Table 1. Reactions of Amides 1 and 5 in Superacid, the Proposed Dicationic Intermediates, and Comparisons to Monocationic
Intermediates
have provided strong evidence for protonation at the carbonyl
group in most cases.4
dication 2. When amide 5 is reacted with C6H6 in TfOH,
dication 6 is formed, and this leads to an acyl-transfer
reaction and the product acetophenone (eq 3). The analogous,
monocationic intermediate (7) from acetanilide is largely
unreactive to benzene (eq 4). The amide-carboxonium group
in dication 6 is clearly more reactive than the amide-
carboxonium group of monocation 7. This suggests that the
adjacent cationic ammonium group enhances the electrophilic
reactivity of the amide-carboxonium group in the dication.
Thus, protonated amides can be part of two types of reactive
dications: the protonated amide group can activate an
adjacent electrophilic center or the protonated amide group
may itself be activated by an adjacent cationic group.
During the past two decades, an active area of research
has involved superelectrophilic and dicationic intermediates.6
Olah was the first to propose the concept of superelectrophilic
reactivity, and since these early reports, this concept has been
extended to many systems, including enzymes.6 In studies
related to Olah’s superelectrophilic activation, we and others
have shown that stable cationic groups are capable of
significantly increasing the reactivities of adjacent electro-
philic groups.7 For example, phosphonium, ammonium, or
pyridinum cations have been shown to greatly increase the
reactivities of adjacent carboxonium ions.8
In this paper, we show that protonated amides can increase
the reactivities of adjacent electrophilic groups, such as the
carboxonium ion. The direct observation of a dicationic
species is also reported. Moreover, we show that protonated
amides can have enhanced electrophilic reactivities when
adjacent to cationic groups. This is demonstrated in several
Friedel-Crafts acylations of benzene using amides.
When amide 1 is reacted with C6H6 in superacidic CF3-
SO3H (triflic acid, TfOH), the condensation product (3) is
formed in good yield (Table 1, eq 1). It is proposed that the
diprotonated intermediate 2 is formed and this dication is
sufficiently electrophilic to attack benzene. Under the same
reaction conditions, cyclohexanone does not react with C6H6
(eq 2), despite the fact that the carbonyl group is completely
protonated, giving the monocationic carboxonium ion (4).
This suggests that the protonated amide group enhances the
electrophilic reactivity of the ketone-carboxonium group in
These two modes of reactivity are demonstrated in several
related systems (Table 2). Friedel-Crafts acylation of
benzene is seen with amides 8-10. Though amide 9 produces
a diprotonated intermediate (17) with significant resonance
stabilization, acyl transfer still occurs giving benzophenone.
In the case of amide 10, reaction occurs at the amide instead
of the ketone, and dication 18a,b is proposed as the
intermediate. This conversion can be explained by noting
that the ketone-carboxonium ion is stabilized by resonance
interactions, including withdrawing electron density from the
nitrogen (i.e., 18b). Like amide 1, the piperidone derivatives
11 and 13 undergo condensation at the ketone group. The
piperidone derivatives (1, 11, and 13) generate ketone-
carboxonium ions (i.e., 2) that do not have significant
resonance stabilization, and so the nucleophilic attack occurs
at the ketone-carboxonium ions. The â-ketoamide (15)
generates dication 19 to give the condensation product 16
in high yield.
(6) (a) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 767. (b)
Nenajdenko, V. G.; Shevchenko, N. E.; Balenkova, E. S.; Alabugin, I. V.
Chem. ReV. 2003, 103, 229. (c) Olah, G. A.; Klumpp, D. A. Acc. Chem.
Res. 2004, in press. (d) Klumpp, D. A. Recent Res. DeV. Org. Chem. 2001,
5, 193-205, Part I.
(7) (a) Denmark, S. E.; Wu, Z. J. Org. Chem. 1998, 63, 2810. (b) Corey,
E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124, 3808. (c) Conroy,
J. L.; Sanders, T. C.; Seto, C. T. J. Am. Chem. Soc. 1997, 119, 4285. (d)
Koltunov, K. Y.; Prakash, G. K. S.; Rasul, G.; Olah, G. A. J. Org. Chem.
2002, 67, 4330.
(8) (a) Zhang, Y.; Aguirre, S. A.; Klumpp, D. A. Tetrahedron Lett. 2002,
43, 6837. (b) Klumpp, D. A.; Lau, S. J. Org. Chem. 1999, 64, 7309. (c)
Klumpp, D. A.; Garza, M.; Jones, A.; Mendoza, S. J. Org. Chem. 1999,
64, 6702. (d) Zhang, Y.; Klumpp, D. A. Tetrahedron Lett. 2002, 43, 6841.
In an attempt to extend the chemistry to carbocations, the
reactions of unsaturated amides were also studied (Scheme
1). Cinnamamide derivatives (20, 23, and 25) react with
benzene to give addition products (22, 24, and 26) in good
yields, presumably through the diprotonated intermediates
such as 21. The pyridine derivative 27 is found to give
indanone 28 as the only major product. Similar to the
Friedel-Crafts acylations involving 5 and 8-10, the py-
ridinum ring appears to enhance the electrophilic reactivity
of the protonated amide group in dication 29. When amides
1790
Org. Lett., Vol. 6, No. 11, 2004