Reactions of 5-, 6-, 7-, 8-hydroxyquinolines and 5-hydroxyisoquinoline with benzene and cyclohexane in superacids

Article abstract of DOI:10.1021/jo020099n

Isomeric 5-, 6-, 7-hydroxyquinolines (11-13) and 5-hydroxyisoquinoline (14) gave N,C-diprotonated dications in CF₃SO₃H-SbF₅ superacid medium. Compounds 11, 13, 14, and 8-hydroxyquinoline (5) underwent selective ionic hydro

Full text of DOI:10.1021/jo020099n

4330
J . Org. Chem. 2002, 67, 4330-4336
Rea ction s of 5-, 6-, 7-, 8-Hyd r oxyqu in olin es a n d
5-Hyd r oxyisoqu in olin e w ith Ben zen e a n d Cycloh exa n e in
Su p er a cid s1
Konstantin Yu. Koltunov, G. K. Surya Prakash,* Golam Rasul, and George A. Olah*
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California,
University Park, Los Angeles, California 90089-1661
olah@usc.edu
Received February 11, 2002
Isomeric 5-, 6-, 7-hydroxyquinolines (11-13) and 5-hydroxyisoquinoline (14) gave N,C-diprotonated
dications in CF3SO3H-SbF5 superacid medium. Compounds 11, 13, 14, and 8-hydroxyquinoline
(5) underwent selective ionic hydrogenation with cyclohexane in the presence of aluminum chloride.
Compounds 11 and 14 condense with benzene in the presence of aluminum halides. The detailed
mechanism of reactions, which involves superelectrophilic dicationic intermediates, is discussed.
In tr od u ction
(Schemes 1 and 2).5 The reason for the dramatic differ-
ence in reactivity of dication 6 and monoprotonated
nonreactive ion 3 was explained by the increased elec-
trophilic activation by the protonated nitrogen in 6. Given
the tendency of hydroxyquinoline 5 to form the reactive
electrophile 6 in strong acids, it seemed likely that
isomeric hydroxyquinolines (hydroxyisoquinolines), con-
taining a nitrogen atom and hydroxy group in different
rings of the quinoline (isoquinoline) system, would also
exibit similar properties. We now report a study on the
superelectrophilic6 activation of 5-, 6-, 7-hydroxyquino-
lines (11-13) and 5-hydroxyisoquinoline (14) with their
reaction with benzene and cyclohexane.
Naphthols and their derivatives are known to react
with benzene, nonactivated arenes, and alkanes in su-
peracids or in the presence of an excess of aluminum
halides to give the corresponding aryltetralones2 and
tetralones.3 It is also recognized that the key intermedi-
ates of these reactions are C,C-diprotonated dications of
naphthols, (structures 1, 2) while the corresponding
monocationic forms (3, 4) are inert.4
Resu lts a n d Discu ssion
NMR Stu d y of P r oton a tion of 11-14. Initially, we
examined the process of protonation of 11-14 in protonic
acids such as CF3CO2H (Ho ) -2.7), CF3SO3H (triflic
acid, Ho ) -14.1), and CF3SO3H-SbF5 acid system at
Recently, one of us has found that 8-hydroxyquinoline
(5) gives the N,C-diprotonated form 6 in superacid CF3-
SO3H-SbF5 and it reacts with cyclohexane and con-
denses with benzene in the presence of aluminum halides
1
room temperature by means of H and 13C NMR spec-
troscopy. Experimentally obtained results are summa-
rized in Table 1. The spectral characteristics of generated
ions are given in Table 2. As expected, in the weakest
trifluoroacetic acid only the N-monoprotonation of pre-
cursors was observed. In the stronger triflic acid the
compounds 11, 12, and 14 gave a mixture of the corre-
sponding N-protonated forms 11a , 12a , 14a , along with
additional ions 11b, 12b, and 14b, which are probably
dicationic species, undergoing to rapid proton exchange
with the acid.7 When dissolved in the CF3SO3H-SbF5
system, compounds 11-14 gave N,C-diprotonated forms
15-18, respectively. The NMR spectra of the dications
(1) Chemistry in Superacids. Part 57. For part 56, see: Olah, G. A.;
Prakash, G. K. S.; Rasul, G. J . Org. Chem. 2001, 66, 9011.
(2) (a) Koptyug, V. A.; Andreeva T. P.J . Org. Chem. USSR. 1971, 7,
2490. (b) Repinskaya, I. B.; Abramov, A. D.; Kuklina, N. A.; Koptyug,
V. A. J . Org. Chem. USSR. 1979, 15, 1973. (c) Repinskaya, I. B.;
Savel’ev, V. A.; Makarova, Z. S.; Koptyug, V. A. J . Org. Chem. USSR.
1980, 16, 1463. (d) Repinskaya, I. B.; Koryabkina, N. A.; Makarova,
Z. S.; Koptyug, V. A. J . Org. Chem. USSR. 1982, 18, 754. (e)
Repinskaya, I. B.; Barkhutova, D. D.; Makarova, Z. S.; Alekseeva, A.
V.; Koptyug, V. A. J . Org. Chem. USSR. 1985, 21, 759. (f) Repinskaya,
I. B.; Koltunov, K. Yu.; Shakirov, M. M.; Shchegoleva, L. N.; Koptyug,
V. A. Russ. J . Org. Chem. 1993, 29, 803. (g) Koltunov, K. Yu.;
Repinskaya, I. B.; Shakirov, M. M.; Shchegoleva, L. N. Russ. J . Org.
Chem. 1994, 30, 88.
1
15-18 contain the signal of the CH2 group around δ H
4 in the proton NMR and δ 13C 40 in the carbon NMR.
At the same time, the proton spectra contains the signal
of the hydrogen bound to nitrogen at δ 1H 11-13.
(3) (a) Koltunov, K. Yu.; Subbotina, E. N.; Repinskaya, I. B. Russ.
J . Org. Chem. 1997, 33, 689. (b) Koltunov, K. Yu.; Ostashevskaya, L.
A.; Repinskaya, I. B. Russ. J . Org. Chem. 1998, 34, 1796. (c) Osta-
shevskaya, L. A.; Koltunov, K. Yu.; Repinskaya, I. B. Russ. J . Org.
Chem. 2000, 36, 1474.
(4) (a) Repinskaya, I. B.; Shakirov, M. M.; Koltunov, K. Yu.;
Koptyug, V. A.J . Org. Chem. USSR. 1988, 24, 1719. (b) Repinskaya,
I. B.; Koltunov, K. Yu.; Shakirov, M. M.; Koptyug, V. A. J . Org. Chem.
USSR. 1992, 28, 785. (c) Koltunov, K. Yu.; Shakirov, M. M.; Repin-
skaya, I. B. Russ. J . Org. Chem. 1998, 34, 595.
(5) (a) Koltunov, K. Yu.; Repinskaya, I. B. Russ. J . Org. Chem. 2000,
36, 446. (b) Koltunov, K. Yu.; Repinskaya, I. B. Russ. J . Org. Chem.
2002, 38, in press.
(6) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 767.
(7) The nature of these ions will be discussed elsewhere.
10.1021/jo020099n CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/11/2002

Reactions of Hydroxyquinolines and -isoquinoline
J . Org. Chem., Vol. 67, No. 12, 2002 4331
Sch em e 1
Sch em e 2
points as minima (number of imaginary frequency
(NIMAG) ) 0). Atomic charges q• were obtained by using
the natural bond orbital analysis12 (NBO) method. For
comparison, the ꢀLUMOs were also calculated by the
MNDO13 method. Results of calculations are presented
in Table 3 and show dramatic difference between the
ꢀLUMOs of monocations 3 and 4 (∼ -7 eV) and dications 6
and 15-18 (∼ -12 eV). The latter are close to ꢀLUMOs of
dications 1 and 2, which means that the conjugation of
the protonated nitrogen site activates the hydroxynaph-
thalenonium ion almost as effectively as an additional
C-protonation. According to Table 3, dications 6, 15, and
18 have close values of q• (0.34-0.36). For this reason,
their relative electrophilicity can be predicted by com-
parison of corresponding values of ꢀLUMO: 6 > 18 > 15.
The electrophilicity of dication 17 should be close to that
of 15 according to their ꢀLUMO data, but a comparison of
the localization of positive charge on their reaction
centers (q• ) 0.3 and 0.34 respectively) shows that 17
must be a weaker electrophile from a kinetic point of
view. Thermodynamically, the dication 16 should be as
reactive as the dication 6 (ꢀLUMO ) -12.201 and -12.263
eV, respectively), but due to the lowest q• value (0.22)
among 6 and 15-18 dications, 16 is the kinetically
weakest electrophile in this group. Summarizing results
of calculations, the relative reactivity of the considered
electrophiles can be presented as follows: 1 > 2, 6 > 18
> 15 > 17 > 16 . 4, 3.
Dications 15 and 18 as well as dication 6 can be regarded
as analogues of 4-hydroxy-1-naphthalenonium ion 3.
Dications 16 and 17 are the analogues of 2-hydroxy-1-
naphthalenonium ion 4.
Ca lcu la tion a l Stu d y of Electr op h ilicities. To in-
vestigate the relative electrophilicity of generated dica-
tions 15-18 and to compare it with the electrophilicity
of chemically inert monocations 3 and 4 and reactive
dications 1, 2, and 6, we calculated the energies of lowest
unoccupied molecular orbitals (ꢀLUMO), the square of the
coefficients of the carbon atom of the reaction center (c•2)
at the LUMO (orbital control of reaction), and atomic
charges of the reaction center (q•) localized on the carbon
atom and pendent hydrogen atom (charge control of
reaction). Among other factors, values of c•2 at LUMO
and q• are important for predicting the positional selec-
tivity of a reaction, in case the electrophile contains more
than one reaction center. For an estimation of “absolute”
electrophilicity, the ꢀLUMO and q• of an electrophile are
important factors.
It is remarkable that the energy levels of LUMO of the
all dications are lower than the energy levels of the
highest occupied molecular orbital (HOMO) of benzene
(-9.782 eV (DFT)), cyclohexane (-9.109 eV, (DFT)), and
methylcyclopentane (-8.883 eV (DFT)). This result al-
lows the possibility of one-electron transfer from the
nucleophile (benzene or cycloalkane) to the dication
(RH22+) with the formation of an intimate radical-cation/
radical-cation pair, which subsequently recombines to
the σ-complex (in case of benzene) or gives the product
of ionic hydrogenation (in case of cycloalkane) (Scheme
Calculations were carried out with the Gaussian 98
program system.8 The geometry optimizations were
performed using the DFT9 method at the B3LYP10/6-31G*
level.11 Vibrational frequencies at the B3LYP/6-31G*//
B3LYP/6-31G* level were used to characterize stationary
3). In this case, positional selectivity of reactions would
+•
be determined by the spin density distribution in RH2
,
which is described approximately by the c2 values at the
(8) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.;
Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.; Daniels,
R. E.; Kudin, K. N.; Strain, M. C.; Farcas, O.; Tomasi, J .; Barone, V.;
Cossi, M.; Cammi, R.; Mennucci, B.; Pomelly, C.; Adamo, C.; Clifford,
S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma,
K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J . B.;
Cioslowski, J .; Ortiz, J . V.; 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.; Nanayakkarra, A.; Gonzalez, C.;
Challacombe, M.; Gill, P. M. W.; J onson, B.; Chen, W.; Wong, M. W.;
Andres, J . L.; Gonzalez, C.; M. Head-Gordon, M.; Pople J . A. Gaussian
98 (Revision A.5); Gaussian, Inc., Pittsburgh, PA, 1998.
2+
LUMO for dications RH2
.
(10) Becke’s three parameter hybrid method using the LYP correla-
tion functional: Becke, A. D.; J . Chem. Phys. 1993, 98, 5648. Lee, C.;
Yang, W.; Parr, R. G. Phys. Rev. B. 1988, 37, 785. Stephens, P. J .;
Devlin, F. J .; Chabalovski, C. F.; Frisch, M. J . J . Phys. Chem. 1994,
98, 11623.
(11) Hehre, W. J .; Radom, L.; Schleyer, P. v. R.; Pople, J . A. Ab Initio
Molecular Orbital Theory; Wiley-Interscience: New York, 1986.
(12) Reed, A. E.; Curtiss, L. A.; Wienhold, F. Chem. Rev. 1988, 88,
899.
(9) Ziegler, T. Chem. Rev. 1991, 91, 651.
(13) Dewar, M. J . S.; Thiel, W. J . Am. Chem. Soc. 1977, 99, 4899.

4332 J . Org. Chem., Vol. 67, No. 12, 2002
Ta ble 1. Ion s, F or m ed u p on P r oton a tion of 11-14
Koltunov et al.
a
The equilibrium ratio of ions at 25 °C, according to 1H NMR data.
Ta ble 2. 1H a n d 13C NMR Da ta of Mon o- a n d Dip r oton a ted Ion s of Com p ou n d s 11-14 a t 25 °Ca
ion
1H NMR signals (J , Hz)b
13C NMR signals
11a c
6.75 d (7.9), 7.09 d (8.6), 7.32 dd (8.3, 5.8), 7.4 t (8.33), 8.31 t (5.8),
8.9 d (8.3), 13.03 br s
110.08, 112.18, 118.7, 121.5, 137.06, 137.69, 142.65,
143.53, 153.35
111.2, 114.95, 121.28, 121.92, 133.8, 139.76, 145.04,
145.98, 159.75
34.78, 119.4, 124.49, 128.18, 148.21, 149.02, 157.46,
174.89, 189.93
109.8, 120.75, 121.11, 127.67, 130.8, 132.67, 139.87,
145.65, 156.69
111.8, 124.17, 127.04, 128.18, 130.43, 133.25, 141.13,
143.16, 159.3
39.06, 117.38, 125.13, 130.65, 136.46, 144.15, 147.03,
155.72, 212.73
101.33, 117.55, 122.81, 124.7, 130.75, 139.85, 141.56,
146.64, 162.85
38.58, 122.44, 127.61, 128.12, 145.06, 148.64, 150.56,
166.16, 208.04
11bd,e 6.49 d (7.8), 7.3 dd (8.5, 5.5), 7.83 d (7.8), 8.27 t (6.8), 8.76 d (8.5),
12.8 br s
15f
3.65 s 2H, 6.43 d (9.5), 7.2 t (7), 7.64 d (9.5), 7.87 t (6), 8.34 d (7),
11.4 br s
12a c
6.96 d (2.5), 7.18 dd (9.4, 2.5), 7.28 dd (8.33, 5.6), 7.49 d (9.4),
8.15 t (5.6), 8.24 d (8.33), 13.18 br s
12bd,g 7.09 d (9.6), 7.45 m, 7.55 d (9.6), 8.12 m, 8.82 d (8.9), 12 br s
16f
3.8 s 2H, 6.36 d (9.5), 7.1 m, 7.48 d (8.5), 7.53 d (9.5), 7.58 t (6.4),
11 br s
6.94 s, 6.96 dd (9, 2.2), 7.14 dd (7.9, 7), 7.49 d (9), 8.14 t (7),
8.27 d (7.9), 12.8 br s
4.12 s 2H, 6.47 d (10), 7.25 bs, 7.78.1 m 3H, 11.55 br s
13a c
17f
14a c 7.03 dd (7.26, 1.2), 7.29 t (7.26), 7.33 d (7.47), 7.8 t (6), 8.14 d (6.63), 119.8, 121.14, 121.45, 128.13, 128.6, 130.3, 132.62, 145.38,
8.8 d (7.26), 12.83 br s
151.87
14bd,e 6.67 d (7.3), 7.69 t (6), 7.71 d (7.6), 8.03 d (6.7), 9.1 d (7.3), 11.85 br s 122.66, 123.93, 124.3, 129.15, 131.93, 132.5, 137.16,
142.89, 157.04
36.45, 125.12, 126.25, 138.59, 140.42, 143.76, 143.97,
185.1, 189.08
18f
3.78 s 2H, 6.68 d (11), 7.8 t (7), 7.86 d (7), 8.11 d (6), 8.14 d (12),
11.8 br s
a
Chemical shifts are given with respect to (CD3)2CO as external standard (2.04 and 206 ppm, respectively, in 1H and 13C NMR spectra).
Protons bonded to oxygen are not observed, due to rapid proton exchange with the acid. c Data for CF3CO2H solution. Data for CF3SO3H
b
d
solution. e H8 signal is not observed due to rapid exchange with protons of acid. f Data for CF3SO3H-SbF5 solution. H5 signal is not
g
observed, due to rapid proton exchange with the acid.
Rea ction s w ith Cycloh exa n e a n d Ben zen e. On the
basis of the ease of formation of dications 15-18 as long-
living species in the explored superacidic systems, we
studied their reactions with cyclohexane and benzene in
these media.
Hydroxyquinolines 11-14 were found to be unreactive
with cyclohexane in CF3SO3H-SbF5 at room temperature
during several hours.14 This indicates that their corre-
sponding dications 15-18 are not as electrophilic as
dication 6, which underwent complete ionic hydrogena-
tion with cyclohexane during a 10 min period under
similar conditions.5 This is in accord with the calcula-
tional results. Successful reaction of compounds 11, 13,
and 14 with cyclohexane occurred, however, by using

Reactions of Hydroxyquinolines and -isoquinoline
J . Org. Chem., Vol. 67, No. 12, 2002 4333
Ta ble 3. En er gies of th e LUMO (ELUMO), th e Squ a r e of th e Coefficiets (c2) on Ca r bon Atom s a t th e LUMO, NBO Ch a r ges
on CH Gr ou p s (q), a n d ∆Hf of Ion s 1-4, 6, 15-20, 22, 23 Ca lcu la ted by th e MNDO a n d DF T Meth od s
5-7 molar excess of aluminum chloride at 90 °C.15
Hydroxyquinoline 11 gave tetrahydroquinoline 8 in 97%
yield over a period of 90 h. The probable mechanism of
the reaction is shown in Scheme 4. According to the
scheme, superelectrophilic dication 15a undergoes selec-
tive ionic hydrogenation with cyclohexane, followed by
similar reaction of dications 19 and 20. The in situ
generated intermediate 19 is an example of superelec-
(14) Compound 13, after 24 h of reaction, gave 30% of 8. Compound
12 after 48 h gave a product of oxidative dimerization, please see: (a)
Chen, Y.-X.; Yang, L.-W.; Li, Y.-M.; Zhou, Z.-Y.; Lam, K.-H., Chan, A.
S. C., Kwong, H.-L. Chirality. 2000, 12, 510. (b) Schmitt, M. M.;
Schuler, E.; Braun, M.; Haring, D.; Schreier, P. Tetrahedron Lett. 1998,
39, 2945.
(15) Under the reaction conditions cyclohexane exists in an equi-
librium with methylcyclopentane, see: Nenitzescu, C. D.; Cantuniari,
R. Chem. Ber. 1933, 66, 1097.

4334 J . Org. Chem., Vol. 67, No. 12, 2002
Koltunov et al.
Sch em e 3
Sch em e 4
trophilic activation of ketone by O-monoprotonation and
additional protonation (or coordination by Lewis acid) of
closely situated nitrogen atom. Recently, a similar type
of superelectrophilic activation of carbonyl-containing
heterocyclic compounds for reactions with arenes has
been demonstrated by Klumpp and co-workers.16 Dication
20 is an example in which the pyridinum nitrogen
dramatically enhances the reactivity of an adjacent
carbon electrophilic center. Previously, the possibility of
generation of such reactive intermediates was shown by
low-temperature NMR for reactions of amino alcohols
with benzene in superacids.17 Calculated ꢀLUMO and q•
values of dications 19 and 20 (X ) H) show them to be
stronger electrophiles than dication 15 (Table 3). This
explains the failure to stop the reaction at the stage of
either ketone (7,8-dihydro-5(6H)-quinolinone) or alcohol
(5,6,7,8-tetrahydro-5-quinolinol).
Sch em e 5
pounds 5 and 14 are considered similar to those described
in Scheme 4.
Hydroxyquinoline 12 is, as expected, inert toward
cyclohexane. But hydroxyquinoline 13 is slowly converted
(50% after 100 h of reaction at 110 °C) to give 8 (Scheme
6). This is in agreement with the higher electrophilicity
of dication 17 predicted by calculations. It is remarkable
that the C7 reaction center of intermediates 22 and 23 is
not included in the conjugated π-system containing the
protonated nitrogen. Nevertheless, it seems to be no
obstacle for this site to enhance the reactivity of the
reaction center through space at close distance. Results
of calculations show the high electrophilicity of dications
22 and 23 (Table 3). Recently, similar superelectrophilic
activation has been demonstrated for 4-piperidinone.16c
The study of reactivity of compounds 11-14 toward
benzene showed all of them to be inert in triflic acid or
in the presence of aluminum halides under mild condi-
tions. Attempts to obtain condensation products in the
CF3SO3H-SbF5 acid system failed because of side reac-
tions. Successful condensations were achieved only by
using 5-10 molar excess of aluminum halides at 80-90
The more reactive hydroxyquinoline 5 was shown to
give 8 (yield 95%) over a 15 h period under similar
reaction conditions. Hydroxyisoquinoline 14 gave 5,6,7,8-
tetrahydroisoquinoline 21 (yield 85%) over 50 h of reac-
tion (Scheme 5). The mechanisms of reaction of com-
(16) (a) Klumpp, D. A.; Lau, S. L.J . Org. Chem. 1999, 64, 7309. (b)
Klumpp, D. A.; J ones, A.; Lau, S.; DeLeon, S.; Garza, M. Synthesis.
2000, 8, 1117. (c) Klumpp, D. A.; Garza, M.; J ones, A.; Mendoza, S. J .
Org. Chem. 1999, 64, 6702. (d) Klumpp, D. A.; Garza, M.; Sanchez, G.
V.; Lau, S.; DeLeon, S. J . Org. Chem. 2000, 65, 8997.
(17) Klumpp, D. A.; Aguirre, S. L.; Sanchez, G. V.; DeLeon, S. Org.
Lett. 2001, 3, 2781.

Reactions of Hydroxyquinolines and -isoquinoline
J . Org. Chem., Vol. 67, No. 12, 2002 4335
Sch em e 6
Sch em e 7
Sch em e 8
were, however, unsuccessful. In further experiments it
was found that the reactions are reversible. Products 24
and 25 gave precursors 11 and 14, respectively, in ∼70%
equilibrium concentration under conditions similar to
that of condensation. For comparison, more reactive
quinoline 5 gave (similarly to 24 and 25) 10 in higher
yield (40-85%), and moreover, it was possible to stop the
reaction at the stage of formation of azatetralone 9 (68%)
(Scheme 2).5b
°C. Hydroxyquinoline 11 upon treatment with aluminum
bromide gave the condensation product followed by
intramolecular cyclization to 5,10-methano-10,11-dihy-
dro-5-hydroxybenzo[4,5]cyclohepta[1,2-b]pyridine (24) in
15-30% yield (Scheme 7).
Hydroxyisoquinoline (14) slowly reacts with benzene
and HBr-AlBr3 at room temperature (100-150 h) or in
the presence of AlCl3 or AlBr3 at 90 °C for 15 h to give
5,10-m et h a n o-10,11-dih ydr o-5-h ydr oxyben zo[4,5]-
cyclohepta[1,2-c]pyridine (25) in 25-40% yield (Scheme
8).
Hydroxyquinolines 12 and 13 were found to be unre-
active toward benzene at 20-120 °C in the presence of
aluminum halides. This can be explained by the relatively
weak electrophilicity of corresponding intermediate ions
16 and 17 and as a consequence of the shift of their
equilibrium reaction with benzene to starting compounds.
Con clu sion s
In summary, we have found that hydroxyquinolines
11-13 and isoquinoline 14 give in CF3SO3H-SbF5 su-
peracidic system N,C-diprotonated dications 15-18, which
can be regarded as superelectrophilic intermediates in
Attempts to increase the yield of 24 and 25 by variation
of reaction conditions or increasing the reaction time

4336 J . Org. Chem., Vol. 67, No. 12, 2002
Koltunov et al.
5,6,7,8-Tetr a h yd r oisoqu in olin e (21): 1H NMR (CDCl3) δ
1.75-1.85 (m, 4H), 2.7 (br s, 4H), 6.93 (d, J 8.3 Hz, 1H), 8.23
(d, J 8.3 Hz, 1H), 8.26 (s, 1H); 13C NMR (CDCl3) δ 22.22, 22.43,
26.09, 28.51, 123.78, 132.9, 146.02, 146.2, 150.23.
5,10-Me t h a n o-10,11-d ih yd r o-5-h yd r oxyb e n zo[4,5]-
cycloh ep ta [1,2-b]p yr id in e (24).
their reactions with benzene and cyclohexane. It was
shown that the computed values of ꢀLUMO and q• of
superelectrophiles could be successfully used for estima-
tion of their reactivity. From a synthetic point of view,
condensation of hydroxyheteroarenes with benzene offers
a new, useful synthetic approach for the preparation of
novel heterocycles. Products 24 and 25 formally belong
to a class of alkaloids and possess previously unknown
carbon skeletons. The reversibility of reactions found can
be utilized for the synthesis of quinolines (isoquinolines)
from corresponding arylquinolones (isoquinolones). Ionic
hydrogenation with cyclohexane was found to be an
alternative way of synthesis of hydroquinolines and
hydroisoquinolines.
Meth od a . To a solution of AlBr3 (2.67 g, 10 mmol) in
benzene (5 mL) was added hydroxyquinoline 11 (0.145 g, 1
mmol). The resulting mixture was saturated with gaseous HBr
(0.33 g, 4 mmol), followed by heating in a flask with a reflux
condenser at 80 °C, under stirring for 16 h. Subsequently, the
mixture was cooled to room temperature and poured over 20
g of ice. The aqueous layer was washed with ether, made basic
with concentrated NaOH and extracted with CHCl3.20 The
organic phase, after washing with H2O and drying over MgSO4,
was concentrated in vacuo to give 24 (65 mg, 29%) as colorless
crystalline product: mp 208-209 °C (acetone); 1H NMR
(CDCl3) δ 2.34 (d, J 9.76 Hz, 1H), 2.55 (ddd, J 9.76, 5.37, 1.22
Hz, 1H), 2.89 (d, J 17.82 Hz, 1H), 3.05 (br s, 1H), 3.39 (dd, J
17.82, 5.13 Hz, 1H), 3.66 (td, J 5.13, 1.22 Hz, 1H), 7.06 (dd, J
7.81, 4.89 Hz, 1H), 7.1-7.22 (m, 3H), 7.29 (dd, J 6.1, 1.5 Hz,
1H), 7.94 (dd, J 7.81, 1.7 Hz, 1H), 8.27 (d, J 4.8 Hz, 1H); 13C
NMR (CDCl3) δ 37.9, 37.91, 49.29, 80.12, 119.07, 121.29,
123.72, 127.12, 127.88, 128.65, 140.83, 143.18, 147.86, 149.75,
153.72; HRMS C15H13NO (M - H+) calcd 222.0919, found
222.0925.
Exp er im en ta l Section
1H and 13C NMR spectra were recorded on a 300 MHz
superconducting NMR spectrometer. High-resolution mass
spectra were measured by the Southern California Mass
Spectrometry Facility at the University of California at
Riverside. Triflic acid, trifluoroacetic acid, aluminum bromide,
and aluminum chloride were purchased from suppliers. An-
timony pentafluoride was distilled under argon. Compounds
5 and 11-14 were purchased and used as received, except 14,
which was recrystallized from ethanol, mp 229-230 °C. High-
temperature reactions (>80 °C) were carried out in 15 mL
pressure tubes.
Gen er a l P r oced u r e for th e P r oton a tion of 11-14.
Samples of 11-14 (20-30 mg) were dissolved in trifluoroacetic
or triflic acid in 5 mm NMR tubes at room temperature.
The triflic acid solutions were kept for 5-24 h until a constant
ratio of derived ions was obtained. For generation of dica-
tions 15-18, SbF5 was added to the previously prepared
solutions of compounds 11-14 in triflic acid (molar ratio
CF3SO3H/SbF5 ) 3:1), the resulting solutions were kept for
2-5 h.
Meth od b. An analogous procedure without saturation of
the reaction mixture with HBr gave 33 mg (15%) of 24.20
5,10-Me t h a n o-10,11-d ih yd r o-5-h yd r oxyb e n zo[4,5]-
cycloh ep ta [1,2-c]p yr id in e (25). Meth od a . To a solution of
AlBr3 (2.67 g, 10 mmol) in benzene (5 mL) was added
hydroxyquinoline 14 (0.145 g, 1 mmol). The resulting mixture
was saturated with gaseous HBr (0.33 g, 4 mmol), stirred at
25 °C for 150 h, and then poured over 20 g of ice. The aqueous
layer was washed with ether, made basic with concentrated
NaOH, and extracted with CHCl3.21 The organic phase after
washing with H2O and drying over MgSO4 was concentrated
in vacuo to give 25 (83 mg, 37%) as colorless crystalline
1
product: mp 222-223 °C (acetone); H NMR (CDCl3) δ 2.32
Gen er a l P r oced u r e for th e Rea ction of 5, 11, 13, a n d
14 w ith Cycloh exa n e. A 0.1 g portion of the hydroxyhet-
eroarene was added to a suspension of 0.65 g of AlCl3 in 3 mL
of cyclohexane. This mixture was stirred at 90 °C (13 was
reacted at 110 °C) for 15-100 h until two distinct layers were
formed, followed by cooling of the mixture poured over several
grams of ice. The aqueous layer was washed with ether and
then made basic with concentrated NaOH and extracted
with ether (5 × 6 mL). The organic phase was dried with
MgSO4. Careful removal of the solvent under reduced pres-
sure provided the products 8 or 21 as colorless liquids. NMR
data of 85b,18 and 2119 were comparable to those previously
reported.
(d, J 10.01 Hz, 1H), 2.55 (ddd, J 10.01, 5.37, 1.22 Hz, 1H),
2.72 (d, J 17.09 Hz, 1H), 3.24 (dd, J 17.09, 4.88 Hz, 1H), 3.65
(td, J 4.88, 1.22 Hz, 1H), 7.11-7.23 (m, 3H), 7.27 (dd, J 6.2,
1.7 Hz, 1H), 7.56 (d, J 5.13 Hz, 1H), 8.1 (s, 1H), 8.29 (d, J 5
Hz, 1H); 13C NMR (CDCl3) δ 31.66, 38.5, 48.72, 79.96, 115.53,
119.36, 123.61, 127.22, 128.07, 128.4, 142.97, 147.1, 149.46,
150.01, 153.54; HRMS
223.0990.
C15H13NO calcd 223.0997, found
Meth od b. Heating a similar reaction mixture at 80 °C for
5 h gave 67 mg (30%) of 25.21
Meth od c. To a suspension of AlCl3 (1.33 g, 10 mmol) in
benzene (5 mL) was added hydroxyquinoline 14 (0.145 g, 1
mmol). The resulting mixture was stirred at 90 °C for 15 h
and after standard workup gave 25 (54 mg, 24%).21
5,6,7,8-Tetr a h yd r oqu in olin e (8): 1H NMR (CDCl3) δ 1.7-
1.9 (m, 4H), 2.7 (t, J 7 Hz, 2H), 2.87 (t, J 7.3 Hz, 2H), 6.95
(dd, J 8.7, 5.3 Hz, 1H), 7.27 (d, J 8.7 Hz, 1H), 8.28 (d, J 5.3
Hz, 1H); 13C NMR (CDCl3) δ 22.5, 22.88, 28.57, 32.29, 120.69,
132.29, 136.58, 146.53, 157.16.
Ack n ow led gm en t . Partial support of the work
by the National Science Foundation is gratefully
acknowledged.
J O020099N
(18) (a) Trofimov, B. A.; Mikhaleva, A. I.; Petrova, O. V. J . Org.
Chem. USSR. 1991, 27, 1713. (b) Honel, M.; Vierhapper, F. N. J . Chem.
Soc., Perkin Trans. 1. 1980, 9, 1933.
(19) (a) Boger, D. L.; Panek, J . S.J . Org. Chem. 1981, 46, 2179. (b)
Gribble, G. W.; Barden, T. C.; J ohnson, D. A. Tetrahedron 1988, 44,
3195.
(20) Workup with Na2CO3 instead of NaOH gave a mixture of 11
and 24 (molar ratio 2:1 to 5:1).
(21) Workup with Na2CO3 instead of NaOH gave a mixture of 14
and 25 (molar ratio 1.5:1 to 3:1).