Knorr cyclizations and distonic superelectrophiles

Article abstract of DOI:10.1021/jo7013092

(Chemical Equation Presented) The acid-catalyzed Knorr cyclization has been studied by experimental and theoretical methods. The results of these studies indicate that β-ketoamides such as acetoacetanilide undergo diprotonation at the two carbonyl oxygen atoms to form distonic superelectrophiles. Direct observation of a dicationic superelectrophile was achieved by low-temperature ¹H, ¹⁵N, and ¹³C NMR from FSO ₃H-SbF₅-SO₂ClF solutions. In synthetic studies, the Bronsted superacid CF₃SO₃H is found to be an effective acid catalyst for the Knorr cyclization.

Full text of DOI:10.1021/jo7013092

In 1964, Staskun published a report describing his studies of
the Knorr cyclization, a synthetic methodology used to prepare
quinolin-2-ones.3 This paper proposes a mechanism in which a
distonic superelectrophile (6) triggers the cyclization chemistry
(eq 1). Staskun noted that both the acid strength and the acid
Knorr Cyclizations and Distonic
Superelectrophiles
Kiran Kumar Solingapuram Sai, Thomas M. Gilbert, and
Douglas A. Klumpp*
Department of Chemistry and Biochemistry, Northern Illinois
UniVersity, DeKalb, Illinois 60115
dklumpp@niu.edu
quantity are important to the cyclization and he suggests that
monocationic intermediates are not sufficiently reactive for the
conversion. Remarkably, he demonstrates this superelectrophilic
chemistry with both Brønsted and Lewis acids. Staskun’s
superelectrophilic dication mechanism has subsequently ap-
peared in reviews and books on heterocyclic chemistry.4
Although admirable as a predecessor of the general concept of
superelectrophilic activation, Staskun’s mechanism is question-
able. At the time of this study, there was a considerable amount
of uncertainty regarding the site of protonation on amides.5 This
question has been resolved over the years and in most cases
oxygen is preferred over nitrogen as the site of protonation.
In the following paper, we examine the Knorr cyclization
using experimental and theoretical methods. Both spectroscopic
data and computational results indicate that an O,O-diprotonated
species is the distonic superelectrophile involved in the Knorr
cyclization. We also report the results from synthetic studies in
which superacidic trifluoromethane-sulfonic acid (CF3SO3H,
triflic acid) is found to be an outstanding acid catalyst for the
Knorr cyclization.
ReceiVed July 5, 2007
The acid-catalyzed Knorr cyclization has been studied by
experimental and theoretical methods. The results of these
studies indicate that â-ketoamides such as acetoacetanilide
undergo diprotonation at the two carbonyl oxygen atoms to
form distonic superelectrophiles. Direct observation of a
dicationic superelectrophile was achieved by low-temperature
1H, 15N, and 13C NMR from FSO3H-SbF5-SO2ClF solu-
tions. In synthetic studies, the Brønsted superacid CF3SO3H
is found to be an effective acid catalyst for the Knorr
cyclization.
With use of stable ion conditions and low-temperature NMR,
a wide variety of onium ions have been directly observed and
characterized.6 However, superelectrophiles have been difficult
to observe with NMR methods, due in part to their low
equilibrium concentrations.2a Of the superelectrophiles that have
been observed by NMR, most of these are distonic superelec-
trophiles. When acetoacetanilide (5) is studied under stable ion
conditions, the data are consistent with the formation of O,O-
diprotonated species (Table 1). In accord with basicity data (pKa,
acetone, -6.5 to -7.2; pKa, N-phenylacetamide, -1 to -2)7
and theoretical calculations (vide infra), the NMR data indicate
that protonation occurs first at the amide group followed by
protonation at the ketone. The signal at δ 168.8 in both CF3-
CO2H and FSO3H can be assigned to the amide carboxonium
carbon. In progressively more acidic media, the ketone carbonyl
resonance is shifted from δ 204.3 in CDCl3 downfield to a value
of δ 237.5 in SbF5-FSO3H-SO2ClF solution. This 13C NMR
resonance is typical for protonated aldehydes and ketones.8 The
15N-labeled acetoacetanilide was also prepared and analyzed in
During the 1960s and 1970s, a number of cationic electro-
philic reagents were shown to have greatly enhanced reactivities
in the presence of superacids. This led to the concept of
superelectrophilic activation, first proposed by Olah and co-
workers in the mid-1970s.1,2 Superelectrophiles can arise from
the protosolvation of a cationic electrophile to generate a doubly
electron deficient superelectrophile. Even partial protonation of
an electrophile can lead to the superelectrophilic species.
Superelectrophilic activation has also been shown to occur with
various Lewis acids.2
Superelectrophiles are separated into two categories based
on the distance between the charge centers.2 Gitionic super-
electrophiles are defined as species in which the two positive
charge centers are separated by no more than one atom. Distonic
superelectrophiles are defined as species in which the two
positive charge centers are separated by two or more atoms.
The protonitronium ion (HONO2+, 1) and the proto-tert-butyl
(2) (a) Olah, G. A.; Klumpp, D. A. Superelectrophiles and Their
Chemistry; Wiley: New York, 2008. (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.
dication (2) are examples of gitionic superelectrophiles, while
the ammonium-carbenium dication (3) and the electrophilic
fluorinating agent, Selectfluor 4, are typical distonic superelec-
trophiles.
(3) Staskun, B. J. Org. Chem. 1964, 29, 1153.
(4) Uff, B. C. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Eds.; Pergamon Press: Oxford, UK, 1985; Vol. 2, p 425.
(5) Olah, G. A.; White, A. M.; O’Brien, D. H. Chem. ReV. 1970, 70,
561.
(6) Olah, G. A.; Laali, K. K.; Wang, Q.; Parkash, G. K. S. Onium Ions;
Wiley: New York, 1998.
(7) Arnett, E. M. Prog. Phys. Org. Chem. 1963, 1, 223.
(1) Olah, G. A.; Germain, A.; Lin, H. C.; Forsyth, D. J. Am. Chem. Soc.
1975, 97, 2928.
10.1021/jo7013092 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/14/2007
J. Org. Chem. 2007, 72, 9761-9764
9761

TABLE 1. Results from the NMR Analysis of Acetoacetanilide (5)
in Solutions of Varying Acidity
TABLE 2. Calculated Relative Stabilities and NMR Data for Ions
6-12 at the MP2/6-311++G(d,p) Level (DFT Calculations,
B3PW91/6-311++G(d,p) Level)a
acidity, temp,
solvent
CDCl3
Ho
°C
25 30.7, 50.6, 120.3,
124.6, 128.9, 137.6,
164.4, 204.3
-2.7 -10 28.1, 46.3, 122.1,
127.3, 128.4, 132.7,
13C signals,a δ
15N signal,a δ
132.0 (doublet)
CF3CO2H
FSO3H
144.1 (doublet)
150.9 (doublet)
162.3 (doublet)
168.8, 209.3
-15
-40 28.4, 42.9, 122.6,
129.3, 129.8, 130.1,
168.8, 220.6
FSO3H, SbF5 -24
-40 29.7, 44.9, 123.5,
(1:1)
126.9, 130.2, 131.7,
165.8, 237.5
a Superacidic samples were prepared with SO2CIF as cosolvent; the 13
C
external standard was d6-acetone; the 15N external standard was 15N-labeled
urea in d4-methanol.
the superacidic solutions. If the N,O-diprotonated species
(dication 6) is generated as the superelectrophilic intermediate,
then a triplet 15N resonance should be visible in the 15N NMR
spectrum (assuming rapid proton exchange does not obscure
1H-15N coupling). In the strongest superacid used, SbF5-
FSO3H-SO2ClF, the 15N resonance appears downfield at δ
162.3 as a doublet. The amide 15N is significantly deshielded
in SbF5-FSO3H-SO2ClF, which is a consequence of the
formation of the neighboring carboxonium ion (and increasing
positive charge). On the basis of these data, it is proposed that
acetoacetanilide (5) forms a significant equilibrium concentration
1
of the O,O-diprotonated species (7). The H NMR spectra of
acetoacetanilide (5) were also obtained from superacidic media
(FSO3H, CF3SO3H, and SbF5-FSO3H solutions at -50 °C),
and the spectra are consistent with the formation of dication 7.
In each of the superacid solutions, the spectra clearly show the
methyl (CH3), methylene (CH2), amide (NH), and phenyl (C6H5)
protons. The spectrum from FSO3H is typical: δ 2.15 (3H),
3.85 (2H), 6.75-6.84 (5H), 9.35 (NH). The carboxonium
proton(s) could not be observed, possibly due to fast exchange
with the acid. With greater acidity, both the NH and the
methylene peaks maintain the same intensity. This observation
argues against the formation of N,O-diprotonated species
(dication 6) and any possible enol-type structures (vide infra).
Model calculations were performed on the protonated prod-
ucts from acetoacetanilide (5) to estimate the relative energies
of the diprotonated species (6-9) and to compare experimental
NMR chemical shift values with those from theory (Table 2).9
Likewise, monocationic products (10-12) were also studied.
At both the ab initio MP2/6-311++G(d,p) and density func-
tional theory B3PW91/6-311++G(d,p) levels of theory,10 the
a The 15N signals are calculated in reference to NH3 (gas phase); the 13
signals are calculated in reference to Si(CH3)4. b Not a stable minimum,
-OH2 bonds set at a fixed length. c Not a stable minimum, -OH bond set
at a fixed length. d Not a stable minimum, -NH bond set at a fixed length.
C
N,O-diprotonated species (6) and the O,O-diprotonated species
(7) are found at energy minima (as determined by frequency
calculations), with structure 6 being at least 8 kcal‚mol-1 less
stable than structure 7. Although the enol-type structure (8) is
at an energy minimum, it is about 14 kcal‚mol-1 less stable
than structure 7. The isomeric enol-type structure (9) is not at
an energy minimum, but rearranges upon optimization. 15N and
13C NMR GIAO data, calculated at the B3PW91/6-311++G-
(d,p)//B3PW91/6-311++G(d,p) and HF/6-311++G(d,p)//MP2/
6-311++G(d,p) levels, indicate that the 15N NMR resonances
are diagnostic for N versus O protonation, as they vary sizably
between 6 and 7 (65-75 ppm). The experimental spectrum from
protonation of compound 5 in SbF5-FSO3H-SO2ClF exhibits
the 15N resonance at δ 162.3, reasonably close to that predicted
for the O,O-diprotonated species (7). The calculated values for
13C resonances differ little for structures 6 and 7, and therefore
they are not as useful in distinguishing between N versus O
protonation, but the calculated 13C resonance for C2 does appear
to rule out the enol-type structure (8) as a major component of
the equilibrium mixture in superacid. In comparing the calcu-
lated and experimental 13C spectra for dication 7, it is seen that
both theoretical models predict the experimental spectrum fairly
well. The density functional B3PW91 performs particularly well
(8) (a) Olah, G. A.; Rasul, G.; York, C. T.; Prakash, G. K. S. J. Am.
Chem. Soc. 1995, 117, 11211. (b) Klumpp, D. A.; Rendy, R.; Zhang, Y.;
Gomez, A.; McElrea, A. Org. Lett. 2004, 6, 1789.
(9) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
A D.; Rabuck, K. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P.
M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.;
Head-Gordon, M.; Replogle, E. S.; Pople. J. A. Gaussian 98, Revision
A.11.4; Gaussian, Inc.: Pittsburgh, PA, 1998.
(10) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Wolinski, K.;
Hinton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112, 8251.
9762 J. Org. Chem., Vol. 72, No. 25, 2007

1650-60 cm-1). Efforts to extend this chemistry to deactivated
aryl systems were not successful, although in the case of the
fluoro-substituted acetoacetanilide, the product (23) yield in-
creases modestly with the use of the stronger superacid system
CF3SO3H-SbF5 (10% mol SbF5). At 25 °C, the cyclizations
leading to 13 and 15 are found to be essentially complete within
30 min (20 equiv of CF3SO3H). The use of CF3SO3H leads to
cyclizations at lower temperatures and in higher yields compared
to H2SO4 or polyphosphoric acid. For example, compound 16
is prepared in 83% yield from 2-benzoylacetanilide at 25 °C in
CF3SO3H, while the same product is formed in 20% and 30%
yields from H3PO4 (140 °C) and H2SO4 (80-90 °C), respec-
tively.3
TABLE 3. Products and Yields from the Reactions of
Acetoacetanilides with CF3SO3H at 25 °C
When compound 25 is reacted with decreasing quantities of
CF3SO3H, the product yield decreases (eq 2). With 1.0 equiv
of acid, no condensation product (15) is formed. In accord with
Staskun’s conclusion, the need for excess superacid suggests
the involvement of diprotonated intermediates. Additionally,
acetoacetanilide (5) was reacted in excess CF3SO3D and
deuterium incorporation was not observed at the amide nitrogen
(eq 3), as verified by 15N NMR and mass spectral analyses.
This indicates that protonation (deuteration) to form the N,O-
diprotonated species (6) is not occurring.13
a Isolated yields of purified products; products were characterized by
1H and 13C NMR and high-resolution mass spectroscopy. b Reaction done
with CF3SO3H-SbF5.
in this regard. In the case of the monoprotonated products (10-
12), only cation 10 (the amide carboxonium ion) is located at
an energy minimum. Efforts to optimize structures 11 and 12
lead to isomerization (to 10); however, with the O-H and N-H
bond fixed, the potential energy and spectral data of 11 and 12
can be estimated. Most notably, the amide carbonyl protonation
is favored by about 10 kcal‚mol-1 over other sites of protonation.
When the results of the above calculations are considered, two
important conclusions can be made: monoprotonation occurs
at the amide and the resulting intermediate (10) is unlikely to
cyclize; both the predicted relative energies and 15N NMR
resonances support the presence of the distonic superelectrophile
7 as the superelectrophilic intermediate in the Knorr cycliza-
tion.11
In conclusion, as Staskun observed, the Knorr cyclization
generally requires heating with an excess of strong acid. This
is consistent with the formation of the dicationic superelectro-
philic species. When the present experimental and computational
results are considered, the evidence clearly suggests the involve-
ment of the O,O-diprotonated species (7) as the superelectrophile
leading to Knorr products. While other diprotonated intermedi-
ates (i.e., enol-type structure 8) cannot be rigorously excluded
as the cyclization precursors, dication 7 is estimated to be at
least 8 kcal‚mol-1 more stable than other dications on the
potential energy surface. Moreover, the NMR spectra indicate
formation of O,O-diprotonated species (7) in superacidic solu-
tion. The superacid, CF3SO3H, is found to be an excellent acidic
reagent for the Knorr cyclization. This is likely due to its ability
to form the requisite diprotonated intermediates.
The Knorr cyclizations are often done with strong mineral
acids and elevated temperatures. For example, with H2SO4 or
H3PO4 as the acid in Knorr cyclizations, it is necessary to use
reaction temperatures in the range of 80-150 °C.3,4 The
involvement of diprotonated intermediates would of course
necessitate the use of these forcing conditions. Over the years,
it has been demonstrated that CF3SO3H is an effective superacid
for promoting reactions involving dicationic, superelectrophilic
species.2a A series of acetoacetanilides were prepared (from the
respective anilines and diketene)12 and reacted in CF3SO3H,
producing good yields of the Knorr cyclization products 13-
24 (Table 3). In general, the cyclizations are best accomplished
with activated aryl-groups. Infrared spectroscopy indicated the
quinolin-2-one structure to be the major component of the
equilibrium mixtures of products 13-24 (CdO stretches at
Experimental Section
Typical Synthetic Procedure. 4-Aminoindan (1.0 g, 7.5 mmol)
is dissolved in 10 mL of anhydrous CH2Cl2 and 0.92 g of diketene
(11 mmol) is added. The mixture is stirred at 25 °C for 2.5 h,
followed by removal of the solvent under vacuum. The product
(N-indan-4-yl-3-oxo-butyramide, 1.41 g, 6.5 mmol, 87%) is isolated
by column chromatography (silica gel, 1:1 hexane:ether).
The N-indan-4-yl-3-oxo-butyramide (0.202 g, 0.92 mmol) is
dissolved in 4 mL of dry CH2Cl2 and CF3SO3H (1.5 mL, 17 mmol)
is slowly added to the solution (with stirring). The resulting mixture
(11) An O,O-diprotonated â-ketoamide was recently proposed by Schlo-
sser and co-workers as an intermediate leading to the 2-methyl-4(1H)-
quinolinones, see: Marull, M.; Lefebvre, O.; Schlosser, M. Eur. J. Org.
Chem. 2004, 54.
(12) Sabri, S. S.; El-Abadelah, M. M.; Al-Bitar, B. A. Heterocycles 1987,
26, 699. (b) Olah, G. A.; Kuhn, S. J. J. Org. Chem. 1961, 26, 225. (c)
Williams, J. W.; Krynitsky, J. A. Organic Syntheses; Horning, E. C., Ed.;
Wiley: New York, 1955; Collect. Vol. III, p 10.
(13) It is not presently clear if the aryl ring is deuterated prior to or after
cyclization.
J. Org. Chem, Vol. 72, No. 25, 2007 9763

is stirred at 25 °C for ca. 15 h and then poured over 5-10 g of ice.
The solution is extracted twice with CHCl3, and the organic phase
is washed twice with water and twice with brine solution, then dried
with anhydrous sodium sulfate. Following column chromatography
(1:1 hexane: ether), 8,9-dihydro-4-methyl-1H-cyclopenta[h]quino-
lin-2(7H)-one (22, 0.167 g, 0.84 mmol, 91%) is isolated as a white
solid, mp 260-263 °C. 1H NMR (CDCl3) δ 10.13 (s, 1H) ,7.51 (d,
1H, J ) 8 Hz), 7.14 (d, 1H, J ) 8 Hz), 6.50 (s, 1H), 3.13 (t, 2H,
J ) 14 Hz), 3.08 (t, 2H, J ) 14 Hz), 2.50 (s, 3H), 2.24-2.28 (mult,
2H). 13C NMR (CDCl3) δ 163.3, 149.3, 147.7, 134.8, 129.3, 123.1,
119.6, 118.9, 118.8, 33.6, 29.4, 25.0, 19.5. Low-resolution mass
spectra (EI) m/z 199 (M+), 154, 115, 77, 44. HRMS calcd for
C13H13ON 199.0997, found 199.0996.
diffuse and polarization functions were included on the hydrogen
atoms, as the optimizations suggested hydrogen bonding in the
acetoanilide cations. Thus, the 6-311++G(d,p) basis set was used
for all reported structures and NMR shift predictions. Cartesian
coordinates for 6-12 at the MP2/6-311++G(d,p) level are available
as Supporting Information.
Acknowledgment. The financial support of the NIH-NIGMS
(GM071368-01), the donors of Petroleum Research Fund (PRF
No. 44697-AC1), administered by the American Chemical
Society, and the Northern Illinois University Foundation is
gratefully acknowledged.
Computational Methods. All calculations were performed with
the GAUSSIAN (G98) code.9 Structures 6-12 were fully optimized
without constraints at the HF/6-311++G(d,p) level, using several
different starting geometries to explore the potential surface and
ensure that the lowest energy conformation was selected. The lowest
energy structures were examined by frequency analysis at this level,
and demonstrated to be minima (no imaginary frequencies). The
structures were then reoptimized by using the MP2 perturbation
theory and B3PW91 density functional theory (DFT) models as
coded in G98.10 Relative energies (Table 2) were corrected with
use of unscaled zero point energies (ZPEs) from the frequency
analysis.
NMR calculations employed the gauge-independent atomic
orbital (GIAO) approach. The models were selected to provide
limited model testing.14 It has been noted that DFT models provide
little improvement over HF for NMR calculations, but that different
structure models can affect NMR results;15 thus the methods selected
were B3PW91 for NMR based on a B3PW91-optimized structure
(denoted B3PW91//B3PW91) as a DFT approach, and the analo-
gously denoted HF//MP2 method as a PT approach. In addition,
Note Added after ASAP Publication. In the version that
was published ASAP on November 14, 2007, equation 2
contained an error, and also the paragraph above it had an
incorrect compound number; the corrected version was pub-
lished ASAP on November 16, 2007.
Supporting Information Available: General experimental
details, characterization data and spectra, representative experi-
mental procedures, and computational data. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO7013092
(14) (a) Check, C. E.; Gilbert, T. M. j. org. chem., 2005, 70, 9828. (b)
Grimme, S. Angew. Chem., Int. Ed. 2006, 45, 4460. (c) Schreiner, P. R.;
Fokin, A. A.; Pascal, R. A., Jr.; de Meijere, A. Org. Lett., 2006, 8, 3635.
(d) Wodrich, M. D.; Corminboeuf, C.; Schleyer, P. v. R. Org. Lett. 2006,
8, 3631.
(15) Foresman, J. B.; Frisch, A. Exploring Chemistry with Electronic
Structure Methods, 2nd ed.; Gaussian, Inc: Pittsburgh, PA, 1996; p 21.
9764 J. Org. Chem., Vol. 72, No. 25, 2007