Cyclizations of phenylethyl-substituted pyridinecarboxaldehydes

Article abstract of DOI:10.1016/j.tet.2013.01.004

Several phenylethyl-substituted pyridinecarboxaldehydes were prepared from 2-bromo-3-pyridine-carboxaldehyde and these substances are found to undergo cyclization reactions in acidic media. In the absence of added nucleophile, acid-promoted cyclization and oxidation (MnO₂) provide an efficient route to 10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ones. Arene nucleophiles may also be added to the acidic mixture to provide good yields of triarylmethane products. Mechanisms are proposed involving dicationic superelectrophilic intermediates.

Full text of DOI:10.1016/j.tet.2013.01.004

Tetrahedron 69 (2013) 2137e2141
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cyclizations of phenylethyl-substituted pyridinecarboxaldehydes
*
Rajasekhar Reddy Naredla, Douglas A. Klumpp
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Several phenylethyl-substituted pyridinecarboxaldehydes were prepared from 2-bromo-3-pyridine-
carboxaldehyde and these substances are found to undergo cyclization reactions in acidic media. In
the absence of added nucleophile, acid-promoted cyclization and oxidation (MnO2) provide an efficient
route to 10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ones. Arene nucleophiles may also be
added to the acidic mixture to provide good yields of triarylmethane products. Mechanisms are proposed
involving dicationic superelectrophilic intermediates.
Received 13 November 2012
Received in revised form 20 December 2012
Accepted 2 January 2013
Available online 8 January 2013
Keywords:
Cycloheptabenzopyridine
Heterocycle
Ó 2013 Elsevier Ltd. All rights reserved.
Superacid
Superelectrophile
FriedeleCrafts
1. Introduction
The cycloheptabenzopyridine ring system and related hetero-
cyclic dibenzepinone analogs are useful building blocks for bi-
ologically active compounds.1 Examples of these compounds
include loratadine (1, H1 histamine antagonist),1h SCH 66336
(2, anti-cancer agent),2 and MK-2461 (3, anti-cancer agent;
Scheme 1).3 The cycloheptabenzopyridine ring system has been
previously prepared by intramolecular cyclizations of carboxylic
acids,4 nitriles,4b,5 alcohols,6 ketones,7 and by other routes.8 For
acid-promoted reactions of carboxylic acids, the cyclization requires
extreme conditions (i.e., polyphosphoric acid, 200 ꢀC).4 Owing tothe
value of these products, new synthetic methods leading to the
cycloheptabenzopyridine ring system are highly desirable. In the
following manuscript, we describe the preparation of several
phenylethyl-substituted pyridinecarboxaldehydes and their cycli-
zation to cycloheptabenzopyridine products.
Scheme 1.
was accomplished using readily available 2-bromo-3-pyridinecar-
boxaldehyde (Scheme 2). Sonogashira coupling provides good
yields of the heterocyclic alkynes (i.e., 4).9 Although reduction of
the triple bond was achieved in quantitative yield, it occurred with
reduction of the carboxaldehyde group to give product 5. Sub-
sequent oxidation to the aldehyde is accomplished readily with
MnO2 providing the desired substrate 6. We also attempted to
2. Results
Our approach to the cycloheptabenzopyridines began with the
preparation of a suitable electrophilic precursor. We envisaged al-
dehydes to be particularly useful precursors, as pyridinecarbox-
aldehydes are known to form exceedingly reactive electrophiles in
acidic media. Thus, the cycloheptabenzopyridines could be
accessed by intramolecular reactions with a phenethyl group.
Preparation of the phenethyl-substituted pyridinecarboxaldehydes
Scheme 2.
* Corresponding author. E-mail address: dklumpp@niu.edu (D.A. Klumpp).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.004

2138
R.R. Naredla, D.A. Klumpp / Tetrahedron 69 (2013) 2137e2141
access compound 6 by a complimentary strategy using Pd-
catalyzed coupling with styrene (Heck reaction). However, this
method did not provide good yields of compound 6. Cyclization was
effected using a mixture of CF3CO2H/CF3SO3H (4:1 molar ratio) to
give the cycloheptabenzopyridine alcohol 7, which was sub-
sequently oxidized to the heterocyclic ketone 8. Neither CF3CO2H or
CF3SO3H alone provides the desired alcohol (7). Triflic acid gives
a complex mixture and trifluoroacetic acid gives only unreacted
starting material. Using this approach, substituted ketones 10 and
12 were prepared in good yields from the corresponding aldehydes
(Eqs. 1 and 2). Isomeric dihydrobenzocycloheptapyridinones may
also be prepared, for example, cyclization of 13 provides ketone 14
in good yield (Eq. 3). Quinoline substrate 15 was also synthesized
using Sonagashira coupling and reduction/oxidation, starting from
2-chloro-6-methoxy-3-quinolinecarboxaldehyde. Subsequent re-
action with acid and then MnO2 provides the tetracyclic ketone 16
(Eq. 4).
carbocation (19). With the formation of the carbocation 19, final
aqueous workup of the reaction gives the alcohol product 7. The
proposed mechanism may explain the need for the acid system,
CF3SO3H/CF3CO2H. Trifluoroacetic acid alone is a rather weak acid
(Ho ꢁ2.7), and thus, it cannot form the requisite superelectrophilic
carboxonium ion (17). Triflic acid itself is a Brønsted superacid (Ho
ꢁ14.1) and it should be capable of effecting this type of trans-
formation.12 Nevertheless, the triflic acid-promoted reactions are
found to give complex mixtures of productsdpossibly due to in-
termolecular reactions (dimerizations, etc.) involving super-
electrophiles 17 and 19. According to Shudo’s analysis of the
CF3SO3H/CF3CO2H acid system,13 our reaction conditions utilize
a mixture having an estimated acidity of ca. Ho ꢁ10.8, less than
CF3SO3H but significantly greater than CF3CO2H. This level of acidity
enables the reactive dications to form. The results also suggest the
trifluoroacetic acid serves the purpose of tempering the reactivity
of the carbocation 19. If the trifluoroacetic acid forms an adduct
(i.e., 20) with the superelectrophilic carbocation 19, then the overall
reactivity of the carbocation should be diminished. Thus, the tri-
fluoroacetic acid would help to compose an ‘electrophilic buffer
system’ in which the overall reactivity of the electrophile is de-
creased. Although the trifluoroacetate ester was not observed in the
product mixture, it would likely hydrolyze during the aqueous
workup (made basic with 10 M NaOH) and the alcohol (7) would be
formed. NMR experimentsddesigned to detect 19 and 20dwere
inconclusive.
ð1Þ
ð2Þ
ð3Þ
We anticipated that ion 19 would be a fairly reactive electro-
philic species. This can be seen in its reactions with arene nulceo-
philes (Scheme 4). When aldehyde 6 is reacted with benzene and
triflic acid, the arylated product 21 is isolated in 81% yield. The
functionalized cycloheptabenzopyridine (21) is the only major
product. This result may be contrasted with the simple cyclization
in triflic acid that leads to complex product mixtures. As a co-
solvent, benzene should react rapidly with the formed
ð4Þ
The key step in this transformation involves formation of dica-
tionic intermediates in the strongly acidic media. The high elec-
trophilic reactivities of dicationic electrophiles have been well
documented10 and pyridinecarboxaldehydes are known to form
these types of superelectrophilic species.11 For example, pro-
tonation at the pyridine ring and carbonyl group leads to formation
of the superelectrophile 17 (Scheme 3). Upon cyclization, further
steps presumably lead to the dicationic oxonium ion (18) and
Scheme 3.
Scheme 4.

R.R. Naredla, D.A. Klumpp / Tetrahedron 69 (2013) 2137e2141
2139
carbocation (19) and this prevents the undesirable side reactions.
Two other arene nucleophiles were reacted with aldehyde 6 in
superacid and the respective products (22 and 23) from bromo-
benzene and ethyl salicylate were also obtained in good yields.
These conversions are accomplished with excellent regioselectivity
(ortho/para, <1:20). Aldehydes 9 and 11 likewise give condensation
products (24e27) in good yields by reactions with arene nucleo-
philes and triflic acid.
In addition to arene nucleophiles, carbocation 19 may be trap-
ped with alcohol or hydride nucleophiles. When compound 6 is
reacted with CF3SO3H/CF3CO2H and the solution quenched with
a mixture of methanol and Na2CO3, the ether product 28 is formed
(Scheme 5). The same aldehyde reacts with NaBH4 in CF3SO3H/
CF3CO2H to provide the cycloheptabenzopyridine (29) as the ex-
clusive product. Previous reports have described NaBH4 reductions
in the presence of neat CF3SO3H,14 however, these reaction condi-
tions only gave an intractable mixture from 6.
a 125 mL high-pressure bomb reactor and stirred under a H2 at-
mosphere (200 psi, 2 h). The resulting solution is then filtered
through Celite and concentrated by rotary evaporation. The crude
alcohol (i.e., 5; 1 mmol) is dissolved in benzene (10 mL) and
manganese(IV) oxide (1.5 g, 17.3 mmol) is added. After stirring at
room temperature for 12 h, the reaction mixture is filtered through
Celite, and concentrated with a rotary evaporator. The resulting
phenethyl-substituted heterocyclic aldehyde is sufficiently pure for
subsequent reaction steps.
4.3. Preparation of 10,11-dihydro-5H-benzo[4,5]cyclohepta
[1,2-b]pyridin-5-one (8) and related ketones
The N-heterocyclic aldehyde (i.e., 6; 1 mmol) is dissolved in
CF3CO2H (2 ml, 26 mmol) and then CF3SO3H (0.5 ml, 6 mmol) is
added slowly. The reaction mixture is stirred for 2 h at 25 ꢀC and
subsequently poured over several grams of ice. The resulting so-
lution is then made basic by addition of NaOH (10 M) and the
aqueous mixture is extracted twice with chloroform. The organic
extract or phase is then washed with water followed by saturated
brine (2ꢂ). The solution is dried with MgSO4, filtered, and con-
centrated with a rotary evaporator. The crude product (i.e., 7) is
dissolved in benzene (10 mL) and manganese(IV) oxide (1.5 g,
17 mmol) is added to the solution. Following a reaction period of
12 h at 25 ꢀC, the mixture is filtered through Celite and concen-
trated with a rotary evaporator. The product is then purified by
silica gel chromatography (hexane/ethyl acetate).
Scheme 5.
4.4. 2-Phenethyl-3-pyridinecarboxaldehyde (6)
3. Conclusion
Isolated as a yellow crystal (Rf 0.43, 3:2 hexanes/ethyl ace-
tate). Mp 46e47 ꢀC. 1H NMR (300 MHz, CDCl3)
d 3.05e3.10 (m,
In summary, we have found that pyridinecarboxaldehydes may
be converted to 10,11-dihydro-5H-benzo[4,5]cyclohepta-[1,2-b]
pyridin-5-ones and related cycloheptabenzopyridines. A mecha-
nism is proposed involving reactive dicationic electrophiles. In the
reactions leading to 10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]
pyridin-5-ones, a mixture of CF3CO2H/CF3SO3H is found to work
best. It is suggested that the trifluoroacetic acid serves to decrease
the electrophilic reactivity of the system and this prevents un-
desirable oligomerization chemistry. Aryl-substituted cyclo-
heptabenzopyridines are formed in good yields by cyclization of
pyridinecarboxaldehydes followed by a FriedeleCrafts reaction
with arene nucleophiles.
2H), 3.49e3.54 (m, 2H), 7.19e7.23 (m, 3H), 7.26e7.29 (m, 2H),
7.35 (dd, J¼7.8, 4.8 Hz, 1H), 8.10 (dd, J¼7.8, 1.9 Hz, 1H), 8.77 (dd,
J¼4.8, 1.7 Hz, 1H) 10.15 (s, 1H); 13C NMR:
d 36.2, 62.9, 121.9, 126.3,
128.5, 128.6, 129.5, 138.0, 140.8, 153.5, 163.1, 190.7. Low-
resolution mass spectrum (EI): 211 (Mþ), 210, 182, 167, 91.
High-resolution mass spectrum, C14H13ON, calcd 211.9972, found
211.10002.
4.5. 10,11-Dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one
(8)
Isolated as a pale yellow crystal (Rf 0.33, 3:2 hexanes/ethyl ac-
etate). Mp 50e52 ꢀC. 1H NMR (300 MHz, CDCl3)
d 3.23e3.27 (m,
4. Experimental section
2H), 3.46e3.50 (m, 2H), 7.26e7.39 (m, 3H), 7.49 (dt, J¼7.4, 1.5 Hz,
1H), 7.94 (dd, J¼7.8, 1.4 Hz, 1H), 8.41 (dd, J¼7.9, 1.6 Hz, 1H), 8.65 (dd,
J¼4.7, 1.8 Hz, 1H); 13C NMR:
d 33.0, 38.4, 121.9, 126.9, 129.0, 130.4,
4.1. Materials and methods
132.9, 133.3, 138.3, 139.0, 141.5, 152.2, 161.7, 193.7. Low-resolution
mass spectrum (EI): 209 (Mþ), 208, 181, 180, 152, 90. High-
resolution mass spectrum, C14H11ON, calcd 209.08407, found
209.08504.
Unless otherwise indicated, all reagents and chemical were
obtained from commercial suppliers. The trifluoromethanesulfonic
acid was distilled from an argon atmosphere prior to its use. All
reactions were done in oven dried glassware with an inert atmo-
sphere (Ar). High-resolution mass spectral analyses were done by
an off-site analytical laboratory, while low-resolution mass spectra
were obtained directly from a gas chromatography instrument
equipped with a mass-selective detector.
4.6. 2-(4-Fluorophenethyl)-3-pyridinecarboxaldehyde (9)
Isolated as a yellow crystal (Rf 0.41, 3:2 hexanes/ethyl acetate).
Mp 45e46 ꢀC. 1H NMR (300 MHz, CDCl3)
d 2.97e3.03 (m, 2H),
3.43e3.48 (m, 2H), 6.87e6.95 (m, 2H), 7.08e7.14 (m, 2H), 7.31 (dd,
J¼7.8, 4.8 Hz, 1H) 8.05 (dd, J¼7.8, 1.9 Hz, 1H), 8.71 (dd, J¼4.8,
4.2. Preparation of phenethyl-substituted heterocyclic alde-
hydes (6, 9, 11, 13, 15)
1.8 Hz, 1H), 10.12 (s, 1H); 13C NMR:
d 35.1, 37.0, 115.2 (d,
JCeF¼20.9 Hz), 121.9, 129.4, 129.9 (d, JCeF¼7.9 Hz), 136.6 (d,
JCeF¼3.2 Hz), 1386, 153.4, 159.8, 161.4 (d, JCeF¼242.5 Hz), 162.7,
190.8. Low-resolution mass spectrum (EI): 229 (Mþ), 212, 200,
109. High-resolution mass spectrum, C14H12FON, calcd 229.09029,
found 229.09072.
The respective alkynyl-substituted heterocycles (i.e., 4) were
prepared using a published procedure.15 A solution is made up
containing the heterocyclic alkyne substrate (500 mg, 2.41 mmol),
20 mL EtOAc, and 0.4 g 5% Pd on carbon. The mixture is placed in

2140
R.R. Naredla, D.A. Klumpp / Tetrahedron 69 (2013) 2137e2141
4.7. 7-Fluoro-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]
pyridin-5-one (10)
144.9, 157.6, 157.8, 193.4. Low-resolution mass spectrum (EI): 289
(Mþ), 288, 274, 260, 246, 217, 108.
Isolated as a yellow oil (Rf 0.31, 3:2 hexanes/ethyl acetate). 1H
4.13. 5-Phenyl-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]
NMR (300 MHz, CDCl3)
d
3.19e3.23 (m, 2H), 3.43e3.46 (m, 2H), 7.16
pyridine (21)
(td, J¼7.9, 2.8 Hz,1H), 7.22e7.28 (m, 1H), 7.32 (dd, J¼8.0, 4.7 Hz,1H),
7.64 (dd, J¼9.6, 2.8 Hz, 1H), 8.40 (dd, J¼8.0, 1.8 Hz, 1H), 8.65 (dd,
Isolated as a brown crystal (Rf 0.43, 3:2 hexanes/ethyl acetate)
J¼4.7,1.8 Hz,1H); 13C NMR:
d
32.3, 38.4,116.9 (d, JCeF¼22.9hz),119.8
MP 107e109 ꢀC. 1H NMR (300 MHz, CDCl3)
d 2.70e2.77 (m, 1H),
(d, JCeF¼21.3 Hz), 122.0, 131.0 (d, JCeF¼7.2 Hz), 132.7, 137.5 (d,
JCeF¼3.2 Hz), 139.2, 139.6 (d, JCeF¼6.4 Hz), 152.4, 161.6 (d,
JCeF¼244.4 Hz), 161.6, 192.1. Low-resolution mass spectrum (EI):
227 (Mþ), 226, 199, 198, 170. High-resolution mass spectrum,
C14H10FON, calcd 227.07464, found 227.07547.
3.08 (dd, J¼23.2, 11.3 Hz, 2H), 3.33e3.40 (m, 1H), 5.22 (s, 1H),
6.89e6.92 (m, 2H), 7.14e7.32 (m, 7H), 7.38e7.41 (m, 1H) 7.61 (dd,
J¼7.6, 1.3 Hz, 1H) 8.53 (d, J¼3.8 Hz, 1H); 13C NMR:
d 30.4, 36.2, 56.9,
121.3, 126.1, 126.4, 127.2, 127.9, 128.3, 130.5, 130.9, 135.0, 139.7,
140.0, 140.5, 144.3, 148.0, 159.5. Low-resolution mass spectrum (EI):
271 (Mþ), 270, 256, 194, 193, 180. High-resolution mass spectrum,
C14H11ON, calcd 271.13610, found 271.13625.
4.8. 2-(4-Methylphenethyl)-3-pyridinecarboxaldehyde (11)
Isolated as a colorless oil (Rf 0.43, 3:2 hexanes/ethyl acetate). 1H
NMR (300 MHz, CDCl3) d 2.32 (s, 3H), 3.00e3.06 (m, 2H), 3.46e3.51
4.14. 5-(4-Bromophenyl)-10,11-dihydro-5H-benzo[4,5]cyclo-
hepta[1,2-b]pyridine (22)
(m, 2H), 7.09 (s, 3H), 7.33 (dd, J¼7.8, 4.8 Hz, 1H), 8.09 (dd, J¼7.8,
1.9 Hz,1H), 8.76 (dd, J¼4.9,1.9 Hz,1H),10.14 (s,1H); 13C NMR:
d
21.0,
Isolated as a pale yellow crystal (Rf 0.42, 3:2 hexanes/ethyl ac-
35.8, 37.0, 121.9, 128.4, 129.2, 129.4, 135.7, 137.7, 137.9, 153.5, 136.2,
190.7. Low-resolution mass spectrum (EI): 225 (Mþ), 197, 196, 181,
105. High-resolution mass spectrum, C15H15ON, calcd 225.11537,
found 225.11628.
etate). Mp 89e90 ꢀC. 1H NMR (300 MHz, CDCl3)
d 2.68e2.78 (m,
1H), 2.96e3.11 (m, 2H), 3.26e3.36 (m, 1H), 5.11 (s, 1H), 6.74 (d,
J¼8.1 Hz, 2H), 7.14e7.35 (m, 7H), 7.58 (d, J¼7.6 Hz, 1H), 8.50e8.52
(m, 1H); 13C NMR:
d 30.4, 36.2, 56.4, 120.2, 121.3, 126.5, 128.1, 128.9,
130.6, 130.8, 131.3, 134.4, 139.6, 139.9, 13.9, 143.4, 148.2, 159.4. Low-
resolution mass spectrum (EI): 351/349 (Mþ), 336/334, 270, 194,
193, 180, 127. High-resolution mass spectrum, C14H11ON, calcd
349.04660, found 349.04740.
4.9. 7-Methyl-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]
pyridin-5-one (12)
Isolated as a pale yellow oil (Rf 0.33, 3:2 hexanes/ethyl acetate).
1H NMR (300 MHz, CDCl3)
d
2.35 (s, 3H), 3.15e3.19 (m, 2H),
3.40e3.43 (m, 2H), 7.13 (d, J¼7.7 Hz, 1H), 8.61 (dd, J¼4.7, 1.8 Hz, 1H);
13C NMR:
20.8, 32.6, 38.5, 121.8, 129.1, 130.7, 133.3, 133.7, 136.5,
4.15. Ethyl 5-(10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]
pyridin-5-yl)-2-hydroxybenzoate (23)
d
138.0, 138.7, 138.9, 152.1, 161.6, 193.8. Low-resolution mass spec-
trum (EI): 223 (Mþ), 222, 208, 194, 180, 152. High-resolution mass
spectrum, C15H13ON, calcd 223.09972, found 223.09911.
Isolated as a pale yellow crystal (Rf 0.3, 3:2 hexanes/ethyl ace-
tate). Mp 131e132 ꢀC. 1H NMR (300 MHz, CDCl3)
d
1.28 (t, J¼7.1 Hz,
3H), 2.70e2.77 (m, 1H), 3.00e3.12 (m, 2H), 3.30e3.38 (m, 1H), 4.30
(q, J¼7.1 Hz, 2H), 5.11 (s, 1H), 6.84 (d, J¼8.7 Hz, 1H), 6.98 (ddd, J¼6.3,
1.8, 0.6 Hz, 1H), 7.15e7.37 (m, 6H), 7.59 (dd, J¼7.8, 1.6 Hz, 1H), 8.51
(dd, J¼4.8, 1.6 Hz, 1H), 7.15e7.37 (m, 6H), 7.59 (dd, J¼7.7, 1.6 Hz, 1H),
4.10. 3-Phenethyl-2-pyridinecarboxaldehyde (13)
Isolated as a pale yellow oil (Rf 0.41, 3:2 hexanes/ethyl acetate).
8.51 (dd, J¼4.8, 1.6 Hz, 1H), 10.72 (s, 1H); 13C NMR:
d 14.0, 30.4, 36.2,
Mp 46e47 ꢀC. 1H NMR (300 MHz, CDCl3)
d
2.87e2.93 (m, 2H),
56.0, 61.4, 112.1, 117.4, 121.3, 126.5, 128.0, 128.1, 130.5, 130.7, 134.2,
134.6, 135.1, 139.1, 139.9, 140.0, 148.0, 159.4, 160.0, 170.0. Low-
resolution mass spectrum (EI): 359 (Mþ), 256, 193, 180. High-
resolution mass spectrum, C23H21O3N, calcd 359.15215, found
359.15300.
3.33e3.38 (m, 2H), 7.18e7.23 (m, 3H), 7.27e7.31 (m, 1H), 7.35 (dd,
J¼7.8, 4.5 Hz, 1H), 7.51 (d, J¼7.8 Hz, 1H), 8.68 (dd, J¼4.8, 1.5 Hz, 1H),
10.21 (s, 1H). 13C NMR:
d 34.0, 37.0, 126.2, 126.7, 128.4, 128.6, 139.4,
139.5, 141.0, 147.9, 149.8, 195.2. Low-resolution mass spectrum (EI):
211 (Mþ), 194, 183, 182, 120, 91.
4.16. 7-Fluoro-5-phenyl-10,11-dihydro-5H-benzo[4,5]cyclohepta
[1,2-b]pyridine (24)
4.11. 6-Methoxy-2-phenethylquinoline-3-carboxaldehyde (15)
Isolated as a pale yellow crystal (Rf 0.32, 3:2 hexanes/ethyl ac-
Isolated as a yellow oil (Rf 0.31, 3:2 hexanes/ethyl acetate). 1H
NMR (300 MHz, CDCl3) d 3.19e3.23 (m, 2H), 3.43e3.46 (m, 2H), 7.16
etate). Mp 74e76 ꢀC. 1H NMR (300 MHz, CDCl3)
d
3.32e3.35 (m, 2H),
3.56e3.60 (m, 2H), 3.94 (s, 3H), 7.17 (d, J¼2.4 Hz, 1H), 7.29 (d,
(td, J¼7.9, 2.8 Hz,1H), 7.22e7.28 (m,1H), 7.32 (dd, J¼8.0, 4.7 Hz, 1H),
J¼8.4 Hz, 1H), 7.35e7.52 (m, 3H), 7.96 (d, J¼9 Hz, 1H), 8.10 (d,
7.64 (dd, J¼9.6, 2.8 Hz, 1H), 8.40 (dd, J¼8.0, 1.8 Hz, 1H), 8.65 (dd,
J¼7.8 Hz, 1H), 8.78 (s, 1H). 13C NMR:
d
33.5, 38.5, 55.6, 105.9, 125.1,
J¼4.7,1.8 Hz,1H); 13C NMR:
32.3, 38.4,116.9 (d, JCeF¼22.9hz),119.8
d
126.9, 127.6, 129.6, 129.6, 130.9, 135.4, 133.0, 137.5, 139.4, 142.4,
144.9, 157.6, 157.8, 193.4. Low-resolution mass spectrum (EI): 291
(Mþ), 263, 262, 247, 219, 91.
(d, JCeF¼21.3 Hz), 122.0, 131.0 (d, JCeF¼7.2 Hz), 132.7, 137.5 (d,
JCeF¼3.2 Hz), 139.2, 139.6 (d, JCeF¼6.4 Hz), 152.4, 161.6 (d,
JCeF¼244.4 Hz), 161.6, 192.1. Low-resolution mass spectrum (EI):
289 (Mþ), 288, 274, 212, 211, 198, 183. High-resolution mass spec-
trum, C20H15NF, calcd 288.11885, found 288.11937.
4.12. 6-Methoxy-6H-benzo[4,5]cyclohepta[1,2-b]quinolin-
12(7H)-one (16)
4.17. 5-(4-Bromophenyl)-7-fluoro-10,11-dihydro-5H-benzo[4,5]
cyclohepta[1,2-b]pyridine (25)
Isolated as a pale yellow crystal (Rf 0.32, 3:2 hexanes/ethyl ac-
etate). Mp 74e76 ꢀC. 1H NMR (300 MHz, CDCl3)
d 3.32e3.35 (m, 2H),
3.56e3.60 (m, 2H), 3.94 (s, 3H), 7.17 (d, J¼2.4 Hz, 1H), 7.29 (d,
Isolated as a yellow oil (Rf 0.41, 3:2 hexanes/ethyl acetate). 1H
J¼8.4 Hz, 1H), 7.35e7.52 (m, 3H), 7.96 (d, J¼9 Hz, 1H), 8.10 (d,
NMR (300 MHz, CDCl3)
d 2.64e2.74 (m, 1H), 2.90e3.08 (m, 2H),
J¼7.8 Hz, 1H), 8.78 (s, 1H); 13C NMR:
d
33.5, 38.5, 55.6, 105.9, 125.1,
3.26e3.33 (m, 1H), 5.04 (s, 1H), 6.73 (d, J¼8.3 Hz, 2H), 6.95 (td,
126.9, 127.6, 129.6, 129.6, 130.9, 135.4, 133.0, 137.5, 139.4, 142.4,
J¼8.3, 2.5 Hz, 1H), 7.06e7.19 (m, 3H), 7.33 (d, J¼8.4 Hz, 2H), 7.56 (d,

R.R. Naredla, D.A. Klumpp / Tetrahedron 69 (2013) 2137e2141
2141
J¼7.5 Hz, 1H), 8.52 (s, 1H); 13C NMR:
d
29.6, 36.1, 56.1, 114.5(d,
Low-resolution mass spectrum (EI): 225 (Mþ), 224, 210, 194, 193,
JCeF¼20.2 Hz), 117.4 (d, JCeF¼21.7 Hz),120.4, 121.5, 128.9, 131.4, 131.9
(d, JCeF¼8.2 Hz), 133.8, 135.5 (d, JCeF¼3.7 Hz), 139.7, 141.8 (d,
JCeF¼6.7 Hz), 142.7, 148.4, 159.2, 161.2 (d, JCeF¼243.7 Hz). Low-
resolution mass spectrum (EI): 369/367 (Mþ), 354/352, 288, 272,
212, 211, 198. High-resolution mass spectrum, C20H15BrFN, calcd
367.03718, found 367.03680.
180, 165, 152.
Acknowledgements
We gratefully acknowledge the support of the NIH-National
Institute of General Medical Sciences (GM085736-01A1).
4.18. 7-Methyl-5-phenyl-10,11-dihydro-5H-benzo[4,5]cyclo-
hepta[1,2-b]pyridine (26)
References and notes
1. (a) Carceller, E.; Merlos, M.; Giral, M.; Balsa, D.; Almansa, C.; Bartroli, J.; Garcia-
Rafanell, J.; Forn, J. J. Med. Chem. 1994, 37, 2697; (b) George Njoroge, F. G.;
Vibulbhan, B.; Pinto, P.; Bishop, W. R.; Bryant, M. S.; Nomeir, A. A.; Lin, C.-C.; Liu,
M.; Doll, R. J.; Girijavallabhan, V.; Ganguly, A. K. J. Med. Chem. 1998, 41, 1561; (c)
Mallams, A. K.; Njoroge, F. G.; Doll, R. J.; Snow, M. E.; Kaminiski, J. J.; Rossman, R.
R.; Vibulbhan, B.; Bishop, W. R.; Kirschmeier, P.; Liu, M.; Bryant, M. S.; Alvarez, C.
S.; Carr, D.; James, L.; King, I.; Li, Z.; Lin, C.-C.; Petrin, J.; Remiszewski, S. R.; Taveras,
A. ,G.; Wang, S.; Wong, J. K.; Catino, J.; Girijav-allabhan, V.; Ganguly, A. K. Bioorg.
Med. Chem. 1997, 5, 93; (d) Liu, W.; Zhou, J.; Zhang, T.; Zhang, H.; Zhu, H.; Cheng,
Y.; Gust, R. Bioorg. Med. Chem. Lett. 2012, 22, 6076; (e) Liu, W.; Zhou, J.; Zhang, T.;
Zhu, H.; Qian, H.; Zhang, H.; Huang, W.; Gust, R. Bioorg. Med. Chem. Lett. 2012, 22,
2701; (f) Oh, S. H.; Kang, J.-H.; Woo, J. K.; Lee, O.-H.; Kim, E. S.; Lee, H.-Y. Int. J.
Cancer 2012, 131, 537; (g) Wu, G. G.; Chen, F. X.; LaFrance, D.; Liu, Z.; Greene, S. G.;
Wong, Y.-S.; Xie, J. Org. Lett. 2011,13, 5220; (h) Wang, Y.; Wang, J.; Lin, Y.; Si-Ma, L.-
F.; Wang, D.-h.; Chen, L.-G.; Liu, D.-K. Bioorg. Med. Chem. Lett. 2011, 21, 4454 and
references cited therein; (i) Liu, G.-Z.; Xu, H.-W.; Chen, G.-W.; Wang, P.; Wang,
Y.-N.; Liu, H.-M.; Yu, D.-Q. Bioorg. Med. Chem. Lett. 2010, 18, 1626.
Isolated as a brown oil (Rf 0.44, 3:2 hexanes/ethyl acetate). 1H
NMR (300 MHz, CDCl3)
d 2.41 (s, 3H), 2.67e2.76 (m, 1H),
3.00e3.13 (m, 2H), 3.30e3.40 (m, 1H), 5.18 (s, 1H), 6.93 (d,
J¼6.9 Hz, 2H), 7.12e7.28 (m, 6H), 7.40 (s, 1H), 7.61 (d, J¼7.3 Hz,
1H), 8.52 (d, J¼3.4 Hz, 1H). 13C NMR:
d 21.0, 30.0, 36.3, 56.9,
121.2, 126.1, 127.2, 128.3, 128.4, 128.5, 130.5, 131.7, 135.1, 135.9,
136.9, 139.6, 140.2, 144.4, 147.9, 159.7. Low-resolution mass
spectrum (EI): 285 (Mþ), 270, 254, 208, 207, 194, 193. High-
resolution mass spectrum, C21H19N, calcd 285.15175, found
285.15260.
4.19. Ethyl 2-hydroxy-5-(7-methyl-10,11-dihydro-5H-benzo[4,5]
cyclohepta[1,2-b]pyridin-5-yl)benzoate (27)
2. Njoroge, F. G.; Taveras, A. G.; Kelly, J.; Remiszewski, S.; Mallams, A. K.; Wolin, R.;
Afonso, A.; Cooper, A. B.; Rane, D. F.; Liu, Y.-T.; Wong, J.; Vibulbhan, B.; Pinto, P.;
Deskus, J.; Alvarez, C. S.; Del Rosario, J.; Connolly, M.; Wang, J.; Desai, J.;
Rossman, R. R.; Bishop, W. R.; Patton, R.; Wang, L.; Kirschmeier, P.; Bryant, M. S.;
Nomeir, A. A.; Lin, C.-C.; Liu, M.; McPhail, A. T.; Doll, R. J.; Girijavallabhan, V. M.;
Ganguly, A. K. J. Med. Chem. 1998, 41, 4890.
Isolated as a pale yellow crystal (Rf 0.3, 3:2 hexanes/ethyl ac-
etate). Mp 121e122 ꢀC. 1H NMR (300 MHz, CDCl3)
d 1.29 (t,
J¼7.1 Hz, 3H), 2.37 (s, 3H), 2.66e2.76 (m, 1H), 2.96e3.09 (m 2H),
3.26e3.36 (m, 1H), 4.30 (q, J¼7.1 Hz, 2H), 5.05 (s, 1H), 6.84 (d,
J¼8.7 Hz, 1H), 6.98e7.02 (m, 1H), 7.09 (s, 2H), 7.13e7.17 (m, 2H),
7.29 (dd, J¼2.3, 1.1 Hz, 1H), 7.58 (dd, J¼7.7, 1.6 Hz, 1H), 8.50 (dd,
3. Katz, J. D.; Jewell, J. P.; Guerin, D. J.; Lim, J.; Dinsmore, C. J.; Deshmukh, S. V.; Pan,
B.-S.; Marshall, C. G.; Lu, W.; Altman, M. D.; Dahlberg, W. K.; Davis, L.; Falcone,
D.; Gabarda, A. E.; Hang, G.; Hatch, H.; Holmes, R.; Kunii, K.; Lumb, K. J.;
Lutterbach, B.; Mathvink, R.; Nazef, N.; Patel, S. B.; Qu, X.; Reilly, J. F.; Rickert, K.
W.; Rosenstein, C.; Soisson, S. M.; Spencer, K. B.; Szewczak, A. A.; Walker, D.;
Wang, W.; Young, J.; Zeng, Q. J. Med. Chem. 2011, 54, 4092.
4. (a) Karcher, S. C.; Laufer, S. A. J. Med. Chem. 2009, 52, 1779; (b) Iwasaki, N.;
Ohashi, T.; Musoh, K.; Nishino, H.; Kado, N.; Yasuda, S.; Kato, H.; Ito, Y. J. Med.
Chem. 1995, 38, 496.
5. Piwinski, J. J.; Wong, J. K.; Green, M. J.; Ganguly, A. K.; Billah, M. M.; West, R. E.;
Kreutner, W. J. Med. Chem. 1991, 34, 461.
6. Kaminski, J. J.; Carruthers, N. I.; Wong, S.-C.; Chan, T.-Z.; Billah, M. M.; Tozzi, S.;
McPhail, A. T. Bioorg. Med. Chem. 1999, 7, 1413.
J¼4.8, 1.7 Hz, 1H), 10.73 (s, 1H); 13C NMR:
d 14.0, 20.9, 30.0, 36.3,
56.0, 61.4, 112.1, 117.4, 121.2, 128.0, 128.5, 130.5, 131.5, 134.3, 134.8,
135.1, 136.0, 136.7, 139.4, 139.7, 148.0, 159.5, 160.0, 170.0. Low-
resolution mass spectrum (EI): 373 (Mþ), 328, 312, 207, 192, 163.
High-resolution mass spectrum, C24H23O3N, calcd 373.16780,
found 373.16863.
7. Schumacher, D. P.; Murphy, B. L.; Clark, J. E.; Tahbaz, P.; Mann, T. A. J. Org. Chem.
1989, 54, 2242.
4.20. 5-Methoxy-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]
pyridine (28)
8. (a) Poirier, M.; Chen, F.; Bernard, C.; Wong, Y.-S.; Wu, G. G. Org. Lett. 2001, 3,
3795; (b) Carson, M. W.; Giese, M. W.; Coghlan, M. J. Org. Lett. 2008, 10, 2701.
9. Park, J. H.; Bhilare, S. V.; Youn, S. W. Org. Lett. 2011, 13, 2228.
10. Olah, G. A.; Klumpp, D. A. Superelectrophiles and Their Chemistry; Wiley & Sons:
Isolated as a pale yellow oil (Rf 0.25, 3:2 hexanes/ethyl acetate).
New York, NY, 2008.
1H NMR (300 MHz, CDCl3)
d 3.05e3.14 (m, 1H), 3.24e3.34 (m, 1H),
11. Klumpp, D. A.; Zhang, Y.; Kindelin, P. J.; Lau, S. Tetrahedron 2006, 62, 5915.
12. Olah, G. A.; Prakash, G. K. S.; Molnar, A.; Sommer, J. M. Superacids, 2nd ed.;
Wiley and Sons: New York, NY, 2009.
13. Saito, S.; Saito, S.; Ohwada, T.; Shudo, K. Chem. Pharm. Bull. 1991, 39, 2718.
14. Olah, G. A.; Wu, A. H. Synlett 1990, 599.
3.40 (s, 3H), 3.49e3.63 (m, 2H), 5.29 (s, 1H), 7.11 (dd, J¼7.8, 4.8 Hz,
1H), 7.18e7.28 (m, 3H), 7.35 (d, J¼7.2 Hz, 1H), 7.74 (dd, J¼7.6, 1.2 Hz,
1H), 8.45 (d, J¼3.6 Hz, 1H); 13C NMR:
d 30.1, 36.2, 57.1, 84.6, 121.1,
126.2, 127.4, 128.5, 129.7, 134.2, 136.5, 138.3, 139.3, 148.3, 158.5.
15. Chandra, A.; Singh, B.; Upadhyay, S.; Singh, R. M. Tetrahedron 2008, 64, 11680.