Aza-Nazarov reaction and the role of superelectrophiles

Article abstract of DOI:10.1021/ol0711570

The superacid-catalyzed reactions of N-acyliminium ion salts have been studied. The new conversions are remarkably similar to the Nazarov reaction and dicationic superelectrophilic species are thought to be involved. Experimental studies show that the cyc

Full text of DOI:10.1021/ol0711570

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3085-3088
Aza-Nazarov Reaction and the Role of
Superelectrophiles
Douglas A. Klumpp,*,† Yiliang Zhang,† Matthew J. O’Connor,†
Pierre M. Esteves,‡ and Leonardo S. de Almeida‡
Department of Chemistry, Northern Illinois UniVersity, DeKalb, Illinois 60115, and
Instituto de Quimica, UniVersidade Federal do Rio de Janeiro, Cidade UniVersitaria,
CT Bloco A, 21949-900, Rio de Janeiro-RJ, Brazil
dklumpp@niu.edu
Received May 17, 2007
ABSTRACT
The superacid-catalyzed reactions of N-acyliminium ion salts have been studied. The new conversions are remarkably similar to the Nazarov
reaction and dicationic superelectrophilic species are thought to be involved. Experimental studies show that the cyclizations may be used
to prepare varied heterocyclic products, while theoretical studies show that formation of the superelectrophiles can lead to very favorable
reaction energetics.
The Nazarov reaction is a useful methodology for the
synthesis of five-member carbocycles.1 The conversion often
involves the cyclization of divinyl ketones and related
compounds in strongly acidic media. On the basis of the
results from kinetic studies and theoretical calculations,
Shudo and Ohwada demonstrated that the superacid-
catalyzed Nazarov cyclization of 1-aryl-2-propen-1-ones to
indanones involves dicationic or superelectrophilic interme-
diates (eq 1).2,3 It was proposed that the monocationic
earlier work, we sought to determine if similar cyclizations
with N-acyliminium salts could be done to provide a new
route to nitrogen-containing heterocycles (i.e., aza-Nazarov
reactions).4 Although a significant amount of electrophilic
chemistry has been accomplished with N-acyliminium salts,5
their use in Nazarov-type cyclizations has not been reported.
Herein we report our results from synthetic studies and
discuss the role of superelectrophiles in these aza-Nazarov
conversions.
Recently, we reported the superacid-catalyzed cyclizations
of N-acyliminium salts to 3-oxo-1,2,3,4-tetrahydroisoquino-
lines and related products.6 Among the systems studied, salt
(2) Suzuki, T.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1997, 119,
6774.
(3) Superelectrophile reviews: (a) Olah, G. A.; Klumpp, D. A. In
Superelectrophiles and Their Chemistry; Wiley: New York, 2007. (b) Olah,
G. A.; Klumpp, D. A. Acc. Chem Res. 2004, 37, 211. (c) Olah, G. A. Angew.
Chem., Int. Ed. Engl. 1993, 32, 767. (d) Olah, G. A.; Prakash, G. K. S.;
Lammertsma, K. Res. Chem. Intermed. 1989, 12, 141.
(4) An earlier study of an aza-Nazarov reaction: Dieker, J.; Fro¨hlich,
R.; Wu¨rthwein, E. U. Eur. J. Org. Chem. 2006, 5339.
(5) (a) Nilson, M. G.; Funk, R. L. Org. Lett. 2006, 8, 3833. (b) Pin, F.;
Comesse, S.; Garrigues, B.; Marchalin, S.; Daiech, A. J. Org. Chem. 2007,
72, 1181. For reviews, see: (c) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J.
H.; Turchi, I. J.; Maryanoff, C. A. Chem. ReV. 2004, 104, 1431. (d)
Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
(6) Zhang, Y.; Kindelin, P. J.; DeSchepper, D.; Zheng, C.; Klumpp, D.
A. Synthesis 2006, 1775.
carboxonium ion (1) is unreactive toward cyclization, but
further protonation generates the dicationic superelectrophile
(2), which leads to the cyclized product. By analogy to this
† Northern Illinois University.
‡ Universidade Federal do Rio de Janeiro.
(1) (a) Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994,
45, 1. (b) Pellisier, H. Tetrahedron 2005, 61, 6479. (c) Frontier, A. J.;
Collison, C. Tetrahedron 2005, 61, 7577.
10.1021/ol0711570 CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/14/2007

Table 1. Results from the Reactions of N-Acyliminium Salts
with CF3SO3H (Isolated Yields Reported)
3 was found to give product 4 as a major product, along
with an unidentified minor product (eq 2). Isolation and
characterization of this minor product revealed its identity
to be that of structure 5. This product arises from a reaction
that is remarkably similar to the Nazarov cyclization (eq 1).
This prompted us to examine other N-acyliminium salts.
Varied salts were prepared and reacted in CF3SO3H at 25
°C to give products from cyclization (Table 1).7 The desired
N-acyliminium salts are prepared in situ by the reaction of
the appropriate acid chloride with the imine (in CH2Cl2).
The cyclization reaction is then accomplished by the addition
of the acid. In general, the cyclization products are formed
in fair to good yields from N-acyliminium salts having
nucleophilic aryl groups. This includes (di- and tri-) meth-
oxyphenyl groups, thienyl, and indole groups. Both acyclic
and cyclic iminium groups undergo the reaction. For
example, the isoindoloisoquinolone ring system (present in
several natural product alkaloids) can be prepared readily
from N-acyliminium salts such as 20 and 22. The effect of
the activated aryl group is seen in the contrasting chemistry
of salts 14 and 16. With the activated aroyl group, salt 14
gives the expected cyclization product (15). However the
benzoyl derivative (16) preferentially reacts at the benzyl
group to give 17 as the only major product. Product 17 is
considered to be the result of a Friedel-Crafts-type reaction.
Cyclization with nonactivated aryl groups may, however, also
be accomplished. This is seen in the cyclization of the
benzoyl and halogen-substituted aroyl groups (compounds
6a, 6c, and 8b; done at 80 °C). Besides superacidic CF3-
SO3H, other Brønsted acids were found to catalyze the
transformations, such as H2SO4 and CF3CO2H. The weaker
acids were found to give the cyclization products at a reduced
rate. For example, 2 equiv of CF3SO3H were reacted with
N-acyliminium salt 10 at 25 °C and within 10 min the
cyclization to 11 was essentially complete. With 2 equiv of
CF3CO2H, the same reaction had only produced 17% yield
of compound 11.
Our earlier results6 suggested that cyclizations to six-
member rings can be favorable reaction paths (eq 2). In this
respect, a number of systems were found to give the products
containing six-member rings (Table 2). With salts 24 and
26, the six-member-ring cyclizations occur instead of the
Nazarov-type cyclization products (five-member rings).
The Nazarov reaction can involve both thermal and
photochemical four π-electron electrocyclic closures.1 In
photolysis experiments, N-acyliminium salts were found to
provide nitrogen heterocycles, but the photochemical conver-
sions differ little from the acid-catalyzed thermal reactions.
For example, photolysis of N-acyliminium salt 6a in super-
acidic CF3SO3H (Ho -14.1)8 provides compound 7a in 56%
yield, while photolysis in the weaker acid CF3CO2H (Ho
-2.7) gives no cyclized product (eq 3). Without UV
irradiation, the same conversion is observed in 53% yield in
superacidic CF3SO3H (80 °C, Table 1) and no cyclization
product is obtained from 6a in CF3CO2H. N-Acyliminium
salt 30 does show differing chemistry from photolytic and
thermal reaction conditions. Photolysis of 30 in CF3CO2H
gives compound 32 as the only major product (eq 4). It is
proposed that cyclization initially occurs to give the stabilized
cation 31 and subsequent ring closure and oxidation leads
to product 32. When salt 30 is reacted in CF3CO2H without
(7) These types of N-acyliminium ion salts are in equilibrium with the
R-chloroamides, see ref 4c.
(8) Olah, G. A.; Prakash, G. K. S.; Sommer, J. In Superacids; Wiley:
New York, 1985.
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Org. Lett., Vol. 9, No. 16, 2007

ated in acetonitrile, no cyclization occurs (even at 80 °C).
The dramatic effect of superacidity in the reaction of 6a to
7a and the need for acidic media in general suggests the
involvement of superelectrophiles in the conversions. These
could be the protosolvated species (38) or the fully formed
dicationic superelectrophile (39). To further explore the
superelectrophilic activation in this cyclization, we studied
the reactions using DFT calculations (Figure 1). In calcula-
Table 2. Results from the Reactions of N-Acyliminium Salts
with CF3SO3H (Isolated Yields Reported)
UV irradiation, the cyclization product 33 is formed, albeit
in low yield (16% isolated yield), along with unidentified
minor products. Photolysis of 33 in CF3CO2H provides
quantitative cyclization to 32. The N-cinnamoyliminium salt
34 does not cyclize under thermal or photochemical reaction
conditions, suggesting the importance of stabilization of the
intermediate carbocation (such as 31). Similar observations
Figure 1. Calculated structures and free energies (B3LYP/6-
311++G(d,p) level) of N-acyliminium ions (40a and 42a), the
corresponding superelectrophiles (40b and 42b), transition states,
and product ions (41a,b and 43a,b).
tions at the B3LYP/6-311++G(d,p) level,10 the monocationic
N-acyliminium ion (40a) is compared to the analogous
superelectrophile (40b). The cyclization of the monocation
40a is found to have a free energy of activation of 29.5 kcal/
mol. Compared to 40a, the cyclic intermediate (41a) is less
stable by 24.2 kcal/mol. In the superelectrophilic reaction,
the free energy of activation is estimated to be 17.5 kcal/
mol and the cyclic intermediate 41b is less stable than 40b
by only 3.2 kcal/mol. Even more pronounced effects are seen
in the cyclization of the methylacryloyl derivative 42.
Reaction of the monocationic N-acyliminium ion 42a leads
to the cationic intermediate (43a) in an endergonic reaction
step. However, the superelectrophilic N-acyliminium ion
have been made in the Nazarov cyclizations.9 Interestingly,
the reaction of N-acyliminium ion salt 35 with CF3CO2H
(no UV irradiation) gives 32 as the only major cyclization
product, along with a substantial amount of the iminium ion
hydrolysis products 36 (formed upon workup; eq 5). Cy-
clization to the six-member ring (i.e., 37) does not occur.
For all of the reported cyclizations, the presence of acid
catalysts is essential. When N-acyliminium salt 10 is gener-
(9) (a) He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125,
14278. (b) Denmark, S.; Jones, T. J. Am. Chem. Soc. 1982, 104, 2642.
(10) (a) Frisch, M. J.; et al. Gaussian 03, Revision B.04; Gaussian, Inc.:
Wallingford,CT, 2004; see the Supporting Information for the full list of
authors and details of the calculations. (b) For a review of calculational
models used in the study of superelectrophiles, see ref 3a, Chapter 2.
Org. Lett., Vol. 9, No. 16, 2007
3087

(42b) leads to the cyclic intermediate (43b) in an exergonic
reaction step. The free energy of activation is likewise
significantly reduced by superelectrophilic activation.
distinguish between these two mechanistic possibilities. It
should also be noted, however, that 5-endo-trig cyclizations
are disfavored according to Baldwin’s rules.12 Consequently,
the four π-electron electrocyclization mechanism may be the
best way to account for these observed reactions.13
These results suggest that superelectrophilic activation
facilitates the cyclizations by destabilizing the N-acyliminium
ion. This leads to the large decrease in the activation energies,
an earlier transition state (note forming bond length), and
more favorable reaction energetics. As described by Shudo
and Ohwada in their studies of the Nazarov reaction,2
dications like 40b exhibit more effective charge delocaliza-
tion into the aryl ring, which facilitates the cyclization.
Charge-charge separation is likely an important driving
force in the formation of intermediates like 41b. From the
synthetic reactions, it is seen that the N-acyliminium ion
cyclization may involve even somewhat deactivated aryl
groups. Although many cyclizations involving N-acylimin-
ium ions have been described over the years, few examples
have involved deactivated aryl groups.4c,d Indeed, our own
previous efforts were unsuccessful in preparing 3-oxo-
1,2,3,4-tetrahydroisoquinolines from the superacid-promoted
reactions of N-acyliminium ions having dichlorophenyl
groups.6 Several examples of intermolecular reactions in-
volving N-acyliminium ions and deactivated arenes have been
reported and these conversions have required highly acidic
conditions.11 The observed high reactivities of the N-
acyliminium ion systems in the above reactions (Table 1)
are consistent with the formation of superelectrophiles. At
present, it is not certain if the observed aza-Nazarov reactions
are pericylic reactions of the Woodward-Hoffmann type
(i.e., four π-electron electrocyclizations) or if the conversions
are more accurately described as Friedel-Crafts-type reac-
tions. Further experimental studies are required to perhaps
In summary, we have found that N-acyliminium ion salts
undergo a cyclization reaction with acid catalysts. The
reaction is similar to the Nazarov cyclization; however, varied
N-heterocyclic products can be prepared. Many intra-
molecular reactions of N-acyliminium ions have been previ-
ously described.5c,d However, our present studies reveal a
new mode of cyclization involving conjugated π-systems
within the N-acyliminium ions. In certain cases, the reactions
are shown to be sensitive to acid strength. Theoretical
calculations also show a dramatic effect with the protonation
of the N-acyliminium ion, including a much more favorable
free energy of activation and reaction. These results suggest
the involvement of superelectrophilic species in these cy-
clization reactions.
Acknowledgment. The financial support of the NIH-
NIGMS (GM071368-01), the Petroleum Research Fund,
administered by the American Chemical Society (PRF No.
44697-AC1), and the Northern Illinois University Foundation
is greatly appreciated (D.A.K.). The financial support of
CNPq, CAPES is gratefully acknowledged (P.M.E.). We also
thank Mr. Patrick Kindelin (Northern Illinois University) for
assistance.
Supporting Information Available: Experimental pro-
cedures, characterization data, and spectra for new com-
pounds, computational data including atomic coordinates, and
thermodynamical parameters (∆H, ∆S, and ∆G at 298 K
and 1 atm) for the calculated species. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) (a) Schmidt, R.; Schlipf, E. Chem. Ber. 1970, 103, 3783. (b) Olah,
G. A.; Wang, Q.; Sandford, G.; Oxyzoglou, A. B.; Prakash, G. K. S.
Synthesis 1993, 1077.
(12) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(13) We thank a reviewer for this insightful suggestion.
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