Charge migration in dicationic electrophiles and its application to the synthesis of aza-polycyclic aromatic compounds

Article abstract of DOI:10.1021/ol060125u

Superacid-promoted reactions of dicationic electrophiles have been studied, and the positive charge centers are found to migrate apart in a predictable manner. Using isotopic labeling the charge migration is found in one system to occur through successive deprotonation-reprotonation steps. The charge migration chemistry is the basis for new general synthetic route to aza-polycyclic aromatic compounds.

Full text of DOI:10.1021/ol060125u

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1233-1236
Charge Migration in Dicationic
Electrophiles and Its Application to the
Synthesis of Aza-polycyclic Aromatic
Compounds
Ang Li, Patrick J. Kindelin, and Douglas A. Klumpp*
Department of Chemistry and Biochemistry, Northern Illinois UniVersity,
DeKalb, Illinois 60115
dklumpp@niu.edu
Received January 16, 2006
ABSTRACT
Superacid-promoted reactions of dicationic electrophiles have been studied, and the positive charge centers are found to migrate apart in a
predictable manner. Using isotopic labeling the charge migration is found in one system to occur through successive deprotonation reprotonation
steps. The charge migration chemistry is the basis for new general synthetic route to aza-polycyclic aromatic compounds.
−
Aza-polycyclic aromatic compounds and the substituted
derivatives have been of interest for their cytotoxic and other
biological activities.1 These types of compounds are also
well-known as products from the incomplete combustion of
organic materials, and several are known to be potent
mutagens and carcinogens.2 Aza-polycyclic aromatic com-
pounds are also thought to be a major component of
interstellar organic matter, some of which have been identi-
fied on the basis of their spectral data.3 Moreover, aza-
polycyclic aromatic compounds have been shown in recent
applications to have useful optical properties. Consequently,
there has been general interest in the development of new
synthetic methodologies for these types of compounds. The
recent development of superelectrophilic chemistry by Olah
and co-workers has stimulated a substantial amount work
related to electrophiles having two or more positive charges.4
Often the stabilities of these dications are related to the
distance between charge centers. Several examples are known
in which dicationic species rearrange to generate more stable
structures having an increased distance between the charge
centers, especially if the rearrangement also leads to elec-
tronic stabilization of the charge center(s).5 In the following
Letter, we report the rearrangements of secondary and tertiary
carbocationic centers to benzylic carbocations in dicationic
systems. This rearrangement is the basis for a new general
route to aza-polycyclic aromatic compounds.
A series of alcohols (1-6) were prepared and reacted with
C6H6 in the presence of the Brønsted superacid CF3SO3H
(Table 1). In all cases, the products (7-11, 13) are generated
from a rearrangement and subsequent phenylation. It is
proposed that the alcohols initially ionize in superacid to
generate 1,4-dications (entries 1-3) or 1,3-dications (entries
4 and 6) and charge migration then occurs to give 1,5-
dications or 1,4-dications, respectively. On the basis of results
from an isotopically labeled substrate (3, entry 3), charge
migration is thought to occur by deprotonation (dedeutera-
(1) (a) Ioanoviciu, A.; Antony, S.; Pommier, Y.; Staker, B. L.; Stewart,
L.; Cushman, M. J. Med. Chem. 2005, 48, 4803. (b) Armenise, D.; Trapani,
G.; Arrivo, V.; Laraspata, E.; Morlacchi, F. J. Heterocycl. Chem. 2000, 37
(6), 1611. (c) Kaloko, J.; Hayford, A. Org. Lett. 2005, 7, 4305.
(2) (a) Borosky, G. L.; Laali, K. K. Org. Biorg. Chem. 2005, 3, 1180.
(b) Schmeltz, I.; Hoffmann, D. Chem. ReV. 1997, 77, 2295.
(3) Mattioda, A. M.; Hudgins, D. M.; Bauschlicher, C. W.; Rosi, M.;
Allamandaola, L. J. J. Phys. Chem. A 2003, 107, 1486.
(4) Olah, G. A.; Klumpp, D. A. Acc. Chem. Res. 2004, 37, 211.
(5) (a) Zhang, Y.; Aguirre, S. A.; Klumpp, D. A. Tetrahedron Lett. 2002,
43, 6837. (b) Klumpp, D. A.; Fredrick, S.; Lau, S.; Prakash, G. K. S.; Jin,
K. K.; Bau, R.; Olah, G. A. J. Org. Chem. 1999, 64, 5152. (c) Taescher,
C.; Sorenson, T. Tetrahedron Lett. 2001, 42, 5339.
10.1021/ol060125u CCC: $33.50
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stable than dication 14. The geometry optimized structure
(14) shows neighboring group participation by a phenonium
ion type of interaction; however, the 1,3-dication (14) is
about 16 kcal/mol less stable than the 1,4-dication (15) at
the B3LYP 6-311G**// B3LYP 6-311G** level of theory.7
Nevertheless, the phenonium ion stabilization may provide
important anchimeric assistance for the ionization of the
alcohol to the dicationic intermediate. This is also evident
from the observed reactivity differences between compound
16 and compound 18: ionization of 16 occurs readily and
gives the arylated product (17) almost quantitatively (eq 1),
whereas compound 18 does not give the substitution product
under similar conditions (eq 2), but instead starting material
18 is recovered.
Table 1. Products and Yields from the Reactions of Alcohol
Substrates (1-7) with CF3SO3H and C6H6
When appropriately substituted N-heterocycles are reacted
with superacidic CF3SO3H, a cyclization gives aza-polycyclic
aromatic compounds from loss of water and benzene (Table
2). For example, this conversion gives benz[c]acridine (26)
in one step from the reaction of the substituted quinoline
(19) and CF3SO3H (entry 1). Other aza-polycyclic com-
pounds prepared by this method include the benz[f]isoquino-
line (27), the benz[g]indazole (29), and the benz[e]imidazole
(28). The conversions are thought to involve several types
of dicationic intermediates (Scheme 1). In the case of
compound 20, protonation of the pyridine ring and alcohol
group leads to the 1,4-dication (34), and this is followed by
charge migration to give the 1,5-dication (35). Cyclization
toward the phenyl group then leads to the formation of the
new ring. Elimination of benzene occurs by the initial ipso-
protonation to form dication (37), with subsequent loss of
benzene and a proton to generate the benz[f]isoquinoline
system. On the basis of this mechanism, we sought to
determine if a larger ring system could be prepared by a
cyclization involving a phenyl-substituted cyclohexyl group
(entry 6, Table 2). When compound 24 is reacted with CF3-
SO3H and the product then aromatized with DDQ, the
phenanthro[9,10-d]oxazole system (31) is produced in fair
yield. Presumably, ionization of compound 24 in the super-
acid also leads to dication formation, charge migration,
cyclization involving the cyclohexyl cation, and benzene
elimination.
a Isolated yields of purified products.
tion)-protonation reaction steps rather than via 1,2-hydride
shifts.6 The migration of the charge is evidently driven by
the formation of the benzylic-type carbocation, as well as
the increasing separation of the two positive charge centers.
The importance of increasing charge separation is seen in
the reaction of compound 5, which ionizes in superacid to
initially generate a 1,5-dication having benzylic stabilization.
Despite the benzylic stabilization, charge migration produces
the 1,6-dication (also benzylic), and product 11 is obtained
in good yield. The thiazole system (6) gives both the
rearrangement (13) and substitution (12) products, and the
relative ratio of the two products varies with temperature.
However if compound 6 is reacted with CF3SO3H for 1 h
and then C6H6 is added, the charge migration product (13)
is formed exclusively. This suggests that the rearrangement
product (13) is the thermodynamically favored product,
whereas product 12 is the kinetically favored product. When
the dicationic intermediates leading to products 12 and 13
are compared, the rearrangement involves the isomerization
of the 1,3-dication to the 1,4-dication. Ab initio calculations
were done on the intermediates (14 and 15), and the
calculations estimate that dication 15 is significantly more
(6) As suggested by a reviewer of this manscript, the deprotonation-
protonation may be more important for systems giving a double bond
conjugated to a pair aromatic systems (such as entry 3), while direct hydride
shift (as a mode of charge migration) may operate in other systems not
having the benefit of trans-stillbene-type conjugation.
(7) For details regarding the computational results, see Supporting
Information.
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Org. Lett., Vol. 8, No. 6, 2006

The utility of the benzene elimination step is shown in
the preparation of a substituted benzo[c]-phenanthrene (40,
eq 3). Several benzo[c]phenanthrenes are known for their
Table 2. Yields of Aza-polycyclic Aromatic Compounds from
the Reactions of Compounds 19-24 with CF3SO3H at 25 °C
anticancer properties and have been extensively studied by
medicinal chemists.8 Recently, Clement and co-workers
described a convenient method for the preparation of
dihydro-benzo[c]phenanthrenes having pendant aryl groups.9
Using this method, 5-fluoro-2-methyl-benzonitrile was re-
acted with benzaldehyde to give the phenyl-substituted
product (39). Reaction of product 39 with CF3SO3H gives
the substituted benzo[c]phenanthrene (40) in good yield. The
benzene elimination step likely involves a triprotonated
intermediate having the ring nitrogen, as well as the amino
and phenyl groups, protonated by the superacid.
The conversions of compounds 19-25 to the respective
aza-polycyclic aromatic compounds represents a new route
to these types of products and involves two novel reaction
steps: separation of the two positive charge centers in the
initially formed dications and the superacid-promoted elimi-
nation of benzene. As in the dicationic reactions with benzene
(Table 1), the conversions leading to aza-polycyclic aromatic
compounds may involve phenonium ion assistance in form-
ing the initial carbocationic intermediate (33 f 34). Charge
migration is driven by the increased separation of the charge
centers and the formation of the benzylic type of carbocation.
With respect to the superacid-promoted elimination of
benzene, ipso-protonation of aryl groups is a known route
to carbocation intermediates (i.e., solvation of tetraphenyl-
methane in strong acid leads to the formation of the trityl
cation).10 To best of our knowledge, elimination of benzene
via ipso-protonation has not been described previously in
the synthetic literature,11 although similar conversions have
been proposed in the superacid-promoted depolymerization
of coals.12 The driving force for this process is likely the
generation of the extended aromatic systems in the aza-
polycycic aromatic products (26-32 and 40). The scope of
this new chemistry is presently being explored.
a Isolated yields of purified products. b Reaction performed at 50 °C.
c Cyclization step followed by reaction with DDQ.
Scheme 1. Proposed Mechanism
Acknowledgment. The financial support of the NIH-
NIGMS (GM071368-01) is greatly appreciated. The Depart-
ment of Chemistry at NIU is thanked for the undergraduate
(8) Nyangulu, J. M.; Hargreaves, S. L.; Sharples, S.; Mackay, S. P.;
Waigh, R. D.; Duval, O.; Mberu, E. K.; Watkins, W. M. Bioorg. Med.
Chem. Lett. 2005, 15 (8), 2007. (b) Vogt, A.; Tamewitz, A.; Skoko, J.;
Sikorski, R. P.; Giuliano, K. A.; Lazo, J. S. J. Biol. Chem. 2005, 280 (19),
19078. (c) Harayama, T. Heterocycles 2005, 65, 697.
(9) Clement, B.; Weide, M.; Wolschendorf, U.; Kock, I. Angew. Chem.,
Int. Ed. 2005, 44, 635.
(10) Fonken, G. J. J. Org. Chem. 1963, 28, 1909.
(11) See, however: (a) Koltunov, K. Yu.; Prakash, G. K. S.; Rasul, G.;
Olah, G. A. Heterocycles 2004, 62, 757. (b) Necula, A.; Racoveanu-
Schiketanz, A.; Gheorghiu, M. D.; Scott, L. T. J. Org. Chem. 1995, 60,
3448.
(12) Shimizu, K.; Ikuo, I. Energy Fuels 1998, 12, 115.
Org. Lett., Vol. 8, No. 6, 2006
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research excellence award (P.J.K.). This manuscript is
dedicated to the fond memory of Professor Roland E. Lehr.
data spectra and mass spectra data, and computational data
and methodology. This material is available free of charge
via the Internet at http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures and characterization data, including 1H and 13C NMR
OL060125U
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Org. Lett., Vol. 8, No. 6, 2006