Preparation of aza-polycyclic aromatic compounds via superelectrophilic cyclizations

Article abstract of DOI:10.1021/jo8003474

(Chemical Equation Presented) Alkenyl-substituted N-heterocycles react in superacidic CF₃SO₃H (triflic acid) to produce dicationic intermediates. These superelectrophiles undergo cyclizations to give varied aza-polycyclic aromatic compounds in generally good yields (27-99%, 16 examples). Theoretical calculations indicate a preference for charge-separated dicationic intermediates.

Full text of DOI:10.1021/jo8003474

SCHEME 1. Ionization of Alcohol 1 in Superacid and Its
Cyclization to Product
Preparation of Aza-Polycyclic Aromatic
Compounds via Superelectrophilic Cyclizations
Ang Li, Thomas M. Gilbert, and Douglas A. Klumpp*
Department of Chemistry and Biochemistry, Northern Illinois
UniVersity, DeKalb, Illinois 60115
dklumpp@niu.edu
ReceiVed February 11, 2008
TABLE 1. Products and Yields from Reactions of Alcohol
(5a-9a) and Olefin Substrates (5b-9b) with CF3SO3H (0.2 mmol of
Substrate, 4 mL of Acid, 24 h)a
Alkenyl-substituted N-heterocycles react in superacidic
CF3SO3H (triflic acid) to produce dicationic intermediates.
These superelectrophiles undergo cyclizations to give varied
aza-polycyclic aromatic compounds in generally good yields
(27–99%, 16 examples). Theoretical calculations indicate a
preference for charge-separated dicationic intermediates.
Superacidic media is well-known for its ability to generate
reactive electrophilic species, many of which are useful in
synthetic methodologies.1 In some cases, it has been demon-
strated that even di- and tricationic, superelectrophilic intermedi-
ates may be formed in superacids. Multiply charged superelec-
trophiles often exhibit novel chemistry, when compared to
monocationic electrophiles.2 The chemistry of superelectrophilic
systems can include unusual rearrangements, reactions with very
weak nucleophiles, functionalization at nonactivated bonds,
remote functionalizations, and other reactions.2 We recently
described a group of reactions involving functionalized N-
heterocycles which produce aza-polycyclic aromatic compounds
(Scheme 1).3 The chemistry involves the ionization of alcohols
(i.e., 1) in superacidic media to form dicationic superelectro-
philes. Charge migration (2 f 3) leads to cyclization, and further
loss of benzene provides the aza-polycyclic aromatic product
(4). The chemistry provides access to a wide variety of
condensed ring systems. In this paper, we report a significant
improvement in this superelectrophilic chemistry and the
preparation of functionalized aza-polycyclic aromatic compounds.
With the involvement of carbocation electrophiles in the
cyclizations, we reasoned that olefinic systems would be superior
to alcohols in generating the required superelectrophiles. In
reactions with comparable alcohol substrates (5a-9a) and
olefinic substrates (5b-9b), it was observed that the olefins
consistently provided better yields of the condensation products
a Isolated yields. b From ref 3.
(10–14; Table 1). Thus, ionization of the alcohol derivative 5a
gives benzo[c]acridine (10) in fair yield (63%), while the olefin
derivative 5b provides compound 10 in 85%. Alcohol 8a does
not give the desired condensation product 13; however, an
intermediate cyclization product (without benzene elimination)
can be isolated in 17% yield (see the Supporting Information).
In the case of H-imidazo[1,2-a]quinoline (14), the alcohol
substrate 9a likewise does not provide the desired product. The
corresponding olefin (9b), however, provides the aza-polycyclic
aromatic compound (14) in fair yield.
In order to further explore the scope of this chemistry, a
variety of functionalized aza-polycyclic aromatic compounds
(25–34) were synthesized from the respective olefinic substrates
(15–24; Table 2). These products include substituted benzoiso-
quinolines (25 and 27) and benzo[c]acridine derivatives (28–30).
In the case of substrate 19, demethylation occurs in the
(1) Olah, G. A.; Prakash, G. K. S.; Sommer, J. Superacids; Wiley: New York,
1985.
(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.
(3) Li, A.; Kindelin, P. J.; Klumpp, D. A. Org. Lett. 2006, 8, 1233.
3654 J. Org. Chem. 2008, 73, 3654–3657
10.1021/jo8003474 CCC: $40.75 2008 American Chemical Society
Published on Web 04/01/2008

TABLE 2. Products and Yields from the Reactions of 15–24 with
CF3SO3H (0.2 mmol of Substrate, 4 mL of acid, 24 h)
Reaction of derivative 35 in CF3SO3H gives a mixture of
isomers 36 and 37 in 62% overall yield (eq 1). The olefinic
substrates (15–24 and 35) were generally prepared using Wittig
and Suzuki coupling reactions, for example in the preparation
of substrate 24 from 3-bromo-4-pyridinecarboxaldehyde (eq 2).
The superacid-promoted cyclizations of the olefinic substrates
likely occur by a mechanism similar to that proposed for the
alcohol substrates (cf. Scheme 1). The key steps involve
formation of two types of dicationic intermediates: the dication
leading to a cyclization and ipso-protonated dication (i.e., 39
and 40). The increased product yields from the olefinic substrates
(compared to similar alcohol substrates) may be the result of at
least two factors. First, ionization of the alcohol leads to an
elimination of water. The water elimination leads to an overall
decrease in the acidity of the reaction media. Second, cyclization
of an alcohol substrate requires a charge migration step (38 f
39). This may slow the conversion and lead to lower yields.
With the olefinic substrates, the required superelectrophilic
intermediate (39) is produced directly from the olefin. Due to
charge–charge repulsive effects, the requisite dication is formed
regioselectively, and this leads to rapid and efficient cyclization.
In order to further study this aspect of the chemistry, the two
possible superelectrophilic regioisomers arising from diproto-
nation of 5b (38 and 39) were compared by theoretical
calculations using the Gaussian program suite.4 Structures 38
and 39 were optimized without symmetry constraints at the HF/
6-31G(d) level and the stationary points shown to be minima
at this level by frequency analysis. The structures were then
reoptimized at the levels listed in Table 3. Energies of the gas-
phase structures were corrected using the appropriately scaled
zero-point energy determined by the frequency analysis.5 At
all levels of theory, the charge-separated dication 39 is found
to be considerably more stable than the isomeric dication 38.
Using the solution-phase model IPCM (single point)//MPW1/
6-311G(d) (dielectric constant ꢀ ) 100), 39 remains 7.4 kcal
mol-1 more stable than 38. Interestingly, the decreased energy
a Isolated yield of pure product. Reaction run at: b 0 °C. c 25 °C. d 50
°C.
(4) 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.; Rega, N.; Salvador, P.; Dannenberg,
J. J.; Malick, D. K.; Rabuck, A. 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.; 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, 2002.
superacidic media at 50 °C to give benzo[c]acridine-3-ol (29a).
At 0 °C, the methoxy-substituted product (29b) is formed, albeit
in low yield. When the 2-phenyl-1-propenyl (20–22) or the
1-phenyl-2-propenyl groups (15) are used, methyl-substituted
arenes (25, 30–32) are formed. Other aza-polycyclic aromatic
compounds (33 and 34) were prepared in reasonably good yields
by cyclization toward naphthyl and pyrenyl ring systems.
(5) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502.
J. Org. Chem. Vol. 73, No. 9, 2008 3655

TABLE 3. Calculated Relative Energies of Dications 38 and 39
relative energy (kcal ·mol-1
aldehyde, 1-phenylimidazole-2-carbaldehyde, was converted to
olefin substrates 9b and 21 by method A.
)
Preparation of Olefin Substrates: Method C [5a, 16–19, 20
(Ph3PC(CH3)Ph used), 23, 24, and 35]. The aldehyde (6 mmol)
and boronic acid (9 mmol) were dissolved in 1,4-dioxane (50 mL).
Potassium phosphate (9 mmol) was added to the solution, followed
by palladium(II) acetate (5 mol %). The mixture was refluxed
overnight, and then H2O (2 mL) was added. The product was
extracted into ether (3 × 40 mL), washed with brine, and dried on
Na2SO4. The crude mixture was subjected to silica gel column
chromatography. The product was further reacted with a Wittig
reagent as described in method A.
Reactions of Olefin Substrates. The olefin substrate (1 mmol)
was added slowly to CF3SO3H (4 mL, 45 mmol) with stirring. If
necessary, CHCl3 (2 mL) could be used as a cosolvent to dissolve
the olefin substrate. After at least 4 h of reaction, the product mixture
was carefully poured over ca. 15 g of ice. The solution was made
basic by slow addition of 10 M NaOH, and then it was extracted
with two 30 mL portions of CHCl3. The organic phase was then
washed with water followed by brine. After drying over anhydrous
Na2SO4, the product was then purified by silica gel chromatography
or recrystallization.
level of theory
39
38
HF/6-311G (d)
B3LYP/6-311G (d)
PBE1/6-311G (d)
MP2/6-311G (d)
IPCMsp//MPW1/6-11G (d)
0.0
0.0
0.0
0.0
0.0
18.0
14.9
10.0
10.3
7.4
difference (between 38 and 39) with the solvation model
probably reflects the impact of the solvation cavity on the
dicationic species. The less stable ion (with more closely
oriented charges) 38 is expected to benefit more form solvolytic
stabilization than does the charge-separated ion 39. Though
calculations have only been done on this one system (5b to 38
and 39), it seems reasonable to expect that other systems will
exhibit similar energy trends. Indeed, the energy difference may
even be greater for other pairs of isomeric dications. This may
further explain the increased yields of aza-polycyclic aromatic
products for olefinic versus alcohol substrates (Table 1).
Ionization of the alcohol substrates requires formation of the
higher energy dications with more closely oriented charges.
In summary, we have found that the superacid-promoted
reactions of alkenyl-substituted N-heterocycles can provide a
wide variety of aza-polycyclic aromatic compounds. It is
proposed that the reactions involve the cyclizations of super-
electrophilic intermediates, formed regioselectively due to
charge–charge repulsive effects. Formation of the condensed
aromatic system is achieved in subsequent steps by ipso-
protonation of a phenyl group and elimination of benzene. From
the examples studied above, this is clearly a useful and general
synthetic route to an important class of compounds, the aza-
polycyclic aromatic compounds.
2,7-Diphenyl-2H-benzo[g]indazole (11): yellow solid; mp
1
99–101 °C; H NMR (CDCl3, 500 MHz) δ 7.40–7.49 (m, 4H),
7.53–7.62 (m, 4H), 7.81 (d, J ) 7.4 Hz, 1H)), 7.91 (dd, J ) 8.3,
1.6 Hz, 1H), 7.99 (d, J ) 7.7 Hz, 1H), 8.07 (d, J ) 1.5 Hz, 1H),
8.39 (s, 1H), 8.81 (d, J ) 8.3 Hz, 1H); 13C NMR (CDCl3, 125
MHz) δ 118.8, 120.2, 120.5, 121.2, 123.2, 124.7, 124.8, 126.0,
126.8, 127.4, 128.9, 129.6, 133.2, 139.8, 140.6, 141.2, 147.5; HRMS
calcd for C23H16N2 320.1313, found 320.1309.
9,10-Difluorobenzo[h]quinoline (26): yellow solid; mp 72–74
1
°C; H NMR (CDCl3, 500 MHz) δ 7.48–7.56 (m, 3H), 7.57–7.64
(m, 1H), 7.69–7.71 (m, 1H), 8.15 (dd, J ) 8.0,1.8 Hz, 1H), 9.10
(m, 1H); 13C NMR (CDCl3, 125 MHz) δ 117.5 (d,, J ) 19.1 Hz),
121.7, 122.1, 123.9, 125.8, 127.1, 127.3, 131.6, 135.7, 145.9, 148.6
(dd, J ) 263, 14.8 Hz), 149.7 (dd, J ) 250, 15 Hz); EI MS (low
res) 215 (M+), 188, 94; HRMS calcd for C13H7F2N 215.0547,
found 215.0545.
Experimental Section
9,10-Difluorobenzo[h]isoquinoline (27): yellow solid; mp
1
113–115 °C; H NMR (CDCl3, 500 MHz) δ 7.40 (dd, J ) 16.9,
General Methods. Triflic acid was purchased from a commercial
supplier and distilled from a dry Ar atmosphere immediately prior
to use. Benzene was dried over 4 Å sieves prior to use, and all
other reagents (except those noted below) were obtained from
commercial suppliers and used as received. High-resolution mass
spectra were obtained from the Mass Spectroscopy Laboratory at
the University of Illinois at Champaign-Urbana.
8.8 Hz, 1H), 7.53–7.76 (m, 3H), 7.74 (d,, J ) 7.3 Hz, 1H), 8.71 (s,
1H), 10.18 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 116.7 (d,, J )
19.3 Hz), 119.5 (d, J ) 8), 121.1, 123.5, 124.8, 125.3, 129.9, 130.5,
136.4, 145.6, 147.9 (dd, J ) 166, 14.1 Hz), 150.0 (dd, J ) 139,
13.9 Hz); EI MS (low res) 215 (M+), 188, 94; HRMS calcd for
C13H7F2N 215.0547, found 215.0549.
1,2-Difluorobenzo[c]acridine (28): yellow solid; mp 194–196
Preparation of Olefin Substrates: Method A [Compounds
6b, 7b, 8b, 15, and 22 (Ph3PC(CH3)Ph Used)]. Benzyltriph-
enylphosphonium (4.8 mmol) bromide is suspended in anhydrous
THF (20 mL) and cooled to –78 °C. To this solution was added
butyllithium (2.4 mL, 4.8 mmol, 2.0 M solution in cyclohexane)
and the mixture stirred for 2 h. The aldehyde or ketone (4 mmol)
was dissolved in anhydrous THF (5 mL) and then slowly added
into the reaction. The solution was then warmed to 25 °C and stirred
for 4 h. The product mixture was quenched with H2O and extracted
with ether (3 × 40 mL). The organic extracts were washed with
brine and then dried with anhydrous Na2SO4. The crude olefins
were then purified by column chromatography (hexane/ether).
Preparation of Olefin Substrates: Method B [Compounds
9b and 21 (Ph3PC(CH3)Ph Used)]. Phenylimidazole (12 mmol)
was dissolved in anhydrous THF (40 mL) and cooled to 0 °C.
Butyllithium (2.4 mL, 4.8 mmol, 2.0 M solution in cyclohexane)
was added. The solution was then warmed to 25 °C and stirred for
2 h. Anhydrous DMF (5 mL) was slowly added to the reaction
mixture and stirred overnight. The product mixture was quenched
with H2O. Extraction with ether was followed by aqueous washes
of brine and drying with anhydrous Na2SO4. The product was then
purified by silica gel chromatography (hexane/ether). The resulting
1
°C; H NMR (CDCl3, 500 MHz) δ 7.55–7.75 (m, 5H), 7.86–7.90
(m, 1H), 8.05–8.06 (d, J ) 8.3, 1H), 8.43–8.45 (d, J ) 8.6, 1H),
8.68 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ not sufficiently soluble
for 13C NMR spectrum; EI MS (low res) 265 (M+), 246, 132;
HRMS calcd for C17H9F2N 265.0703, found 265.0705.
5-Methyl-2-phenyl-1-oxa-3-azacyclopenta[a]naphthalene (32):
1
white solid; mp 146–148 °C; H NMR (CDCl3, 500 MHz) δ 2.77
(s, 3H), 7.54–7.58 (m, 4H), 7.63–7.68 (m, 2H), 8.06 (d, J ) 8.4
Hz, 1H), 8.28–8.34 (m, 3H); 13C NMR (CDCl3, 125 MHz) δ 20.0,
118.8, 120.4, 120.6, 125.3, 125.5, 126.5, 127.3, 127.5, 128.9, 130.8,
131.0, 131.8, 138.1, 145.4, 162.2; EI MS (low res) 259 (M+), 128,
102; HRMS calcd for C18H13NO 259.0997, found 259.0995.
Pyreno[2,1-h]isoquinoline (34): yellow solid; mp 136–138 °C;
1H NMR (CDCl3, 500 MHz) δ 7.84–7.88 (m, 2H), 8.07–8.12 (m,
3H), 8.21–8.24 (m, 2H), 8.31 (d, J ) 7.7 Hz, 1H), 8.36 (d, J ) 9.3
Hz, 1H), 8.52 (s, 1H), 8.80 (d, J ) 5.2 Hz, 1H), 9.34 (d, J ) 9.3
Hz, 1H), 10.49 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 120.8,
123.7, 124.6, 124.9, 125.1, 125.2, 125.4, 125.5, 125.6, 126.5, 126.5,
126.9, 127.4, 127.9, 128.5, 130.3, 130.5, 130.9, 131.6, 132.0, 136.8,
144.5, 150.9; EI MS (low res) 303 (M+), 151, 135; HRMS calcd
for C23H13N 303.1048, found 303.1053.
3656 J. Org. Chem. Vol. 73, No. 9, 2008

2,3-Dihydro-1,4-dioxa-12-azabenzo[b]chrysene (36): yellow
solid; mp 144–146 °C; 1H NMR (CDCl3, 500 MHz) δ 4.45 (s, 2H),
4.51(s, 2H), 7.30 (d, J ) 8.9 Hz, 1H), 7.57–7.60 (t, J ) 7.5 Hz,
1H), 7.75 (d, J ) 9.3 Hz, 1H), 7.80–7.84 (m, 1H), 8.02–8.06 (m,
2H), 8.35 (d, J ) 8.9 Hz, 1H), 8.64 (s, 1H), 9.04 (d, J ) 8.9 Hz,
1H); 13C NMR (CDCl3, 125 MHz) δ 64.5, 64.6, 117.7, 118.5, 120.3,
124.5, 125.0, 125.5, 125.5, 126.2, 126.8, 127.8, 128.3, 129.6, 129.6,
135.0, 138.1, 143.2, 147.7, 148.0; EI MS (low res) 287 (M+), 231,
203; HRMS calcd for C19H13NO2 287.0946, found 287.0949.
2,3-Dihydro-1,4-dioxa-13-azapentaphene (37): yellow solid;
mp 161–163 °C; 1H NMR (CDCl3, 500 MHz) δ 4.44 (s, 4H), 7.34
(s, 1H), 7.56–7.67 (m, 3H), 7.80 (m, 1H), 8.02 (d, J ) 7.8 1H),
8.35 (m, 1H), 8.60 (s, 1H), 8.98 (s, 1H); 13C NMR (CDCl3, 125
MHz) δ 64.4, 64.7, 112.9, 114.4, 124.1, 124.6, 125.6, 126.7, 126.8,
127.7, 129.3, 129.4, 129.5, 134.8, 134.8, 144.3, 145.7, 147.5, 147.5;
EI MS (low res) 287 (M+), 231, 203; HRMS calcd for C19H13NO2
287.0946, found 287.0948.
Acknowledgment. Grateful acknowledgement is made to the
donors of the American Chemical Society Petroleum Research
Fund for support of this work (PRF no. 44697-AC1).
Supporting Information Available: NMR spectra and
computational methods and results. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO8003474
J. Org. Chem. Vol. 73, No. 9, 2008 3657