nitrate 6a
was obtained in a slight excess over that of 5a . It is of
interest that at pH 1.4 as weak an oxidant as molecular
oxygen was able to bring about conversion of 1a to 5a
and 6a , albeit at slow rate, with a product distribution
similar to that obtained with persulfate and Fenton
reagent. In air-equilibrated solution at pH 1.4, decay of
1a was negligible in the absence of oxidant over at least
30 min. No detectable formation of 5a or 6a was
observed rigorously under oxygen-free conditions.
Oxid a tion of Su bstitu ted 5,6-Dih yd r oxyin d oles
a n d Der iva tives in Acid ic Med iu m . With these
results available, another series of experiments was
aimed at investigating the generality of the cyclotrimer-
ization pathway and the effects of substituents on the
course of the reaction. In the first instance, the possible
involvement of the NH center in the acid-promoted
oxidation of 5,6-dihydroxyindoles was probed using as
substrate 5,6-dihydroxy-1-methylindole (1b). Oxidation
of this compound under the usual conditions afforded,
after acetylation, the corresponding trimers 5b and 6b
in comparable yields.
formed. This observation has prompted us to investigate
in detail the oxidation chemistry of 1a at acidic pH and
to extend the study to a series of structurally related
compounds, including 5- and 6-hydroxyindole and their
O-alkyl derivatives.
Resu lts a n d Discu ssion
St r u ct u r a l Ch a r a ct er iza t ion of t h e P r od u ct s
F or m ed by Acid -P r om oted Oxid a tion of 1a . The
ability of persulfate to bring about oxidation of various
phenolic substrates in acidic media9 inspired choice of
this reagent to investigate oxidation of 1a and related
compounds. Careful analysis (TLC, HPLC) of reaction
mixtures obtained by oxidation of 1a at acidic pH, e.g.,
1.4 or 3, followed by acetylation of the ethyl acetate-
extractable fractions, revealed the formation of two main
species whose chromatographic and spectrophotometric
properties did not match with those of any known
oligomer of 1a . The more abundant of the two products
gave a distinct pseudomolecular ion peak (M + H)+ in
the mass spectrum (FAB) at m/z 694, indicating a trimer
1
of 1a . The H NMR and the 13C NMR spectra displayed
a relatively low number of resonances, denoting a highly
symmetric structure. Only two singlets were present in
the aromatic region of the proton spectrum, one of which
shifted unusually downfield at δ 8.59.
Though structurally related (pseudomolecular ion peak
at m/z 694), the companion product exhibited more
1
complex H and 13C NMR spectra, including a charac-
teristic set of three relatively downfield singlets (1H each)
at δ 8.36, 8.43, and 8.67 compatible with an isomer in
which the symmetrical structural architecture was dis-
rupted. On the basis of these data, the products could
be formulated as the symmetrical 2,3,7,8,12,13-hexaac-
etoxydiindolo[3,2-a:3′,2′-c]carbazole (5a ) and its unsym-
metrical isomer, 2,3,6,7,11,12-hexaacetoxydiindolo[2,3-
a:2′,3′-c]carbazole10 (6a ).
Apparently, the low yields of 5a and 6a were partly
due to the instability of their nonacetylated precursors
in the oxidative reaction medium. This was checked in
separate experiments in which removal of the acetyl
groups by mild alkaline hydrolysis caused the deprotected
Since the typical oxidation behavior of 5,6-dihydroxy-
indoles is governed by the peculiar position of the
o-dihydroxy functionality, causing generation of highly
unstable indolequinones,11 it seemed of interest to inves-
tigate whether the o-dihydroxy group is directly involved
(10) For nomenclature and numbering system of diindolocarbazoles,
see: Kaneko, T.; Matsuo, M.; Iitaka, Y. Chem. Pharm. Bull. 1981, 29,
3499-3506.
(11) Napolitano, A.; Pezzella, A.; d’Ischia, M.; Prota, G. Tetrahedron
Lett. 1996, 37, 4241-4242.
(9) Minisci, F.; Citterio, A. Acc. Chem. Res. 1983, 16, 27-32.

7004 J . Org. Chem., Vol. 63, No. 20, 1998
Manini et al.
Ta ble 1. Yield s of F or m a tion a of Diin d oloca r ba zoles
5a -6a a n d of Dim er s 2a -3a by Oxid a tion of 1a w ith
Va r iou s Oxid a n ts in Acid ic Med ia
considered important at this stage to assess whether such
a group is still susceptible to oxidation with persulfate
at acidic pH 3. For this purpose, preclusion of the
cyclotrimerization route was deemed necessary and this
was anticipated in the presence of a methyl group on the
pyrrole moiety of the indole ring. Accordingly, 5,6-
dihydroxy-2-methylindole (1e) was subjected to oxidation
and was found to give, after acetylation, a complex
pattern of products virtually identical to those formed
at neutral pH, reflecting oxidation at the catechol func-
tionality.14
Oxid a tion of 5- a n d 6-Hyd r oxyin d oles a n d De-
r iva tives in Acid ic Med iu m . In another set of experi-
ments we examined the oxidation behavior of 5- and
6-hydroxy- and -alkoxyindoles, to specifically evaluate
and discriminate the relative effects of electron donating
groups present on either the 5- or 6-position of the indole
ring.
oxidant
pH
5a
33
12
7
4
1
6a
2a
3a
1d b
(NH4)2S2O8
(NH4)2S2O8
1.4
3.0
5.0
5.0
6.0
6.0
7.4
7.4
1.4
3.0
1.4
3.0
21
8
5
5
1
5
12
17
25
37
35
55
8
10
20
22c
16
(NH4)2S2O8
(NH4)2S2O8/Cu2+
(NH4)2S2O8
trace
trace
(NH4)2S2O8/Cu2+
(NH4)2S2O8
trace
1
2
3
3
4
(NH4)2S2O8/Cu2+
Ce(NH4)2(NO3)6
Ce(NH4)2(NO3)6
O2
7
8
10
9
17c
14
8c
Fe2+/H2O2
9
a
Percent yields determined at 30 min (HPLC). Data are means
of two or three experiments. Normally, S.D. did not exceed (10%.
Unreacted 1a , recovered as the acetyl derivative. c Determined
b
after 24 h.
When 5-hydroxyindole (9a ) and 5-methoxyindole (9b)
were subjected to persulfate oxidation at pH 1.4, only the
latter gave a cyclotrimerization product, identified as the
unsymmetrical diindolocarbazole 10, along with the
indoxyl red dimer 11 and the trimers 12 and 13, whereas
the former afforded a pattern of products virtually
superimposable to those obtained by oxidation at neutral
pH,8 with no detectable formation of cyclic trimers.
in the acid-promoted cyclotrimerization route. To this
aim, the oxidation reaction was carried out on suitable
derivatives of 1a protected on the hydroxyl groups,
namely, 5,6-dimethoxyindole (1c) and 5,6-diacetoxyindole
(1d ), to which access to the corresponding semiquinones
and quinones was clearly precluded.
Persulfate oxidation of 1c at pH 1.4 afforded the
corresponding trimers 5c and 6c in good overall yield
(70%). Separation of the individual components proved,
however, difficult despite considerable efforts. By close
scrutiny of the 1H NMR spectrum of the mixture, a
prevalent formation of the unsymmetrical trimer 6c could
be observed.
Quite surprisingly, oxidation of 1d at acidic pH failed
to afford any diindolocarbazole derivative. Whatever the
oxidant concentration and reaction times, substrate
consumption was largely incomplete, and complex mix-
tures of products were invariably obtained, of which 5,6-
diacetoxyoxindole (7) was the only isolable component
(26%).
The observed suppression of the acid-driven cyclotri-
merization pathway in the oxidation of 1d was conceiv-
ably a consequence of the lower electron donating prop-
erties of the acetoxyl groups with respect to hydroxyl and
alkoxyl groups, entailing that the latter groups were
critical for viability of the cyclotrimerization route. To
further probe this issue, recourse was made to the
oxidation of the parent heterocycle, indole. This under-
went slow conversion under the same reaction conditions
adopted for oxidation of 1a and derivatives, affording as
main products oxindole and the trimer 8,12 with no
detectable formation of diindolocarbazoles.
Such a different behavior might be taken to indicate
that, because of hindered resonance delocalization of the
lone pair into the pyrrole moiety, the hydroxyl group on
the 5-position is unable to activate the indole ring toward
the acid-induced polymerization route, whereby viability
of the phenolic oxidation route still constitutes the most
accessible option. Alkylation of the hydroxyl group,
however, partially hinders this oxidative route in 9b,
allowing the cyclotrimerization pathway to become com-
petitive.
Since at low pH the catechol functionality of 1a is
virtually undissociated (pKa ) 8.913) and is thus antici-
pated to be relatively more resistant to oxidation, it was
Both 6-hydroxyindole (14a ) and 6-benzyloxyindole
(14b) proved susceptible to acid-promoted oxidation to
(12) Remers, W. A.; Brown, R. K. In Indoles; Houlihan, W. J ., Ed.;
Wiley-Interscience: New York, 1972; Part I, pp 145-152.
(13) Murphy, B. P.; Schultz, T. M. J . Org. Chem. 1985, 50, 2790-
2791.
(14) Napolitano, A.; Crescenzi, O.; Tsiakas, K.; Prota, G. Tetrahedron
1993, 49, 9143-9150.

Oxidative Polymerization of 5,6-Dihydroxyindoles
J . Org. Chem., Vol. 63, No. 20, 1998 7005
give complex patterns of products comprising diindolo-
carbazole derivatives. While 14b was oxidized to the
corresponding symmetrical diindolocarbazole 16, 14a
gave as the main isolable product a tetramer in which a
6-acetoxyindol-3-yl unit was apparently linked to an
unsymmetrical diindolocarbazole skeleton at one of the
7-positions of the fused 6-hydroxyindole rings. Unfortu-
nately, attempts to establish the exact position of attach-
ment of the indole unit by NMR techniques gave incon-
clusive results, so the product was only tentatively
formulated as 15.
The isolation of 17 and 18 furnished circumstantial,
yet convincing evidence to suggest that formation of
diindolocarbazoles is triggered by the reversible, acid-
induced dimerization of 1a via an indolylindoline inter-
mediate.15 This intermediate, isolated as the acetyl
derivative 17, represents a branching point from which
two divergent routes depart, one driven by oxidants and
leading to diindolocarbazoles and the other involving
acid-induced ring opening,15 to afford a trimer, obtained
as 18 after acetylation (Scheme 1).
In the former route, the crucial steps would be dehy-
drogenation of the indolylindoline to a 2,3′-biindolyl and
its subsequent reaction with protonated 1a to give
isomeric terindolyls which would readily cyclize to diin-
dolocarbazoles in an acidic medium.16 By delocalizing a
higher electron density into the pyrrole moiety of the
indole ring,8b the electron donating hydroxyl and alkoxyl
groups would expectedly facilitate the initial protonation
and dimerization equilibria and would accentuate the
oxidizability of the intermediate indolylindoline, which
is critical to tip the balance of competing routes in favor
of the cyclotrimerization process. The factors governing
the regiochemical outcome are intriguing and difficult to
rationalize on the basis of available evidence. It is
possible that the problem is somewhat compounded by
the lack of complete product inventories, due to the
complexity of the mixtures, and by differences in the
inherent stability of the two isomers.
The one-pot formation of symmetrical diindolocarba-
zoles by oxidation of an indole substrate is, to the best of
our knowledge, unprecedented. Unsymmetrical diindolo-
carbazole has however been reported to form in up to 19%
yield by reaction of indole with Ti(III)- or Fe(II)-
hydrogen peroxide systems in acidic media.10
Mech a n istic Issu es. Having investigated the main
structural factors inducing formation of cyclic trimers
from 5,6-dihydroxyindole derivatives, we returned to the
oxidation of 1a at acidic pH to glean some information
on the nature of possible intermediates in the construc-
tion of the isomeric diindolocarbazole rings.
By stopping the persulfate oxidation of 1a after 1 or 2
s with sodium dithionite, it was possible to isolate small
amounts of two species as the acetyl derivatives. The
faster migrating of these species on TLC (silica gel) was
identified as the indolylindoline 17 by straightforward
spectral analysis. That the compound was not produced
by reduction of a 2,3′-biindolyl precursor during workup
was confirmed in separate experiments in which 17 could
be obtained by usual workup of a reaction mixture but
omitting treatment with sodium dithionite.
Con clu d in g Rem a r k s
In this paper we have described novel oxidation
pathways of 5,6-dihydroxyindoles and related compounds
in acidic media leading to unusual symmetrical and/or
unsymmetrical diindolocarbazoles as the most typical
products. The cyclotrimerization reactions can be brought
about by various oxidizing systems and occur only with
electron-rich indoles carrying hydroxyl or alkoxyl groups,
but not acetoxyl groups.
Besides expanding current knowledge of the oxidation
chemistry of 5,6-dihydroxyindoles and related systems,
the results of this study shed light on new reactions of
potential synthetic value for preparation of hitherto little
investigated diindolocarbazoles. Reported routes to this
heterocyclic system generally involve multistep ap-
proaches and lead to complex mixtures of products with
variable overall yields.16 For synthetic purposes, control
over formation of symmetrical versus unsymmetrical
trimers appears a desirable goal. The pursuit of this
objective as a means for expanding the synthetic scope
The other compound proved to be a trimer (pseudo-
molecular ion peak at m/z 742 by FAB-MS) and was
readily identified as 18 by NMR analysis. TLC and
HPLC analysis showed that 17 was present during the
very first minutes, whereas 18 survived for a longer time,
though only traces could be detected after 30 min. No
detectable amount of the 2,2′-dimer 4a or of other isolable
dimers of 1a was found by careful analysis of the reaction
mixture, most of the remaining material being difficult
to isolate and characterize.
(15) Remers, W. A.; Brown, R. K. In Indoles; Houlihan, W. J ., Ed.;
Wiley-Interscience: New York, 1972; Part I, pp 66-70.
(16) (a) Bergman, J .; Eklund, N. Tetrahedron 1980, 36, 1445-1450.
(b) Bergman, J .; Eklund, N. Tetrahedron 1980, 36, 1439-1443. (c)
Bocchi, V.; Palla, G. Tetrahedron 1986, 42, 5019-5024. (d) Eissenstat,
M. A.; Bell, M. R.; D’Ambra, T. E.; Alexander, E. J .; Daum, S. J .;
Ackerman, J . H.; Gruett, M. D.; Kumar, V.; Estep, K. G.; Olefirowicz,
E. M.; Wetzel, J . R.; Alexander, M. D.; Weaver, J . D.; Haycock, D. A.;
Luttinger, D. A.; Casiano, F. M.; Chippari, S. M.; Kuster, J . E.;
Stevenson, J . I.; Ward, S. J . J . Med. Chem. 1995, 16, 3094-3105.

7006 J . Org. Chem., Vol. 63, No. 20, 1998
Manini et al.
Sch em e 1. Ma in Rea ction P a th w a ys in th e Acid -P r om oted Oxid a tion of 1a
Oxid a t ion of In d olic Com p ou n d s in Acid ic Med ia .
Gen er a l P r oced u r e. To a solution of the indole at indicated
concentration in 0.1 M phosphoric acid, pH 1.4, unless
otherwise stated, was added a freshly prepared aqueous
solution of ammonium persulfate to the desired concentration.
The progress of the reaction was monitored by TLC. When
required, cupric acetate was added at equimolar concentration
with respect to the indole substrate. Sodium dithionite was
then added, and the mixture was rapidly extracted three times
with ethyl acetate. The combined organic extracts were
washed with small quantities of brine and water, carefully
dried over anhydrous sodium sulfate, and concentrated by
rotary evaporation at ambient temperature. When appropri-
ate, the residue was acetylated overnight with acetic anhydride/
pyridine. Adherence to this protocol was imposed by the need
to destroy excess oxidant and prevent undesired oxidative
degradation of the labile products after the reaction had gone
to completion or during workup.
Oxidations with ceric ammonium nitrate were carried out
as above by adding equimolar amounts of the oxidant to the
substrate in 0.1 M phosphate buffer, pH 1.4 or 3.0. When most
of the substrate was consumed (TLC evidence), sodium dithio-
nite was added and the mixture rapidly extracted with ethyl
acetate and subjected to workup as above.
Oxidations with the Fenton reagent were carried out in 0.1
M perchloric acid, pH 3.0, essentially as described by Kaneko
et al.10 under a nitrogen atmosphere.
of these reactions holds mechanistic interest as well and
may disclose new facets of theoretical and practical
relevance.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. 1H NMR and 13C
NMR spectra were recorded on apparatuses operating at 400,
250, or 200 MHz with tetramethylsilane as internal reference.
Wherever necessary, 1H NMR and 13C NMR assignments were
supported by appropriate 2D heteronuclear correlation and
DEPT experiments. Mass spectra were recorded using the
electron ionization (EI) at 70 eV or the fast atom bombardment
(FAB) techniques. For FAB-MS spectra, glycerol was prefer-
ably used as the matrix. Thin-layer chromatography (TLC)
was performed on glass plates coated with a 0.25 or 0.5 mm
layer of silica gel 60 F254. Analytical and preparative HPLC
were carried out on reverse phase C18 columns (4.6 × 250 mm
and 22 × 250 mm, respectively). The flow rate was 1 mL/min
for analytical runs and 10 mL/min for preparative chroma-
tography.
5,6-Dihydroxyindole (1a ),17 5,6-dihydroxy-2-methylindole
(1e),14 and 5,6-dihydroxy-1-methylindole (1b)17 were prepared
by literature methods. 5,6-Diacetoxyindole (1d ) and 6-benzyl-
oxyindole (14b) were kindly provided by Clairol Research
Laboratories (Stamford, CT). 6-Hydroxyindole (14a ) was
obtained by catalytic hydrogenolysis18 of 14b. All other indoles
were commercially available. Ammonium persulfate was
crystallized twice from hot water before use.
Oxidations with molecular oxygen were carried out by
bubbling oxygen gas through a solution of the substrate in 0.1
M phosphoric acid, pH 1.4. Product analysis and workup were
as above.
Oxid a tion of 1a . From 500 mg of 1a (10 mM) oxidized
with ammonium persulfate (755 mg, 10 mM) was obtained
2,3,7,8,12,13-hexaacetoxydiindolo[3,2-a:3′,2′-c]carbazole (5a ) as
(17) Benigni, J . D.; Minnis, R. L. J . Heterocycl. Chem. 1965, 2, 387-
392.
(18) Ram, S.; Ehrenkaufer, R. E. Synthesis 1988, 91-95.

Oxidative Polymerization of 5,6-Dihydroxyindoles
J . Org. Chem., Vol. 63, No. 20, 1998 7007
a pale green solid (225 mg, 29%) which separated from the
acetylated mixture taken up in ethyl acetate: mp 282 °C dec;
UV (DMSO) λmax (log ꢀ) 317 (4.58), 338 (4.40, sh), 346 (4.03)
nm; 1H NMR (DMSO-d6) δ 12.20 (s, 1H × 3), 8.56 (s, 1H × 3),
7.58 (s, 1H × 3), 2.46 (s, 3H × 3), 2.41 (s, 3H × 3); 13C NMR
(DMSO-d6) δ 169.1, 168.7, 138.3, 135.9, 135.9, 134.56, 119.4,
113.5, 105.4, 100.5, 20.6, 20.3; MS (FAB) m/z 694; HRMS calcd
for C36H28N3O12 (M+ + 1) 694.1673, found 694.1669. Anal.
Calcd for C36H27N3O12: C, 62.34; H, 3.92; N, 6.06. Found: C,
62.26; H, 3.90; N, 6.09.
+ 1) 736.2143, found 736.2150. Anal. Calcd for C39H33N3O12
C, 63.67; H, 4.52; N, 5.71. Found: C, 63.74; H, 4.54; N, 5.63.
Evaporation of the acetone washings to dryness afforded
pure 6b (Rf ) 0.70, chloroform-acetone 8:2 v/v) as a greenish
solid (180 mg, 24%): mp 237 °C dec; UV (DMSO) λmax (log ꢀ)
303 (3.22), 356 (2.78) nm; 1H NMR (DMSO-d6) δ 8.40 (s, 1H),
8.39 (s, 1H), 8.33 (s, 1H), 7.72 (s, 1H × 2), 7.68 (s, 1H), 4.35 (s,
3H), 4.15 (s, 3H), 4.10 (s, 3H), 2.40 (s, 3H × 6); 13C NMR19
(DMSO-d6) δ 168.9 (3C), 168.5 (3C), 141.7, 141.2, 140.0, 139.7,
138.7, 138.6, 136.0, 135.7, 135.4, 131.2, 126.5, 120.5, 119.8,
119.0, 116.5, 115.7 (2C), 114.8, 109.4, 107.6, 106.0, 105.7, 104.6
(2C), 37.1, 36.7, 35.7, 20.7 (3C), 20.4 (3C); MS (FAB) m/z 736;
:
Preparative TLC of the residue (silica gel, 0.5 mm, eluent
benzene-acetone 65:35 v/v) gave a little more 5a (Rf ) 0.33)
and 2,3,6,7,11,12-hexaacetoxydiindolo[2,3-a:2′,3′-c]carbazole
(6a ) (Rf ) 0.24) as a brown solid which was crystallized from
methanol (147 mg, 19%): mp 251 °C dec; UV (EtOH) λmax (log
ꢀ) 247 (3.98), 315 (3.96), 331 (3.78, sh), 359 (3.48, sh), 377 (3.27,
HRMS calcd for
736.2148. Anal. Calcd for C39H33N3O12: C, 63.67; H, 4.52; N,
5.71. Found: 63.61; H, 4.49; N, 5.61.
C
39H34N3O12 (M+ + 1) 736.2143, found
Oxid a tion of 1c. From 500 mg of 1c (5 mM), oxidized with
ammonium persulfate (645 mg, 20 mM) was obtained a green
solid (345 mg, 70%) containing 2,3,7,8,12,13-hexamethoxydi-
indolo[3,2-a:3′,2′-c]carbazole (5c) and 2,3,6,7,11,12-hexa-
methoxydiindolo[2,3-a:2′,3′-c]carbazole (6c) as an intimate
mixture which could not be separated:20 1H NMR (DMSO-d6)
(mixture, integrated areas refer to each set of resonances) δ
11.45 (s, 1H × 3), 11.40 (s, 1H), 10.95 (s, 1H), 10.85 (s, 1H),
8.17 (s, 1H × 2), 8.16 (s, 1H), 8.14 (s, 1H × 3), 7.33 (s, 1H ×
3), 7.29 (s, 1H), 7.25 (s, 1H × 2), 4.03 (s, 3H), 4.00 (s, 3H),
3.93 (s, 3H), 3.91 (s, 3H × 3); MS (FAB) m/z 526; HRMS calcd
for C30H28N3O6 (M+ + 1) 526.1979, found 526.1971.
1
sh), 400 (3.06); H NMR (DMSO-d6) δ 12.11 (s, 1H), 11.72 (s,
1H), 11.63 (s, 1H), 8.67 (s, 1H), 8.43 (s, 1H), 8.36 (s, 1H), 7.79
(s, 1H), 7.79 (s, 1H), 7.63 (s, 1H), 2.59 (s, 3H), 2.46 (s, 3H),
2.45 (s, 3H × 2), 2.42 (s, 3H × 2); 13C NMR (DMSO-d6) δ 169.3
(3C), 168.8 (3C), 139.5 (2C), 138.3, 136.3, 136.0 (2C), 135.3,
135.2, 130.2, 126.7, 122.7, 120.1, 120.0, 119.6, 115.2, 114.5,
114.3, 113.5, 110.1, 107.9, 106.3, 106.2, 105.6, 105.4, 20.7 (3C),
20.6 (3C); MS (FAB) m/z 694; HRMS calcd for C36H28N3O12
(M+
36H27N3O12: C, 62.34; H, 3.92; N, 6.06. Found: C, 62.43; H,
+ 1) 694.1673, found 694.1675. Anal. Calcd for
C
3.92; N, 6.10.
For isolation of intermediate products, 1a (200 mg) was
oxidized as above, except that the reaction was stopped after
about 1 s by treatment with sodium dithionite. After acety-
lation of the ethyl acetate-extractable fraction, the residue was
chromatographed on silica gel plates (0.5 mm layer, eluent
benzene-acetone 65:35 v/v) to give, besides much unreacted
starting material as the acetyl derivative 1d , N,5,6-triacetoxy-
2-(5′,6′-diacetoxyindol-3′-yl)indoline (17) (Rf ) 0.36) and im-
pure 18 (Rf ) 0.18).
Oxid a tion of 1d . From 500 mg of 1d (10 mM), oxidized
with ammonium persulfate (704 mg, 15 mM) in 0.1 M
phosphate buffer, pH 3, 5,6-diacetoxyoxindole (7) (Rf ) 0.28)
could be isolated by preparative TLC (benzene-acetone 65:
35 v/v), as a yellow solid (139 mg, 26%): mp 185-186 °C; UV
(EtOH) λmax (log ꢀ) 251 (3.00), 286 (2.25) nm; 1H NMR (acetone-
d6) δ 9.49 (s, 1H), 7.09 (s, 1H), 6.76 (s, 1H), 3.48 (s, 2H), 2.25
(s, 3H), 2.24 (s, 3H); 13C NMR (acetone-d6) 176.8, 169.1, 168.7,
142.8, 142.4, 137.8, 124.4, 120.7, 105.4, 36.2, 20.5 (2C); MS
(EI) m/z 249; HRMS calcd for C12H11NO5 (M+) 249.0637, found
249.0630. Anal. Calcd for C12H11NO5: C, 57.83; H, 4.45; N,
5.62. Found: C, 57.90; H, 4.39; N, 5.70.
17: 31 mg (9%); mp 136-137 °C; UV (EtOH) λmax (log ꢀ) 262
(4.10), 286 (3.96) nm; 1H NMR (acetone-d6) δ 10.34 (s, 1H),
8.05 (s, 1H), 7.27 (s, 1H), 7.23 (d, J ) 1.8 Hz, 1H), 7.06 (s,
1H), 7.05 (s, 1H), 5.97 (dd, J ) 9.8, 1.9 Hz, 1H), 3.81 (ddd, J
) 16.1, 9.8, 1.1 Hz, 1H), 3.04 (dd, J ) 16.3, 2.1 Hz, 1H), 2.28
Oxid a tion of 1e. Oxidation of 1e with ammonium persul-
fate, as reported in the general procedure, afforded a complex
pattern of products identical to that obtained by oxidation at
neutral pH.14 By preparative TLC (chloroform-methanol 8:2
containing 1% acetic acid) three main oligomers could be
isolated (see Supporting Information), which proved identical
(1H and 13C NMR, TLC, EI-MS) with authentic samples.
Oxid a tion of 9a . Oxidation of 9a as reported in the general
procedure afforded a complex pattern of products identical to
that obtained by oxidation at neutral pH.8 By preparative TLC
(benzene-acetone 65:35 v/v), four main oligomers could be
isolated (see Supporting Information) which proved identical
(1H and 13C NMR, TLC, EI-MS) with authentic samples.8
Oxid a tion of 9b. From 500 mg of 9b (10 mM), oxidized
with ammonium persulfate (7.26 g, 50 mM), 3,6,11-trimeth-
oxydiindolo[2,3-a:2′,3′-c]carbazole (10), the indoxyl red deriva-
tive 11, 2,2-bis(5-methoxyindol-3-yl)-5-methoxyindol-3-one (12),
and 4,4-bis(5-methoxyindol-3-yl)indol-5(4H)-one (13) were ob-
tained by preparative TLC (benzene-acetone 8:2 v/v).
10: green solid (133 mg, 26%); Rf ) 0.53; mp 217 °C dec;
UV (EtOH) λmax (log ꢀ) 252 (4.73), 311 (4.61), 359 (4.48), 403
(s, 3H), 2.23 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 2.11 (s, 3H); 13
C
NMR (acetone-d6) 169.7, 169.4, 169.2, 168.9, 168.9, 142.1,
142.0, 139.6, 139.1, 137.5, 135.3, 129.5, 124.4, 122.7, 120.4,
118.6, 113.1, 112.4, 107.0, 58.8, 37.8, 23.6, 20.5 (4C); MS (EI)
m/z 508; HRMS calcd for C26H24N2O9 (M+) 508.1482, found
508.1477. Anal. Calcd for C26H24N2O9: C, 61.42; H, 4.76; N,
5.51. Found: C, 61.33; H, 4.70; N, 5.45.
The band containing 18 was rechromatographed on HPLC,
mobile phase 0.1 M acetic acid-acetonitrile 60:40 v/v, to give
pure 18: 16 mg (5%); mp 158-160 °C; UV (EtOH) λmax (log ꢀ)
227 (3.98), 275 (3.29, sh), 288 (3.37), 294 (3.35, sh) nm; 1H NMR
(acetone-d6) δ 10.08 (s, 1H × 2), 7.80 (s, 1H), 7.55 (s, 1H), 7.29
(s, 1H × 2), 7.22 (s, 1H × 2), 7.17 (d, J ) 1.8 Hz, 1H × 2), 7.06
(s, 1H), 4.75 (t, J ) 7.3 Hz, 1H), 3.51 (d, J ) 7.3 Hz, 2H), 2.21
(s, 3H × 3), 2.19 (s, 3H × 2), 2.15 (s, 3H), 1.73 (s, 3H); 13C
NMR (acetone-d6) 169.4 (2C), 169.2 (3C), 168.7, 168.6, 141.1,
139.7, 139.1 (2C), 136.9 (2C), 135.5, 135.0 (2C), 132.3, 125.2
(2C), 125.1 (2C), 125.0, 119.4, 118.8 (2C), 113.2 (2C), 106.6 (2C),
37.0, 35.7, 23.6, 20.5 (3C), 20.5 (3C); MS (FAB) m/z 742; HRMS
calcd for C38H36N3O13 (M+ + 1) 742.2249, found 742.2244. Anal.
Calcd for C38H35N3O13: C, 61.54; H, 4.76; N, 5.67. Found: C,
61.68; H, 4.71; N, 5.61.
Oxid a tion of 1b. From 500 mg of 1b (10 mM), oxidized
with ammonium persulfate (700 mg, 10 mM) was obtained a
mixture of 2,3,7,8,12,13-hexaacetoxy-5,10,15-trimethyldiin-
dolo[3,2-a:3′,2′-c]carbazole (5b) and 2,3,6,7,11,12-hexaacetoxy-
9,14,15-trimethyldiindolo[2,3-a:2′,3′-c]carbazole (6b) as a solid
which separated from the acetylated mixture taken up in ethyl
acetate. Extensive washing of the solid with boiling acetone
gave a white solid19 consisting of virtually pure 5b (195 mg,
26%): mp 293 °C dec; UV (DMSO) λmax (log ꢀ) 324 (4.85), 341
(4.57, sh), 356 (4.23) nm; 1H NMR (DMSO-d6) δ 8.02 (s, 1H ×
3), 7.48 (s, 1H × 3), 3.97 (s, 3H × 3), 2.48 (s, 3H × 3), 2.38 (s,
3H × 3); MS (FAB) m/z 736; HRMS calcd for C39H34N3O12 (M+
1
(4.09) nm; H NMR (DMSO-d6) δ 11.61 (s, 1H), 11.30 (s, 1H),
11.19 (s, 1H), 8.27 (d, J ) 2.4 Hz, 1H), 8.23 (d, J ) 2.4 Hz,
1H), 8.19 (d, J ) 2.4 Hz, 1H), 7.68 (d, J ) 8.7 Hz, 1H), 7.67 (d,
J ) 8.7 Hz, 1H), 7.66 (d, J ) 8.7 Hz, 1H), 7.10 (dd, J ) 8.2,
2.3 Hz, 1H), 7.08 (dd, J ) 8.8, 2.6 Hz, 1H), 7.05 (dd, J ) 7.3,
2.6 Hz, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 4.00 (s, 3H); 13C NMR
(DMSO-d6) 153.8, 152.9, 152.8, 133.7, 133.6, 133.2, 130.1,
126.9, 123.4, 123.3, 122.7, 122.5, 113.8, 113.2, 112.9, 112.4,
112.0, 111.8, 111.3, 107.9, 105.9, 104.1, 104.0, 103.5, 56.1, 55.3
(19) Compounds 5b and 6b were only sparingly soluble in DMSO
and acetone and insoluble in all other solvents examined. The
exceedingly low solubility of 5b prevented acquisition of its 13C NMR
spectrum, whereas a poor spectrum was obtained in the case of 6b
even after a high number of scans.

7008 J . Org. Chem., Vol. 63, No. 20, 1998
Manini et al.
(2C); MS (EI) m/z 435; HRMS calcd for C27H21N3O3 (M+)
435.1584, found 435.1590. Anal. Calcd for C27H21N3O3: C,
74.47; H, 4.86; N, 9.65. Found: C, 74.56; H, 4.82; N, 9.52.
11: purple solid (104 mg, 20%); mp 205-207 °C; Rf ) 0.75;
UV (EtOH) λmax (log ꢀ) 278 (2.95), 305 (2.62), 368 (2.15), 561
zyloxydiindolo[3,2-a:3′,2′-c]carbazole (16) could be obtained by
preparative TLC (benzene-acetone 9:1 v/v) as a gray solid (46
mg, 24%): Rf ) 0.37; mp 229-230 °C; UV (EtOH) λmax (log ꢀ)
246 (3.39), 272 (3.30), 315 (3.40), 341 (2.89), 382 (2.20) nm; 1H
NMR (acetone-d6) δ 10.90 (s, 1H × 3), 8.37 (d, J ) 9.1 Hz, 1H
× 3), 7.55 (dd, J ) 7.2, 1.7 Hz, 1H × 2 × 3), 7.41 (dd, J ) 7.2,
1.7 Hz, 1H × 2 × 3), 7.37 (dd, J ) 7.2, 1.7 Hz, 1H × 3), 7.30
(d, J ) 2.4 Hz, 1H × 3), 7.02 (dd, J ) 9.1, 2.4 Hz, 1H × 3),
5.24 (s, 2H × 3); 13C NMR (acetone-d6) 157.2, 141.1, 139.1,
129.5, 129.2, 128.7, 128.6, 121.2, 118.2, 109.8, 102.1, 97.6, 71.1;
MS (FAB) m/z 664; HRMS calcd for C45H34N3O3 (M+ + 1)
664.2602, found 664.2614. Anal. Calcd for C45H33N3O3: C,
81.43; H, 5.01; N, 6.33. Found: C, 81.57; H, 5.08; N, 6.28.
Oxid a t ion of In d ole. From 500 mg of indole (10 mM),
oxidized with ammonium persulfate (950 mg), oxindole and 8
could be obtained by preparative TLC (benzene-acetone 8:2
v/v).
1
(2.09) nm; H NMR (acetone-d6) δ 11.06 (s, 1H), 8.46 (s, 1H),
8.05 (d, J ) 2.6 Hz, 1H), 7.44 (d, J ) 8.8 Hz, 1H), 7.23 (dd, J
) 6.5, 2.4 Hz, 1H), 7.05 (dd, J ) 7.1, 2.7 Hz, 1H), 7.04 (d, J )
2.2 Hz, 1H), 6.90 (dd, J ) 8.8, 2.6 Hz, 1H), 3.86 (s, 3H), 3.84
(s, 3H); 13C NMR (acetone-d6) 196.4, 159.7, 158.4, 157.2, 156.9,
133.1, 132.7, 128.1, 124.6, 122.1, 121.5, 114.0, 113.6, 111.3,
108.2, 106.0, 56.3, 55.9; MS (EI) m/z 306; HRMS calcd for
C
C
18H14N2O3 (M+) 306.1005, found 306.0998. Anal. Calcd for
18H14N2O3: C, 70.58; H, 4.61; N, 9.15. Found: C, 70.71; H,
4.72; N, 9.10.
12: yellow-green solid (67 mg, 14%); mp 201-203 °C; Rf )
0.49; UV (EtOH) λmax (log ꢀ) 275 (4.41), 298 (4.38), 343 (3.88),
360 (3.94), 382 (3.75), 404 (3.78), 430 (3.64) nm; 1H NMR
(acetone-d6) δ 9.97 (s, 1H × 2), 7.26 (d, J ) 8.8 Hz, 1H × 2),
7.21 (dd, J ) 9.0, 2.7 Hz, 1H), 7.20 (d, J ) 2.4 Hz, 1H × 2),
7.06 (d, J ) 2.7 Hz, 1H), 7.03 (d, J ) 9.0 Hz, 1H), 6.96 (d, J )
2.5 Hz, 1H × 2), 6.77 (s, 1H), 6.71 (dd, J ) 8.8, 2.5 Hz, 1H ×
2), 3.77 (s, 3H), 3.55 (s, 3H × 2); 13C NMR (acetone-d6) 202.0,
157.7, 154.3 (2C), 153.8, 133.5 (2C), 128.2, 127.5 (2C), 125.6
(2C), 120.6, 115.7 (2C), 114.8, 112.8 (2C), 112.0 (2C), 105.5,
103.9 (2C), 69.9, 56.0, 55.5 (2C); MS (EI) m/z 453; HRMS calcd
for C27H23N3O4 (M+) 453.1690, found 453.1681. Anal. Calcd
for C27H23N3O4: C, 71.51; H, 5.11; N, 9.27. Found: C, 71.42;
H, 5.13; N, 9.34.
13: orange solid (72 mg, 14%); mp 227-228 °C; Rf ) 0.25;
UV (EtOH) λmax (log ꢀ) 289 (3.76), 350 (3.62), 446 (3.10) nm;
1H NMR (acetone-d6) δ 10.56 (s, 1H), 9.89 (s, 1H × 2), 7.47 (d,
J ) 9.7 Hz, 1H), 7.24 (d, J ) 8.8 Hz, 1H × 2), 6.94 (t, J ) 2.7
Hz, 1H), 6.86 (d, J ) 2.5 Hz, 1H × 2), 6.79 (d, J ) 2.6 Hz, 1H
× 2), 6.69 (dd, J ) 8.8, 2.5 Hz, 1H × 2), 5.84 (t, J ) 2.2 Hz,
1H), 5.68 (d, J ) 9.7 Hz, 1H), 3.57 (s, 3H × 2); 13C NMR
(acetone-d6) 201.2, 154.7 (2C), 133.5, 133.4, 128.0 (2C), 126.5
(2C), 126.4, 125.2, 122.5 (2C), 122.3, 119.5, 117.4 (2C), 112.3
(2C), 111.6 (2C), 111.4, 105.0 (2C), 55.3 (2C), 55.0; MS (EI)
m/z 423; HRMS calcd for C26H21N3O3 (M+) 423.1584, found
423.1593. Anal. Calcd for C26H21N3O3: C, 73.74; H, 5.00; N,
9.92. Found: C, 73.81; H, 5.10; N, 9.80.
Oxindole: 195 mg (26%); Rf ) 0.34; mp 124-126 °C (lit.21
mp 126-127 °C). 8: 162 mg (32%); Rf ) 0.45; mp 240-242
°C (lit.22 mp 243-245.5 °C). All other properties (1H and 13C
NMR, TLC, EI-MS) were identical with those of authentic
samples.
Ack n ow led gm en t. This work was supported in part
by grants from MURST, CNR (Rome), and Lawrence
M. Gelb Research Foundation (Stamford, CT). We thank
Miss Silvana Corsani for technical assistance, the
Centro Interdipartimentale di Metodologie Chimico-
fisiche of Naples University for NMR spectra, and
the Servizio di Spettrometria di Massa del CNR e
dell’Universita`, Naples, and Drs. P. Traldi and R.
Seraglia (CNR, Padua) for mass spectra.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 5a , 6a , 10, 16, 17 and 18. 1H NMR
spectra of 5b, 6b, 5c+6c (mixture), and 15. Spectral data of
8. Structures of oligomers obtained by oxidation of 1e and 9a
in acidic medium (29 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.
Oxid a tion of 14a . From 100 mg of 14a (20 mM), oxidized
with ammonium persulfate (172 mg, 20 mM), tetramer 15
could be obtained by preparative TLC (benzene-acetone 7:3
v/v) as a brown solid (7 mg, 5%): Rf ) 0.43; mp 163-165 °C;
UV (EtOH) λmax (log ꢀ) 255 (3.83), 310 (3.72), 351 (3.51), 369
(3.12), 391 (3.03) nm; 1H NMR (acetone-d6) δ 10.87 (s, 1H),
10.78 (s, 1H), 10.69 (s, 1H), 10.38 (s, 1H), 8.87 (d, J ) 9.4 Hz,
1H), 8.76 (d, J ) 9 Hz, 1H), 8.32 (d, J ) 9 Hz, 1H), 7.79 (m,
1H), 7.53 (d, J ) 9 Hz, 1H), 7.47 (d, J ) 2 Hz, 1H), 7.43 (d, J
) 2 Hz, 1H), 7.38 (d, J ) 2 Hz, 1H), 7.26 (d, J ) 9 Hz, 1H),
7.14 (dd, J ) 9, 2 Hz, 1H), 6.93 (dd, J ) 9, 2 Hz, 1H), 6.89 (dd,
J ) 9, 2 Hz, 1H), 2.34 (s, 3H × 2), 2.31 (s, 3H), 2.30 (s, 3H);
MS (FAB) m/z 693; HRMS calcd for C40H29N4O8 (M+ + 1)
693.1987, found 693.1992.
J O980875K
(20) Attempts to separate 5c and 6c by crystallization, TLC, or
HPLC were frustrated by their extreme insolubility and the similar
chromatographic behavior under a variety of conditions. Removal of
impurities could only be achieved by repeated washings with acetone.
In three different reactions, 5c:6c ratios were found to be in the range
of 0.33-0.5, as apparent from integrated signal areas in the 1H NMR
spectra of the mixtures. The solubility problem and the tendency of
the compounds to exhibit signal broadening prevented acquisition of
a meaningful 13C NMR spectrum. In spite of our efforts, a satisfactory
result of elemental analysis could not be obtained. To show the purity
of the sample, a copy of the 1H NMR spectrum (400 MHz) is provided
as Supporting Information.
(21) Neil, A. B. J . Am. Chem. Soc. 1953, 75, 1508.
(22) Witkop, B.; Patrick, J . B. J . Am. Chem. Soc. 1951, 73, 713-
718.
Oxid a tion of 14b. From 200 mg of 14b (10 mM), oxidized
with ammonium persulfate (307 mg, 15 mM), 2,7,12-triben-