Aryl grignard reagents in chemodivergent N-and C-arylations: Concise access to two families of tetracyclic fused carbazoles from 6-nitroquinolines

Article abstract of DOI:10.1002/ejoc.201101848

The reaction between aryl Grignard compounds and 5-methoxy-6-nitroquinoline derivatives in THF was found to proceed in a chemodivergent mode that depended on the functional groups present in the heterocyclic ring. Thus, the reactions that started from carbostyril derivatives afforded 6-(arylamino)carbostyrils as the major products, whereas those that started with 2-alkoxyquinolines gave exclusively 5-arylquinolines. Both types of products were transformed into tetracyclic fused linear or angular carbazole systems by using palladium-promoted oxidative coupling or Cadogan reactions, respectively. In the course of this work, an unprecedented oxidative demethylation by palladium acetate of 1,4-dimethoxybenzene systems to the corresponding quinones was discovered. The reaction between aryl Grignard compounds and 5-methoxy-6-nitroquinoline derivatives in THF proceeded in a chemodivergent mode that depended on the electron-withdrawing or electron-releasing nature of the functional groups present in the heterocyclic ring to give N-arylation or C ⁵-arylation products, respectively.

Full text of DOI:10.1002/ejoc.201101848

FULL PAPER
DOI: 10.1002/ejoc.201101848
Aryl Grignard Reagents in Chemodivergent N- and C-Arylations: Concise
Access to Two Families of Tetracyclic Fused Carbazoles from 6-Nitroquinolines
Juan Domingo Sánchez,[a] Riccardo Egris,[a] Subbu Perumal,[b] Mercedes Villacampa,[a] and
J. Carlos Menéndez*[a]
Keywords: Medicinal chemistry / Nitrogen heterocycles / C-C coupling / C-N coupling / Chemoselectivity / Fused-ring
systems
The reaction between aryl Grignard compounds and 5-
methoxy-6-nitroquinoline derivatives in THF was found to
proceed in a chemodivergent mode that depended on the
functional groups present in the heterocyclic ring. Thus, the
reactions that started from carbostyril derivatives afforded 6-
(arylamino)carbostyrils as the major products, whereas those
that started with 2-alkoxyquinolines gave exclusively 5-aryl-
quinolines. Both types of products were transformed into
tetracyclic fused linear or angular carbazole systems by using
palladium-promoted oxidative coupling or Cadogan reac-
tions, respectively. In the course of this work, an unprece-
dented oxidative demethylation by palladium acetate of 1,4-
dimethoxybenzene systems to the corresponding quinones
was discovered.
Introduction
The carbazole nucleus is widespread in nature[1] and is
also a key structural fragment in compounds with a broad
range of biological activities (Figure 1). Known in the anti-
cancer field, ellipticine forms covalent bonds with DNA,
following its oxidative metabolism to 13-hydroxyellipticine
and ellipticine N2-oxide.[2,3] 1,4-Carbazolequinones are also
of interest in this field, and the alkaloid murrayaquinone A
and a number of its synthetic analogues have shown prom-
ising cytotoxicities.[4] In addition, the alkaloid calo-
thrixin B, initially identified as an antimalarial, shows a
high (nanomolar) in-vitro cytotoxicity against HeLa cancer
cells that is explained by the fact that it is a potent poison
of human topoisomerase I[5] and generates reactive oxygen
species intracellularly.[6]
In connection with our work on antitumor activity in
compounds containing a 2,5,8-quinolinetrione moiety fused
to a variety of rings, most notably benzene and pyridine,[7]
we are interested in the preparation of new hybrid com-
pounds (i.e., 1 and 2) that combine carbazole and quinoline
substructures. Our plan for the preparation of 1 involves
the N-arylation of a suitable precursor followed by an intra-
molecular Pd-promoted cyclodehydrogenation reaction.
The N-arylation step would normally be carried out by the
Figure 1. Some representative bioactive carbazolequinone deriva-
tives.
treatment of an aromatic amine with a suitable electrophilic
arylation reagent,[8] but we reasoned that using a nitro de-
rivative[9] as a substrate for the nucleophilic arylation would
save one step, as this would be the most feasible precursor
to an aromatic amine. Because of the presence of a 1,4-
dimethoxybenzene fragment, compounds 1 should easily
transform into the corresponding quinones by an oxidative
demethylation reaction. Regarding compounds 2, they may
be accessed through a C-arylation ortho to an aromatic ni-
tro group that is followed by an intramolecular Cadogan
reaction (Scheme 1). Thus, our overall protocol is based on
the exploitation of chemodivergent modes of reaction be-
tween aryl Grignard compounds and substrates containing
a 5-methoxy-6-nitroquinoline unit, with the aim of estab-
lishing reaction conditions that allow the Grignard reagents
to produce either a N-arylation product by attack on the
nitro group or a C-arylation product by displacement of the
alkoxy group. Literature precedent on the synthetic applica-
[a] Departamento de Química Orgánica y Farmacéutica,
Facultad de Farmacia, Universidad Complutense,
28040 Madrid, Spain
Fax: +34-91-3941822
E-mail: josecm@farm.ucm.es
[b] Department of Organic Chemistry, School of Chemistry,
Madurai Kamaraj University,
Madurai 625021, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101848.
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tions of the reactions between arylmagnesium halides and negative charge on the oxygen atom. For the electrostatic
nitroarenes was scarce and includes Knochel’s pioneering potential surfaces of compounds 3 and 4, which clearly
studies on the preparation of diarylamines from nitroarenes show the same effects, see the Supporting Information.
and aryl Grignard reagents, in a reaction that starts with
the nucleophilic attack of the organometallic species on the
O=N bond of the nitro group.[10] Literature precedent for
the reaction of aryl Grignard compounds and o-alkoxyni-
troarenes favored the C-arylation product, as biaryls were
the sole products in the reaction between 1-methoxy-2-ni-
tronaphthalenes and aryl Grignard reagents.[11] However,
we expect that the combination of an increase in the electro-
philicity of the nitro group with an increase in steric hin-
Figure 2. Calculated electrostatic charges for selected atoms of
drance of the 5-methoxy group by introducing a substituent
at C-4 might achieve the N-arylation product. Thus, we
chose compound 3 for this purpose, as it contains an elec-
tron-withdrawing α,β-unsaturated carbonyl unit conjugated
to a nitro group at C-6 and a methyl group peri to the meth-
oxy leaving group at C-5. On the other hand, reversing
these effects should allow the reaction to follow its natural
course, leading to the C-arylation products. For this reason,
we decided to study the arylation of compound 4, which
contains an electron-releasing substituent conjugated to the
nitro group, namely the C2–OMe substituent. However, we
recognize that this compound is a challenging substrate for
our reaction, as the presence of a methoxy group at the
quinoline C-2 position could allow a third mode of aryl-
ation, leading to its displacement by the Grignard reagent.
In this case, we hope that the well-known preference of
quinolines through a reaction at C-5 would play in our
favor.
compounds 3 and 4.
Results and Discussion
The preparation of the starting material is summarized
in Scheme 2. Compound 3 was prepared by N-methylation
of 5 under phase-transfer catalysis conditions, using our
previously published procedure.[12] The synthesis of 4 was
achieved by O-methylation of 5 with methyl iodide in the
presence of silver oxide as the base.
Scheme 2. Preparation of starting materials. Reagents and condi-
tions: (i) CH3I, CHCl3, NBu4HSO4, solid KOH, room temp.,
24 h;[11] (ii) CH3I, benzene, Ag2O, room temp., 72 h.
Once compounds 3 and 4 were available, we studied the
reactions between 3 and the arylmagnesium bromides in
THF (tetrahydrofuran), and the results are summarized in
Scheme 3 and Table 1.[13] Contrary to the literature pre-
cedent but in agreement with our expectations, the main
reaction products were diarylamines 6, which can be ex-
plained by the steric inhibition of the resonance of the nitro
group in 3 (i.e., C-5). In agreement with this explanation,
the chemoselectivity in favor of the N-arylation product was
complete when an o-substituted Grignard reagent was em-
ployed (Table 1, Entry 2). The reaction did not show a clear
Scheme 1. Summary of our method for the preparation of tetracyc-
lic carbazole/quinoline hybrids 1 and 2 from a common precursor.
This proposal for the reactivity of compounds 3 and 4 influence from the electron density of the aromatic substitu-
was supported by ab initio computational studies carried ents of the Grignard reagents, as shown by comparing the
out at the B3LYP/6-31G* level, which show that C-5 is reactions leading to compounds bearing alkyl, alkoxy, and
more electrophilic in compound 4 than in 3 according to halogen substituents (Table 1, Entries 4, 6–8). According to
the calculated electrostatic charges shown in Figure 2. Bear- the literature,[11b] the reaction between 1-methoxy-2-nitron-
ing in mind that the reaction on the nitro group starts by aphthalene and 1-naphthylmagnesium bromide exclusively
an attack of the Grignard compound on the O=N bond, gave the 1,1Ј-binaphthyl product, therefore, we studied the
this reaction should be easier in compound 3 which has less equivalent reaction for our substrate. In our case, we found
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Aryl Grignard Reagents in Chemodivergent N- and C-Arylations
Scheme 3. Reaction between carbostyril derivative 3 and aryl Grignard reagents. Independent confirmation of the structure of compounds
6.
that the reaction completely deviated towards N-arylation nard reagent in the initial reaction led to an unstable hy-
and gave 6i as the only product. On the other hand, the less droxylamine derivative that required an additional step for
hindered 2-naphthylmagnesium bromide gave a mixture of its in situ reduction.[10] The direct isolation of the di-
compounds 6j and 7j. It is pertinent to mention that the arylamines under our conditions may be a consequence of
reaction between compound 4 and the less hindered vinyl- our use of a large excess amount of the arylmagnesium
magnesium bromides exclusively afforded 5-vinylindoles.[12] compound, which would transform the intermediate hy-
The diarylamine structure of compounds 6 was deduced droxylamine species into the observed diarylamine accord-
from spectroscopic data and confirmed by the independent ing to the mechanism shown in Scheme 4.[17] In all cases,
synthesis of compound 6d. Thus, reduction of the nitro the biaryls formed as side products in this mechanism were
group in 3 with stannous chloride in hydrochloric acid af- detected in the crude reaction products.
forded amine 8 which then underwent a N-arylation to give
compound 6d by a ligand-coupling reaction[14] which in-
volved treatment with p-tolyllead triacetate[15] in the pres-
ence of copper acetate under Barton conditions.[16]
Table 1. Yields of compounds 6 and 7 from the reaction between
compound 3 and phenylmagnesium bromides.
Entry Compound
R2
R3
R4
% 6[a]
% 7[a]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
H
Me
H
H
H
H
H
H
H
H
Me
H
OMe
H
H
H
H
H
Me
H
OMe
Cl
44
65
43
41
36
38
36
42
18
0
2
13
19
33
31
29
Scheme 4. Proposed mechanism for the N-arylation of nitro deriva-
tives 3.
Next, we examined the reactions between 2-methoxy-
quinoline derivative 4 and the aryl Grignard reagents, with
the results summarized in Scheme 5 and Table 2. The reac-
tions in THF were completely chemo- and regioselective
and afforded 5-arylquinolines 9 as the only products, with
no observed traces of N- or C2-arylation products. Interest-
g
h
H
F
[a] Isolated yields.
The isolation of compounds 6 is of interest, because it ingly, when the reaction with p-chlorophenylmagnesium
constitutes one of a few examples of using aryl Grignard bromide was carried out in a diethyl ether/THF mixture,
reagents for the preparation of diarylamines by 1,2-nucleo- both C5- and N-arylation reactions took place, affording a
philic attack on a nitro group. Although this type of aryl- mixture of the expected compound 9g and the C-arylation
ation is described in the literature, using 2.5 equiv. of Grig- product 10, which was identified by NMR spectroscopic
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J. C. Menéndez et al.
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data but could not be purified. This solvent-associated dif- oxidative demethylation, as shown in the case of 11h. When
ference in behavior can be attributed to the known differ- compound 6b was employed as the starting material, the
ences in the composition of solutions for Grignard com- major product was compound 12 (Scheme 7). The forma-
pounds in diethyl ether and THF and is associated with the tion of 12 is of interest, as it constitutes an example of the
Schlenk equilibrium. Thus, in diethyl ether the Grignard functionalization of an unactivated C–H bond through an
reagent exists primarily as the RMgX species, but THF oxidative palladium-catalyzed reaction.[20] Finally, the
solutions contain RMgX in addition to R2Mg and naphthyl derivatives 6i and 6j could not be cyclized in the
MgX2.[18]
presence of palladium acetate.
Table 3. Yields of tetracyclic fused carbazoles 1 and 11.
Entry Compound
R3
R4
% 1[a]
% 11[a]
1
2
3
4
5
6
7
a
c
d
e
f
g
h
H
Me
H
OMe
H
H
H
H
H
Me
H
OMe
Cl
F
25
0
0
0
0
33
32
59
25[b]
45[c]
48
69
29
47
[a] Isolated yields after chromatography. [b] 52% based on reco-
vered starting material. [c] 91% based on recovered starting mate-
rial.
The observed Pd-promoted in situ oxidative demethyl-
ations were unprecedented, albeit not general, as shown by
simple dialkoxyarylamines lacking the carbostyril moiety
not forming quinones under the same conditions. Palla-
dium acetate was recently found to act as a N-demethyl-
ation agent, but to leave phenolic O-methyl groups un-
changed.[21] On the other hand, the treatment of compound
6c with palladium acetate in refluxing acetic acid for 17 h
led to recovered starting material, therefore, the explanation
of an initial acid-catalyzed demethylation reaction leading
to the hydroquinone followed by air oxidation can be dis-
carded. We propose that the reaction starts by palladation
of the carbostyril carbonyl oxygen, which is aided by conju-
gation with one of the methoxy substituents. Nucleophilic
attack by the liberated acetate anion would explain the first
Scheme 5. C5-arylation of compounds 4 with phenylmagnesium
bromides.
Table 2. Results obtained in the synthesis of compounds 9.
Entry
Compound
R4
% 9[a]
1
2
3
4
5
9a
9d
9f
9g
9h
H
Me
OMe
Cl
57
60
88
62
60
F
[a] Isolated yields after chromatography.
With compounds 6, 7, and 9 in hand, we undertook their demethylation, and a similar mechanism would then take
cyclization to afford the fused carbazoles. First, we exam- place at the other methoxy group along with elimination of
ined the palladium-catalyzed oxidative cyclization of com- Pd0 to lead to the observed products (Scheme 8).
pounds 6.[19] The treatment of 6 with palladium acetate in
The angularly fused carbazoles (i.e., compounds 2) were
refluxing acetic acid afforded the expected fused dimeth- obtained by the Cadogan reaction, which involves re-
oxycarbazoles 1, but unexpectedly in most cases, the major duction of the nitro group with triethyl phosphite to give a
products were quinones 11, which were obtained directly nitrene that then adds to the adjacent aromatic ring in an
without an independent oxidative demethylation step intramolecular fashion (Scheme 9). The Cadogan reaction
(Scheme 6 and Table 3). Furthermore, isolated compounds was carried out by heating at reflux or under microwave-
1 could be transformed into the corresponding quinones 11 assisted conditions[22] in a focused microwave oven and pro-
using the well-known cerium ammonium nitrate-promoted ceeded uneventfully, leading to the desired compounds 2a
Scheme 6. Domino Pd-promoted oxidative cyclization–oxidative demethylation process.
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Aryl Grignard Reagents in Chemodivergent N- and C-Arylations
Scheme 7. Results of the reaction between compound 6b and palladium acetate.
characterized independently. However, the reaction starting
from compound 7j showed full regioselectivity and gave 2aj
as the only product, undoubtedly because of the preference
for reactions at α-positions of naphthalene derivatives.
Table 4. Yields of compounds 2.
Entry Compound
R3
R4
Method[a]
% Yield[b]
1
2
3
4
5
6
7
8
2aa
2ad
2ad
2af
2af
2ag
2ah
2ah
2ba
2bd
2bf
2bg
2bh
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
OMe
OMe
Cl
F
F
H
A
A
B
A
B
A
A
B
B
B
B
B
B
55
53
50
51
56
30
39
56
45
55
87
46
46
9
10
11
12
13
Me
OMe
Cl
Scheme 8. Mechanistic rationalization of the palladium acetate-
promoted oxidative demethylation.
F
[a] Method A: reflux, 160 °C, 3 h; Method B: focused microwave,
300 W, 180 °C, 25 min. [b] Isolated yields after chromatography or
crystallization.
and 2b in yields in the 40–55% range as shown in Table 4.
For some cases (Table 4, Entries 2–5), we compared the mi-
crowave-assisted method with the more traditional reflux
conditions and found that the microwave conditions gave
similar or better yields, proceeding in shorter reaction times
and affording the final products in higher purity. When the
reaction was carried out from compound 7e, bearing an R3
substituent, it afforded an approximate 1:1 mixture of the
regioisomeric carbazoles which could not be separated and
Conclusions
We have shown that the reaction of arylmagnesium
bromides with 5-methoxy-6-nitroquinolines provides
chemodivergent access to 6-arylamino- or 5-arylquinolines,
depending on the presence of electron-withdrawing or elec-
tron-releasing substituents, respectively, on the heterocyclic
ring. These synthetic intermediates allow an efficient entry
into tetracyclic fused linear or angular carbazole systems,
using palladium-promoted oxidative coupling or Cadogan
reactions, respectively. Some unexpected modes of reactivity
were uncovered in the course of this work, including an
unprecedented oxidative demethylation by palladium acet-
ate of 1,4-dimethoxybenzene systems to the corresponding
quinones and a palladium-catalyzed oxidative functionali-
zation of an unactivated C–H bond.
Scheme 9. Synthesis of compounds 2a and 2b by the Cadogan reac-
tion of 7 and 9, respectively.
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H, OCH3), 3.99 (s, 3 H, OCH3), 6.14 (br. s, 1 H, NH), 6.23 (s, 1
H, 3-H), 6.92 (d, J = 7.6 Hz, 4Ј-H), 7.03–7.06 (m, 2 H, 7-H, 5Ј-H),
7.28–7.39 (m, 2 H, 2Ј-H, 6Ј-H) ppm. 13C NMR (63 MHz, CDCl3,
25 °C): δ = 22.0 (CH3-3Ј), 23.7 (CH3-4), 36.4 (NCH3), 57.5
(OCH3), 62.0 (OCH3), 106.8 (C-7), 114.7 (C-6Ј), 118.5 (C-4Ј), 118.8
(C-4a), 122.4 (C-2Ј), 123.8 (C-3), 127.6 (C-8a), 129.8 (C-5Ј), 131,8
(C-6), 139.9 (C-3Ј), 141.8 (C-5), 143.5 (C-1Ј), 145.9 (C-8), 146.1 (C-
4), 163.3 (C-2) ppm. C20H22N2O3 (338): calcd. C 70.99, H 6.55, N
8.28; found C 70.75, H 6.50, N 8.13.
Experimental Section
General Methods: All reagents (Aldrich, Fluka, SDS, Probus) and
solvents (SDS) were of commercial quality and were used as re-
ceived. Reactions were monitored by thin layer chromatography on
aluminium plates coated with silica gel and fluorescent indicator
(SDS CCM221254). Separations by flash chromatography were
performed on silica gel (SDS 60 ACC 40–63 μm). Melting points
were measured with a Reichert 723 hot-stage microscope. Reactions
under microwave irradiation were carried out in a CEM Discover
focused microwave reactor. Infrared spectra were recorded with a
Perkin–Elmer Paragon 1000 FTIR spectrophotometer as thin films
on NaCl disks or as KBr pellets. NMR spectroscopic data were
recorded with Bruker Avance 250 spectrometers operating at 250
5,8-Dimethoxy-1,4-dimethyl-6-(p-tolylamino)quinolin-2(1H)-one
(6d): Pale brown oil (498 mg, 41%). IR (KBr): ν = 3365, 2922,
˜
1
1646, 1599 cm–1. H NMR (250 MHz, CDCl3, 25 °C): δ = 2.26 (s,
3 H, 4Ј-CH3), 2.61 (d, J = 0.9 Hz, 3 H, 4-CH3), 3.67 (s, 3 H,
NCH3), 3.75 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 5.98 (br. s, 1 H,
NH), 6.50 (d, J = 0.9 Hz, 1 H, 3-H), 7.01 (d, J = 8.3 Hz, 2 H, 3Ј-
H, 5Ј-H), 7.06 (s, 1 H, 7-H), 7.12 (d, J = 8.3 Hz, 2Ј-H, 6Ј-H) ppm.
13C NMR (63 MHz, CDCl3, 25 °C): δ = 21.1 (CH3-4Ј), 23.7 (CH3-
4), 36.4 (NCH3), 57.5 (OCH3), 61.9 (OCH3), 105.9 (C-7), 118.6 (C-
2Ј, C-6Ј), 118.7 (C-4a), 123.8 (C-3), 127.2 (C-8a), 130.5 (C-3Ј, C-
5Ј), 131.3 (C-6), 132.6 (C-4Ј), 140.7 (C-5), 141.2 (C-1Ј), 145.9 (C-
4, C-8), 163.2 (C-2) ppm. C20H22N2O3 (338): calcd. C 70.99, H
6.55, N 8.28; found C 70.75, H 6.50, N 8.30.
1
and 500 MHz for H NMR and 63 and 125 MHz for 13C NMR,
respectively (CAI de Resonancia Magnética Nuclear, Universidad
Complutense). Elemental analyses were determined by the CAI de
Microanálisis Elemental, Universidad Complutense, using a Leco
932 combustion microanalyzer.
General Procedure for the Reaction of Compound 3 with Arylmagne-
sium Bromides (Compounds 6 and 7): To a solution of 1,4-dimethyl-
5,8-dimethoxy-6-nitroquinolin-2(1H)-one (3, 1 g, 3.59 mmol) in dry
THF (50 mL) was added the suitable arylmagnesium bromide
(commercially available solution in THF, 3 equiv.). The naphthyl
Grignard reagents were prepared from the corresponding bromide
and magnesium. The reaction mixture was stirred at –10 °C for
1 h and then poured into a saturated aqueous solution of NH4Cl
(15 mL). The resulting mixture was extracted with EtOAc
(3ϫ20 mL). The combined organic layers were washed with brine
(2ϫ15 mL), dried with Na2SO4, and concentrated. The residue was
purified by flash chromatography on silica gel (petroleum ether/
ethyl acetate, 2:1).
5,8-Dimethoxy-6-(3-methoxyphenylamino)-1,4-dimethylquinolin-
2(1H)-one (6e): Pale brown oil (458 mg, 36%). IR (KBr): ν = 3433,
˜
1
1645, 1607 cm–1. H NMR (250 MHz, CDCl3, 25 °C): δ = 2.55 (s,
3 H, 4-CH3), 3.62 (s, 3 H, NCH3), 3.73 (s, 3 H, OCH3), 3.74 (s, 3
H, OCH3), 3.77 (s, 3 H, OCH3), 6.16 (br. s, 1 H, NH), 6.44 (d, J
= 0.9 Hz, 1 H, 3-H), 6.45–6.47 (m, 1 H, 2Ј-H), 6.60–6.71 (m, 2 H,
4Ј-H, 5Ј-H), 7.11–7.19 (m, 2 H, 7-H, 6Ј-H) ppm. 13C NMR
(63 MHz, CDCl3, 25 °C): δ = 23.7 (CH3-4), 36.4 (NCH3), 55.6
(OCH3-3Ј), 57.4 (OCH3), 62.0 (OCH3), 103.1 (C-2Ј), 106.3 (C-7),
107.5 (C-6Ј), 109.9 (C-4Ј), 118.7 (C-4a), 123.7 (C-3), 127.9 (C-8a),
130.7 (C-5Ј), 131.4 (C-6), 142.3 (C-5), 145.1 (C-1Ј), 145.8 (C-8),
146.1 (C-4), 161.2 (C-3Ј), 163.2 (C-2) ppm. C20H22N2O4 (354):
calcd. C 67.78, H 6.26, N 7.90; found C 67.58, H 6.33, N 7.92.
5,8-Dimethoxy-1,4-dimethyl-6-(phenylamino)quinolin-2(1H)-one
(6a): Yellow solid (510 mg, 44%), m.p. 85–86 °C. IR (KBr): ν =
˜
3387, 2921, 1648, 1601 cm–1. H NMR (250 MHz, CDCl3, 25 °C):
1
δ = 2.62 (s, 3 H, 4-CH3), 3.68 (s, 3 H, NCH3), 3.78 (s, 3 H, OCH3),
3.83 (s, 3 H, OCH3), 6.00 (br. s, 1 H, NH), 6.52 (s, 1 H, 3-H), 6.97
(t, J = 7.4 Hz, 1 H, 4Ј-H), 7.07–7.12 (m, 3 H, 7-H, 2Ј-H, 6Ј-H),
7.34–7.27 (m, 2 H, 5Ј-H, 3Ј-H) ppm. 13C NMR (63 MHz, CDCl3,
25 °C): δ = 23.7 (CH3-4), 36.4 (NCH3), 57.5 (OCH3), 62.1 (OCH3),
106.7 (C-7), 117.7 (C-2Ј, C-6Ј), 118.8 (C-4a), 121.5 (C-4Ј), 123.9
(C-3), 127.8 (C-8a), 130.0 (C-3Ј, C-5Ј), 131.7 (C-6), 141.8 (C-5),
143.5 (C-8), 145.9, 146.0 (C-4, C-1Ј) 163.2 (C-2) ppm. C19H20N2O3
(324): calcd. C 70.35, H 6.21, N 8.64; found C 70.12, H 6.11, N
8.59.
5,8-Dimethoxy-6-(4-methoxyphenylamino)-1,4-dimethylquinolin-
2(1H)-one (6f): Yellow oil (483 mg, 38 %). IR (KBr): ν = 3139,
˜
2923, 1646, 1599 cm–1. 1H NMR (250 MHz, CDCl3, 25 °C): δ =
2.61 (d, J = 0.6 Hz, 3 H, 4-CH3), 3.69 (s, 3 H, NCH3), 3.72 (s, 3
H, OCH3), 3.79 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 5.87 (br. s, 1
H, NH), 6.77 (s, 1 H, 3-H), 6.89 (d, J = 8.9 Hz, 2 H, 3Ј-H, 5Ј-H,
partially overlapped with 7-H signal), 6.91 (s, 1 H, 7-H), 7.08 (d, J
= 8.9 Hz, 2 H, 2Ј-H, 6Ј-H) ppm. 13C NMR (63 MHz, CDCl3,
25 °C): δ = 23.6 (CH3-4), 36.4 (NCH3), 56.0 (OCH3-4Ј), 57.5
(OCH3), 61.9 (OCH3), 104.6 (C-7), 115.3 (C-3Ј, C-5Ј), 118.8 (C-
4a), 122.1 (C-2Ј, C-6Ј), 123.9 (C-3), 126.5 (C-8a), 134.0 (C-6), 135.9
(C-1Ј), 140.0 (C-5), 145.9 (C-8), 146.1 (C-4), 155.7 (C-4Ј), 163.1 (C-
2) ppm. C20H22N2O4 (354): calcd. C 67.78, H 6.26, N 7.90; found
C 67.63, H 6.17, N 7.83.
5,8-Dimethoxy-1,4-dimethyl-6-(o-tolylamino)quinolin-2(1H)-one
(6b): Pale brown oil (790 mg, 65%). IR (KBr): ν = 3392, 2936,
˜
1
1651, 1599 cm–1. H NMR (250 MHz, CDCl3, 25 °C): δ = 2.32 (s,
3 H, 2Ј-CH3), 2.64 (d, J = 0.8 Hz, 3 H, 4-CH3), 3.70 (s, 3 H,
NCH3), 3.75 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 5.72 (br. s, 1 H,
NH), 6.53 (d, J = 0.8 Hz, 1 H, 3-H), 6.93 (s, 1 H, 7-H), 6.94–6.99
(m, 1 H, 6Ј-H), 7.18–7.24 (m, 3 H, 3Ј-H, 4Ј-H, 5Ј-H) ppm. 13C
NMR (63 MHz, CDCl3, 25 °C): δ = 18.3 (CH3-2Ј), 23.7 (CH3-4),
36.4 (NCH3), 57.6 (OCH3), 61.9 (OCH3), 106.5 (C-7), 117.8 (C-6Ј),
118.7 (C-4a), 122.3 (C-4Ј), 124.0 (C-3), 127.4 (C-5Ј), 127.5 (C-8a),
128.4 (C-2Ј), 131.5 (C-3Ј), 132.4 (C-6), 141.3 (C-1Ј), 141.5 (C-5),
145.8 (C-8), 146.0 (C-4), 163.2 (C-2) ppm. C20H22N2O3 (338):
calcd. C 70.99, H 6.55, N 8.28; found C 71.05, H 6.60, N 8.18.
6-(4-Chlorophenylamino)-5,8-dimethoxy-1,4-dimethylquinolin-
2(1H)-one (6g): Yellow solid (463 mg, 36%), m.p. 110–112 °C. IR
(KBr): ν = 3433, 2926, 1655, 1601 cm–1 1H NMR (250 MHz,
.
˜
CDCl3, 25 °C): δ = 2.62 (d, J = 0.9 Hz, 3 H, 4-CH3), 3.67 (s, 3 H,
NCH3), 3.79 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 5.93, (br. s, 1
H, NH), 6.53 (d, J = 0.9 Hz, 1 H, 3-H), 7.01 (d, J = 8.8 Hz, 2 H,
3Ј-H, 5Ј-H), 7.04 (s, 1 H, 7-H), 7.26 (d, J = 8.8 Hz, 2 H, 2Ј-H, 6Ј-
H) ppm. 13C NMR (63 MHz, CDCl3, 25 °C): δ = 23.7 (CH3-4),
36.4 (NCH3), 57.5 (OCH3), 62.1 (OCH3), 106.7 (C-7), 118.7 (C-2Ј,
C-6Ј), 118.8 (C-4a), 123.6 (C-4Ј), 124.1 (C-3), 126.1 (C-8a), 129.9
5,8-Dimethoxy-1,4-dimethyl-6-(m-tolylamino)quinolin-2(1H)-one
(6c): Pale brown oil (521 mg, 43%). IR (KBr): ν = 3413, 2935, (C-3Ј, C-5Ј), 131.1 (C-6), 142.1, 142.2 (C-5, C-1Ј), 145.8 (C-8),
˜
1
1645, 1601 cm–1. H NMR (250 MHz, CDCl3, 25 °C): δ = 2.47 (s,
146.0 (C-4), 163.2 (C-2) ppm. C19H19ClN2O3 (358.5): calcd. C
3 H, 3Ј-CH3), 2.74 (s, 3 H, 4-CH3), 3.81 (s, 3 H, NCH3), 3.91 (s, 3 63.60, H 5.34, N 7.81; found C 63.51, H 5.25, N 7.72.
2380
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2375–2385

Aryl Grignard Reagents in Chemodivergent N- and C-Arylations
6-(4-Fluorophenylamino)-5,8-dimethoxy-1,4-dimethylquinolin- 8), 163.0 (C-2) ppm. C19H18N2O4 (338): calcd. C 67.44, H 5.36, N
2(1H)-one (6h): Pale brown solid (515 mg, 42%), m.p. 110–112 °C.
8.28; found C 67.52, H 5.41, N 8.30.
1
IR (KBr): ν = 3317, 2935, 1654, 1600 cm–1. H NMR (250 MHz,
˜
8-Methoxy-1,4-dimethyl-6-nitro-5-(p-tolyl)quinolin-2(1H)-one (7d):
CDCl3, 25 °C): δ = 2.59 (s, 3 H, 4-CH3), 3.66 (s, 3 H, NCH3), 3.74
(s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 6.01 (br. s, 1 H, NH), 6.48 (s
1 H, 3-H), 6.95 (s, 1 H, 7-H), 6.99–7.08 (m, 4 H, 2Ј-H, 3Ј-H, 5Ј-H,
6Ј-H) ppm. 13C NMR (63 MHz, CDCl3, 25 °C): δ = 23.6 (CH3-4),
36.4 (NCH3), 57.5 (OCH3), 61.9 (OCH3), 105.8 (C-7), 116.5 (d, J
= 22.6 Hz, C-3Ј, C-5Ј), 118.8 (C-4a), 120.3 (d, J = 7.7 Hz, C-2Ј, C-
6Ј), 123.9 (C-3), 127.4 (C-8a), 132.5 (C-6), 139.5 (d, J = 2.4 Hz, C-
1Ј), 141.3 (C-5), 145.8 (C-8), 146.0 (C-4), 158.4 (d, J = 240 Hz, C-
4Ј), 163.1 (C-2) ppm. C19H19FN2O3 (342): calcd. C 66.66, H 5.59,
N 8.18; found C 66.46, H 5.61, N 8.21.
Pale brown solid (158 mg, 13%), m.p. 181–183 °C. IR (KBr): ν =
˜
3141, 1665, 1607, 1567, 1522 cm–1. 1H NMR (250 MHz, CDCl3,
25 °C): δ = 1.63 (d, J = 0.9 Hz, 3 H, 4-CH3), 2.41 (s, 3 H, 4Ј-CH3),
3.85 (s, 3 H, NCH3), 3.99 (s, 3 H, OCH3), 6.52 (d, J = 0.9 Hz, 1
H, 3-H), 7.12–7.21 (m, 4 H, 2Ј-H, 3Ј-H, 5Ј-H, 6Ј-H), 7.36 (s, 1 H,
7-H) ppm. 13C NMR (63 MHz, CDCl3, 25 °C): δ = 21.8 (CH3-4Ј),
24.9 (CH3-4), 37.3 (NCH3), 57.0 (OCH3), 106.8 (C-7), 123.2 (C-5),
125.6 (C-3), 126.9 (C-4a), 129.3 (C-2Ј, C-6Ј), 130.5 (C-3Ј, C-5Ј),
133.1 (C-4Ј), 136.2 (C-8a), 139.2 (C-1Ј), 146.4 (C-6), 148.2 (C-4),
148.4 (C-8), 163.0 (C-2) ppm. C19H18N2O4 (338): calcd. C 67.44,
H 5.36, N 8.28; found C 67.40, H 5.31, N 8.19.
5,8-Dimethoxy-1,4-dimethyl-6-(naphthalen-1-ylamino)quinolin-
2(1H)-one (6i): Yellow oil (685 mg, 51%). IR (KBr): ν = 3321, 2932,
˜
8-Methoxy-5-(3-methoxyphenyl)-1,4-dimethyl-6-nitroquinolin-
1646, 1603, 1576, 1513, 1482 cm–1. 1H NMR (250 MHz, CDCl3,
25 °C): δ = 2.67 (s, 3 H, 4-CH3), 3.67 (s, 3 H, NCH3), 3.75 (s, 3 H,
OCH3), 3.84 (s, 3 H, OCH3), 6.34 (br. s, 1 H, NH), 6.55 (br. s, 1
H, 3-H), 6.93 (s, 1 H, 7-H), 7.26–7.40 (m, 1 H, 2Ј-H), 7.43–7.61
(m, 4 H, 3Ј-H, 4Ј-H, 6Ј-H, 7Ј-H), 7.89–7.93 (m, 1 H, 5Ј-H), 8.07–
8.11 (m, 1 H, 8Ј-H) ppm. 13C NMR (63 MHz, CDCl3, 25 °C): δ =
23.7 (CH3-4), 36.4 (NCH3), 57.4 (OCH3), 62.3 (OCH3), 106.7 (C-
7), 114.5 (C-2Ј), 121.9 (C-4Ј, C-8Ј), 123.1 (C-4a), 124.0 (C-3), 126.3
(C-7Ј), 126.5 (C-4Јa, C-6Ј), 126.8 (C-3Ј), 127.7 (C-8a), 129.1 (C-5Ј),
133.1 (C-6), 135.1 (C-8Јa), 139.3 (C-1Ј), 141.4 (C-5), 145.9 (C-8),
146.1 (C-4), 163.3 (C-2) ppm. C23H22N2O3 (374): calcd. C 73.78,
H 5.92, N 7.48; found C 73.81, H 6.02, N 7.43.
2(1H)-one (7e): Pale brown solid (241 mg, 19%), m.p. 160–161 °C.
1
IR (KBr): ν = 3057, 2941, 1659, 1607, 1570, 1524, 1048 cm–1. H
˜
NMR (250 MHz, CDCl3, 25 °C): δ = 1.69 (s, 3 H, 4-CH3), 3.79 (s,
3 H, NCH3), 3.84 (s, 3 H, 3Ј-OCH3), 3.99 (s, 3 H, 8-OCH3), 6.52
(s, 1 H, 3-H), 6.77–6.79 (m, 1 H, 2Ј-H), 6.86–6.83 and 6.93–6.97
(2m, 2 H, 4Ј-H, 6Ј-H), 7.29 (dd, J = 8.1 and 7.7 Hz, 1 H, 5Ј-H),
7.37 (s, 1 H, 7-H) ppm. 13C NMR (63 MHz, CDCl3, 25 °C): δ =
24.6 (CH3-4), 37.3 (NCH3), 55.7 (OCH3-3Ј), 57.0 (OCH3-8Ј), 106.8
(C-7), 114.5 (C-4Ј), 116.6 (C-2Ј), 122.9 (C-5), 123.3 (C-6Ј), 125.7
(C-3), 126.8 (C-4a), 129.6 (C-5Ј), 136.2 (C-8a), 137.3 (C-1Ј), 146.3
(C-6), 148.1 (C-4), 148.5 (C-8), 159.6 (C-3Ј), 162.9 (C-2) ppm.
C19H18N2O5 (354): calcd. C 64.40, H 5.12, N 7.91; found C 64.36,
H 5.18, N 7.86.
5,8-Dimethoxy-1,4-dimethyl-6-(naphthalen-2-ylamino)quinolin-
2(1H)-one (6j): Pale brown solid (268 mg, 20%), m.p. 174–176 °C.
8-Methoxy-5-(4-methoxyphenyl)-1,4-dimethyl-6-nitroquinolin-
1
IR (KBr): ν = 3326, 2932, 1648, 1603 cm–1. H NMR (250 MHz,
˜
2(1H)-one (7f): Pale brown oil (420 mg, 33%). IR (KBr): ν = 3139,
˜
1
1646, 1599, 1513, 1494 cm–1. H NMR (250 MHz, CDCl3, 25 °C):
CDCl3, 25 °C): δ = 2.64 (d, J = 1.0 Hz, 3 H, 4-CH3), 3.71 (s, 3 H,
NCH3), 3.79 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 6.18 (br. s, 1 H,
NH), 6.54 (d, J = 1.0 Hz, 1 H, 3-H), 7.22 (s, 1 H, 7-H), 7.25–7.36
and 7.40–7.47 (2m, 4 H, Ar), 7.67 (d, J = 8.0 Hz, 1 H, 4Ј-H), 7.76–
7.82 (m, 2 H, Ar) ppm. 13C NMR (63 MHz, CDCl3, 25 °C): δ =
23.7 (CH3-4), 36.5 (NCH3), 57.5 (OCH3), 62.2 (OCH3), 107.3 (C-
7), 111.3 (C-1Ј), 118.8 (C-4a), 120.1 (C-3Ј), 124.0 (C-3), 124.1 (C-
6Ј), 126.8 (C-8Ј), 127.1 (C-7Ј), 128.1 (C-5Ј), 128.2 (C-8a), 129.6 (C-
4Јa), 129.9 (C-4Ј), 131.5 (C-6), 135.0 (C-8Јa), 141.4 (C-5), 142.4 (C-
2Ј), 145.9 (C-8), 146.0 (C-4), 163.2 (C-2) ppm. C23H22N2O3 (374):
calcd. C 73.78, H 5.92, N 7.48; found C 73.66, H 5.90, N 7.41.
δ = 1.64 (d, J = 0.9 Hz, 3 H, 4-CH3), 3.84 (s, 3 H, NCH3), 3.85 (s,
3 H, 4Ј-OCH3), 3.98 (s, 3 H, 8-OCH3), 6.53 (d, J = 0.9 Hz, 1 H, 3-
H), 6.91 (d, J = 8.8 Hz, 2 H, 3Ј-H, 5Ј-H), 7.14 (d, J = 8.8 Hz, 2 H,
2Ј-H, 6Ј-H), 7.35 (s, 1 H, 7-H) ppm. 13C NMR (63 MHz, CDCl3,
25 °C): δ = 25.0 (CH3-4), 37.3 (NCH3), 55.6 (OCH3-4Ј), 57.0
(OCH3-8), 106.8 (C-7), 114.0 (C-3Ј, C-5Ј), 123.4 (C-4a), 125.5 (C-
3), 126.8 (C-5), 127.9 (C-1Ј), 131.7 (C-2Ј, C-6Ј), 136.0 (C-8a), 146.6
(C-6), 148.4 (C-4), 148.5 (C-8), 160.3 (C-4Ј), 163.1 (C-2) ppm.
C19H18N2O5 (354): calcd. C 64.40, H 5.12, N 7.91; found C 64.34,
H 5.17, N 7.79.
8-Methoxy-1,4-dimethyl-6-nitro-5-phenylquinolin-2(1H)-one (7a):
5-(4-Chlorophenyl)-8-methoxy-1,4-dimethyl-6-nitroquinolin-2(1H)-
Pale brown solid (210 mg, 18%), m.p. 172–174 °C. IR (KBr): ν =
˜
one (7g): Yellow solid (399 mg, 31%), m.p. 139–141 °C. IR (KBr): ν
˜
3142, 2960, 1648, 1600, 1554 cm–1. 1H NMR (250 MHz, CDCl3,
25 °C): δ = 1.60 (d, J = 1.0 Hz, 3 H, 4-CH3), 3.86 (s, 3 H, NCH3),
4.00 (s, 3 H, OCH3), 6.52 (d, J = 1.0 Hz, 1 H, 3-H), 7.27–7.29 (m,
2 H, Ph), 7.37–7.43 (m, 4 H, 7-H, Ph) ppm. 13C NMR (63 MHz,
CDCl3, 25 °C): δ = 24.9 (CH3-4), 37.3 (NCH3), 57.0 (OCH3), 106.9
(C-7), 125.8 (C-3, C-5), 127.1 (C-4a), 128.5 (C-2Ј, C-6Ј), 129.2 (C-
4Ј), 130.6 (C-3Ј, C-5Ј), 136.1, 136.2 (C-1Ј, C-8a), 146.6 (C-6), 148.0
(C-4), 148.5 (C-8), 162.9 (C-2) ppm. C18H16N2O4 (324): calcd. C
66.66, H 4.97, N 8.64; found C 66.57, H 5.05, N 8.61.
= 2926, 1663, 1623, 1606, 1517 cm–1. 1H NMR (250 MHz, CDCl3,
25 °C): δ = 1.64 (d, J = 1.0 Hz, 3 H, 4-CH3), 3.86 (s, 3 H, NCH3),
4.01 (s, 3 H, OCH3), 6.54 (d, J = 1.0 Hz, 1 H, 3-H), 7.21 (d, J =
8.4 Hz, 2 H, 3Ј-H, 5Ј-H), 7.38 (d, J = 8.4 Hz, 2 H, 2Ј-H, 6Ј-H,
partially overlapped with 7-H signal), 7.40 (s, 1 H, 7-H) ppm. 13C
NMR (63 MHz, CDCl3, 25 °C): δ = 25.4 (CH3-4), 37.3 (NCH3),
57.1 (OCH3), 107.0 (C-7), 122.9 (C-4a), 125.8 (C-5), 126.1 (C-3),
128.9 (C-2Ј, C-6Ј), 132.0 (C-3Ј, C-5Ј), 134.8 (C-1Ј, C-4Ј), 136.4 (C-
8a), 146.4 (C-6), 147.6 (C-4), 148.8 (C-8), 162.9 (C-2) ppm.
C18H15ClN2O4 (358.5): calcd. C 60.26, H 4.21, N 7.81; found C
60.25, H 4.18, N 7.74.
8-Methoxy-1,4-dimethyl-6-nitro-5-(m-tolyl)quinolin-2(1H)-one (7c):
Pale brown solid (24 mg, 2%). IR (KBr): ν = 2922, 1660, 1572,
˜
1
1523, 1051 cm–1. H NMR (250 MHz, CDCl3, 25 °C): δ = 1.63 (s,
5-(4-Fluorophenyl)-8-methoxy-1,4-dimethyl-6-nitroquinolin-2(1H)-
3 H, 3Ј-CH3), 2.37 (s, 3 H, 4-CH3), 3.86 (s, 3 H, NCH3), 4.00 (s, 3 one (7h): Yellow solid (356 mg, 29%), m.p. 106–108 °C. IR (KBr):
H, OCH3), 6.53 (s, 1 H, 3-H), 7.06–7.08 and 7.25–7.27 (2m, 4 H,
ν = 2937, 2853, 1665, 1605, 1575, 1522, 1443 cm–1 1H NMR
.
˜
2Ј-H, 4Ј-H, 5Ј-H, 6Ј-H), 7.38 (s, 1 H, 7-H) ppm. 13C NMR (250 MHz, CDCl3, 25 °C): δ = 1.60 (s, 3 H, 4-CH3), 3.83 (s, 3 H,
(63 MHz, CDCl3, 25 °C): δ = 21.8 (CH3-3Ј), 24.9 (CH3-4), 37.3 NCH3), 3.98 (s, 3 H, OCH3), 6.52 (s, 1 H, 3-H), 7.07 (m, 2 H, 3Ј-
(NCH3), 57.0 (OCH3), 106.8 (C-7), 123.0 (C-5), 125.7 (C-3), 127.1
H, 5Ј-H), 7.24 (m, 2 H, 2Ј-H, 6Ј-H), 7.38 (s, 1 H, 7-H) ppm. 13C
(C-4a), 127.8 (C-6Ј), 128.4 (C-4Ј), 129.9 (C-2Ј), 131.2 (C-5Ј), 136.0, NMR (63 MHz, CDCl3, 25 °C): δ = 25.2 (CH3-4), 37.3 (NCH3),
136.1 (C-1Ј, C-8a), 138.2 (C-3Ј), 146.3 (C-6), 148.2 (C-4), 148.4 (C- 57.0 (OCH3), 106.9 (C-7), 115.8 (d, J = 21.8 Hz, C-3Ј, C-5Ј), 123.1
Eur. J. Org. Chem. 2012, 2375–2385
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2381

J. C. Menéndez et al.
(C-5), 125.9 (C-4a), 126.0 (C-3), 132 (d, J = 2.7 Hz, C-1Ј), 132.4 to 1:1) to afford compound 6d (228 mg, 75%), which was identical
FULL PAPER
(d, J = 8.2 Hz, C-2Ј, C-6Ј), 136.3 (C-8a), 146.5 (C-6), 147.7 (C-
4), 148.7 (C-8), 162.9 (C-2), 166.6 (d, J = 239.4 Hz, C-4Ј) ppm.
C18H15FN2O4 (342): calcd. C 63.15, H 4.42, N, 8.18; found C 63.23,
H 4.50, N 8.21.
in all respects to the sample obtained by the alternative method
described above which started from nitro derivative 3.
General Procedure for the Preparation of Compounds 9: To a solu-
tion of 2,5,8-trimethoxy-4-methyl-6-nitroquinoline (4, 100 mg,
0.36 mmol) in THF (10 mL) was added the suitable arylmagnesium
bromide (commercially available solution in THF, 1.1 mmol). The
reaction mixture was stirred at –30 °C for 1–3 h and then poured
8-Methoxy-1,4-dimethyl-5-(naphthalen-2-yl)-6-nitroquinolin-2(1H)-
one (7j): Brown solid (322 mg, 24%), m.p. 143–145 °C. IR (KBr):
ν = 2934, 2836, 1661, 1605, 1570, 1518, 1449 cm–1. 1H NMR
˜
(250 MHz, CDCl3, 25 °C): δ = 1.56 (d, J = 1.0 Hz, 3 H, 4-CH3), into a saturated aqueous solution of NH4Cl (15 mL). The resulting
3.89 (NCH3), 4.08 (OCH3), 6.52 (d, J = 1.0 Hz, 1 H, 3-H), 7.43
mixture was extracted with EtOAc (3ϫ20 mL), and the combined
(dd, J = 8.4 Hz, J = 1.8 Hz, 3Ј-H), 7.44 (s 1 H, 7-H), 7.51–7.60 (m, organic layers were washed with brine (2ϫ15 mL), dried with
2 H, 6Ј-H, 7Ј-H), 7.70 (s, 1 H, 2Ј-H), 7.78–7.82 (m, 1 H, 4Ј-H),
Na2SO4, and evaporated. The residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate mix-
7.86–7.91 (m, 2 H, 5Ј-H, 8Ј-H) ppm. 13C NMR (63 MHz, CDCl3,
25 °C): δ = 25.2 (CH3-4), 37.3 (NCH3), 57.0 (OCH3), 107.0 (C-7), ture, 3:1).
123.3 (C-5), 125.8 (C-3), 127.1 (C-4a), 127.2, 127.3, 128.1, 128.2,
5-Phenyl-2,8-dimethoxy-4-methyl-6-nitroquinoline (9a): Brownish
128.5, 128.6, 129.5, 133.0 (C-4Јa), 133.4 (C-8Јa), 133.7 (C-2Ј), 136.3
(C-8a), 146.6 (C-6), 148.1 (C-4), 148.6 (C-8), 162.9 (C-2) ppm.
C22H18N2O4 (374): calcd. C 70.58, H 4.85, N 7.48; found C 70.49,
H 4.77, N 7.41.
solid (100 mg, 57%), m.p. 184–186 °C. IR (NaCl): ν = 1582, 1504,
˜
1
1322 cm–1. H NMR (250 MHz, CDCl3, 25 °C): δ = 1.74 (s, 3 H,
4-CH3), 4.02 (s, 3 H, OCH3), 4.05 (s, 3 H, OCH3), 6.67 (s, 1 H, 3-
H), 7.17–7.26 (m, 3 H), 7.26–7.33 (m, 3 H) ppm. 13C NMR
(63 MHz, CDCl3, 25 °C): δ = 24.2, 53.4, 56.7, 102.6, 117.4, 124.6,
125.3, 127.9, 128.4, 130.4, 136.5, 140.7, 147.1, 150.1, 154.5,
162.6 ppm. C18H16N2O4 (324): calcd. C 66.66, H 4.97, N 8.64;
found C 66.58, H 5.04, N 8.60.
2,5,8-Trimethoxy-4-methyl-6-nitroquinoline (4): To a solution of 4-
methyl-5,8-dimethoxy-6-nitroquinolin-2(1H)-one
(5,
1.2 g,
4.56 mmol) in dry benzene (100 mL) were added silver oxide (1.1 g,
4.56 mmol) and methyl iodide (3.4 g, 24 mmol, divided into 3 por-
tions that were added every 24 h). The mixture was stirred at room
temperature for 72 h, protected from light and humidity. The re-
sultant suspension was filtered, and the organic layer was evapo-
rated to dryness. The residue was chromatographed on silica gel
(ethyl acetate/petroleum ether, gradient from 8:2 to 1:1) to yield
compound 4 (775 mg, 61%) as a yellow solid together with the
recovered starting material (250 mg, 25%). Data for 4: M.p. 155–
5-(4-Methylphenyl)-2,8-dimethoxy-4-methyl-6-nitroquinoline (9d):
Yellow solid (109 mg, 60%), m.p. 203–205 °C. IR (NaCl): ν = 1608,
˜
1505 cm–1. 1H NMR (250 MHz, CDCl3, 25 °C): δ = 1.88 (d, J =
0.9 Hz, 3 H, 4-CH3), 2.45 (s, 3 H, 4Ј-CH3), 4.13 (s, 3 H, 8-OMe),
4.15 (s, 3 H, 2-OMe), 6.78 (d, J = 0.9 Hz, 1 H, 3-H) 7,22 (br. s, 4
H, 2Ј-H, 3Ј-H, 5Ј-H, 6Ј-H), 7.28 (s, 1 H, 7-H) ppm. 13C NMR
(63 MHz, CDCl3, 25 °C): δ = 21.3 (CH3-4Ј), 24.3 (CH3-4), 53.4
(OCH3-2), 56.6 (OCH3-8), 102.5 (C-7), 117.3 (C-3), 124.7 and 125.3
(C-4a, C-5), 128.6 (C-3Ј, C-5Ј), 130.1 (C-2Ј, C-6Ј), 133.3 (C-1Ј),
138.3, 140.6 and 147.3 (C-6, C-8a, and C-4Ј), 150.3 (C-4), 154.3
(C-8), 162.6 (C-2) ppm. C19H18N2O4 (338): calcd. C 67.44, H 5.36,
N 8.28; found C 67.46, H 5.39, N 8.23.
156 °C. IR (KBr): ν = 1581, 1323 cm–1. 1H NMR (250 MHz,
˜
CDCl3, 25 °C): δ = 2.86 (d, J = 0.9 Hz, 3 H, 4-CH3), 3.92 (s, 3 H,
5-OCH3), 4.08 (s, 3 H, 8-OCH3), 4.14 (s, 3 H, 2-OCH3), 6.84 (d, J
= 0.9 Hz, 1 H, 3-H), 7.49 (s, 1 H, 7-H) ppm. 13C NMR (63 MHz,
CDCl3, 25 °C): δ = 23.3 (CH3-4), 53.6 (OCH3-2), 56.7 (OCH3-8),
63.5 (OCH3-5), 103.9 (C-7), 116.7 (C-3), 120.9 (C-4a), 137.8 (C-6),
142.9 (C-8a), 147.4 (C-5), 149.3 (C-4), 150.7 (C-8), 163.6 (C-
2) ppm. C13H14N2O5 (278): calcd. C 56.11, H 5.07, N 10.07; found
C 56.21, H 4.98, N 10.22.
5-(4-Methoxyphenyl)-2,8-dimethoxy-4-methyl-6-nitroquinoline (9f):
Yellow solid (168 mg, 88%), m.p. 200–202 °C. IR (NaCl): ν = 1605,
˜
1
1582, 1504 cm–1. H NMR {250 MHz, [D6]DMSO (deuterated di-
methyl sulfoxide)}: δ = 1.90 (d, J = 0.7 Hz, 3 H, 4-CH3), 3.89 (s, 3
H, 4Ј-OCH3), 4.12 (s, 3 H, 8-OCH3), 4.15 (s, 3 H, 2-OCH3), 6.78
(d, J = 0.7 Hz, 1 H, 3-H), 6.95 (d, J = 8.8 Hz, 2 H, 3Ј-H, 5Ј-H),
7.23 (d, J = 8.8 Hz, 2 H, 2Ј-H, 6Ј-H), 7.27 (s, 1 H, 7-H) ppm. 13C
NMR (63 MHz, [D6]DMSO): δ = 24.4 (CH3-4), 53.4 (OCH3-4Ј),
55.2 (OCH3-8), 56.6 (OCH3-2), 102.4 (C-7), 113.4 (C-3Ј, C-5Ј),
114.7 (C-5), 117.3 (C-3), 124.9 (C-4a), 128.3 (C-1Ј), 131.4 (C-2Ј, C-
6Ј), 140.5 (C-6), 147.5 (C-8a), 150.2 (C-4), 154.3 (C-8), 159.7 (C-
4Ј), 162.6 (C-2) ppm. C19H18N2O5 (354): calcd. C 64.40, H 5.12, N
7.91; found C 64.38, H 5.19, N 7.83.
6-Amino-5,8-dimethoxy-1,4-dimethylquinolin-2(1H)-one (8): To a
suspension of nitro compound 3 (278 mg, 1 mmol) in hydrochloric
acid (35% aqueous solution, 7 mL) was added stannous chloride
dihydrate (1.12 g, 50 mmol of SnCl2). The reaction was stirred for
24 h at room temp. and then was basified to pH = 10 with sodium
hydroxide (20% aqueous solution). The resulting mixture was ex-
tracted with chloroform (4ϫ30 mL), and the combined organic
layers were dried with Na2SO4 and evaporated to yield compound
8 (228 mg, 92%). 1H NMR (250 MHz, CDCl3, 25 °C): δ = 2.58 (d,
J = 0.9 Hz, 3 H, 4-CH3), 3.67 (s, 3 H, OCH3), 3.78 (s, 6 H, OCH3
and NCH3), 3.90 (br. s, 2 H, NH2), 6.45 (d, J = 0.9 Hz, 3-H), 6.62
(s, 1 H, 7-H) ppm. 13C NMR (63 MHz, CDCl3, 25 °C): δ = 22.9
(CH3-4), 35.8 (NCH3), 56.7 (OCH3-8), 60.3 (OCH3-5), 104.3 (C-
7), 118.1 (C-4a), 123.1 (C-3), 125.1 (C-8a), 135.1 (C-6), 137.5 (C-
5), 145.2 (C-4), 145.6 (C-8), 162.5 (C-2) ppm.
5-(4-Chlorophenyl)-2,8-dimethoxy-4-methyl-6-nitroquinoline
(9g):
Yellow solid (120 mg, 62%), m.p. 169–171 °C. IR (NaCl): ν = 1518,
˜
1
1320 cm–1. H NMR (250 MHz, CDCl3): δ = 1.90 (s, 3 H, CH3),
4.15 (s, 3 H, OCH3), 4.17 (s, 3 H, OCH3), 6.82 (s, 1 H), 7.30–7.33
(m, 3 H), 7.43 (d, J = 8.3 Hz, 1 H) ppm. 13C NMR (63 MHz,
CDCl3): δ = 24.7, 53.5, 56.7, 102.5, 117.7, 123.9, 124.4, 128.2,
131.7, 134.7, 135.0, 140.7, 147.1, 149.7, 154.7, 162.7 ppm.
C18H15N2O4Cl (358): calcd. C 60.26, H 4.21, N 7.81; found C
60.38, H 4.44, N 7.75.
Synthesis of Compound 6d by N-Arylation of 8: A solution of amine
8 (225 mg, 0.9 mmol), p-tolyllead triacetate (0.56 g, 1.17 mmol),
and copper(II) acetate (20 mg) in dichloromethane (10 mL) was
stirred at room temperature for 6 h. The reaction mixture was fil-
tered through a layer of alumina which then was washed with
dichloromethane (2ϫ20 mL). The combined organic layers were
evaporated, and the residue was purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate, gradient from 8:2
5-(4-Fluorophenyl)-2,8-dimethoxy-4-methyl-6-nitroquinoline
(9h):
Yellow solid (115 mg, 60%), m.p. 168–170 °C. IR (NaCl): ν = 1580,
˜
1520, 1330 cm–1. 1H NMR (250 MHz, CDCl3): δ = 1.86 (d, J =
0.9 Hz, 3 H, 4-CH3), 4.13 (s, 3 H, 2-OCH3), 4.15 (s, 3 H, 8-OCH3),
2382
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2375–2385

Aryl Grignard Reagents in Chemodivergent N- and C-Arylations
6.79 (d, J = 0.9 Hz, 1 H, 3-H), 7.10–7.16 (m, 2 H, 3Ј-H, 5Ј-H), 7.30
(s, 1 H, 7-H, partially overlapped with 2Ј-H and 6Ј-H signal), 7.28–
spectroscopic data could not be obtained because of low solubility.
MS: m/z = 306 [M]+, 278, 277. C18H14N2O3 (306): calcd. C 70.58,
7.33 (m, 2 H, 2Ј-H, 6Ј-H) ppm. 13C NMR (63 MHz, CDCl3): δ = H 4.61, N 9.15; found C 70.61, H 4.55, N 8.97.
24.5 (CH3-4), 53.5 (OCH3-2), 56.6 (OCH3-8), 102.5 (C-7), 115.1 (d,
1,4,9-Trimethyl-1H-pyrido[3,2-b]carbazole-2,5,11(6H)-trione (11d):
J = 21.7 Hz, C-3Ј, C-5Ј), 117.6 (C-3), 124.1 (C-5), 124.6 (C-4a),
132.1 (d, J = 8.1 Hz, C-2Ј, C-6Ј), 132.3 (d, J = 3.7 Hz, C-1Ј), 140.7
and 147.3 (C-6 and C-8a), 149.8 (C-4), 154.7 (C-8), 162.7 (C-2),
162.9 (d, J = 248.9 Hz, C-4Ј) ppm. C18H15N2O4F (342): calcd. C
63.15, H 4.42, N 8.18; found C 63.11, H 4.45, N 8.13.
Dark red solid (52 mg, 45%), m.p. Ͼ300 °C. IR (KBr): ν = 3500–
˜
1
2500, 1650 cm–1. H NMR (250 MHz, [D6]DMSO): δ = 2.44 (s, 3
H, 9-CH3), 2.57 (s, 3 H, 4-CH3), 3.84 (s, 3 H, 1-CH3), 6.59 (s, 1 H,
3-H), 7.24 (d, J = 8.7 Hz, 1 H, 8-H), 7.45 (d, J = 8.7 Hz, 1 H, 7-
H), 7.87 (s, 1 H, 10-H) 12.86 (br. s, 1 H, 6-H) ppm. MS: m/z = 306
[M]+, 77. C18H14N2O3 (306): calcd. C 70.58, H 4.61, N 9.15; found
C 70.57, H 4.58, N 9.07.
General Procedure for the Preparation of Compounds 1 and 11: A
solution of the suitable compound 6 (1 equiv.) and Pd(OAc)2
(2 equiv.) in acetic acid (15 mL) was heated at 120 °C for 16 h under
an argon atmosphere. The reaction mixture was evaporated to dry-
ness, and the residue was chromatographed on silica gel (ethyl acet-
ate/petroleum ether gradient) to give compound 1 and/or 10.
8-Methoxy-1,4-dimethyl-1H-pyrido[3,2-b]carbazole-2,5,11(6H)-
trione (11e): Brownish solid (44 mg, 48%), m.p. 272–275 °C. IR
(KBr): ν = 3500–2500, 1651 cm–1 1H NMR (250 MHz, [D6]-
.
˜
DMSO): δ = 2.56 (s, 3 H, 4-CH3), 3.79 (s, 6 H, 1-CH3, 8-OCH3),
6.57 (s, 1 H, 3-H), 6.97 (d, J = 8.6, 2.2 Hz, 2 H, 7-H, 9-H), 7.92
(dd, J = 8.6 Hz, 1 H, 10-H), 12.75 (br. s, 1 H, 6-H) ppm. 13C NMR
spectroscopic data could not be obtained because of low solubility.
MS: m/z = 322 [M]+, 294, 293. C18H14N2O4 (322): calcd. C 67.07,
H 4.38, N 8.69; found C 67.12, H 4.41, N 8.60.
5,11-Dimethoxy-1,4-dimethyl-1H-pyrido[3,2-b]carbazol-2(6H)-one
(1a): Orange solid (29 mg, 25%), m.p. 270–272 °C. IR (KBr): ν
˜
1
= 3202, 2930, 1635, 1587, 1550, 1484, 1437, 1230 cm–1. H NMR
(250 MHz, CDCl3, 25 °C): δ = 2.74 (s, 3 H, 4-CH3), 3.85 (s, 3 H,
1-CH3), 3.99 (s, 3 H, OCH3), 4.05 (s, 3 H, OCH3), 6.54 (s, 1 H, 3-
H), 7.28–7.34 (m, 1 H, 9-H), 7.51–7.52 (m, 2 H, 7-H, 8-H), 8.31
(d, J = 7.9 Hz, 1 H, 10-H), 8.34 (br. s, 1 H, 6-H) ppm. 13C NMR
(63 MHz, CDCl3, 25 °C): δ = 23.7, 36.1, 61.8, 62.3, 111.2, 116.5,
120.6, 121.4, 122.3, 122.5, 124.0, 127.8, 128.9, 130.7, 139.1, 140.3,
141.2, 146.4, 163.8 ppm. C19H18N2O3 (322): calcd. C 70.79, H 5.63,
N 8.69; found C 70.82, H 5.71, N 8.60.
9-Methoxy-1,4-dimethyl-1H-pyrido[3,2-b]carbazole-2,5,11(6H)-
trione (11f): Red solid (82 mg, 69%), m.p. Ͼ300 °C. IR (KBr): ν =
˜
1
3500–2500, 1646 cm–1. H NMR (250 MHz, [D6]DMSO): δ = 2.56
(s, 3 H, 4-CH3), 3.83 and 3.84 (2 s, 6 H, 1-CH3, 9-OCH3), 6.57 (s,
3 H, 3-H), 7.03 (m, 1 H, 8-H), 7.45 (m, 2 H, 7-H, 10-H) ppm. 13C
NMR spectroscopic data could not be obtained because of low
solubility. MS: m/z = 322 [M]+, 294, 293. C18H14N2O4 (322): calcd.
C 67.07, H 4.38, N 8.69; found C 66.99, H 4.31, N 8.57.
9-Chloro-5,11-dimethoxy-1,4-dimethyl-1H-pyrido[3,2-b]carbazol-
2(6H)-one (1g): Yellow solid (32 mg, 33%). IR (KBr): ν = 3429,
˜
2929, 1650, 1494 cm–1. 1H NMR (250 MHz, CDCl3, 25 °C): δ =
2.73 (d, J = 1.1 Hz, 3 H, 4-CH3), 3.85 (s, 3 H, 1-CH3), 3.97 (s, 3
H, OCH3), 3.99 (s, 3 H, OCH3), 6.55 (d, J = 1.1 Hz, 1 H, 3-H),
7.43–7.46 (m, 2 H, 7-H, 8-H), 8.27 (d, J = 1.9 Hz, 1 H, 10-H), 8.33
(br. s, 1 H, 6-H) ppm. 13C NMR (63 MHz, CDCl3, 25 °C): δ =
23.7, 36.0, 61.9, 62.4, 104.9, 112.2, 122.9, 123.4, 125.9, 127.8, 129.1,
130.6, 131.2, 139.2, 139.5, 139.9, 140.2, 146.3, 163.7 ppm.
9-Chloro-1,4-dimethyl-1H-pyrido[3,2-b]carbazole-2,5,11(6H)-trione
(11g): Red solid (26 mg, 29%), m.p. Ͼ300 °C. IR (KBr): ν = 3500–
˜
2500, 1664, 1649 cm–1. 1H NMR (250 MHz, [D6]DMSO): δ = 2.55
(s, 3 H, 4-CH3), 3.83 (s, 3 H, 1-CH3), 6.58 (s, 1 H, 3-H), 7.24–7.32
(m, 1 H, 8-H), 7.55–7.59 (m, 1 H, 7-H), 7.69–7.72 (m, 1 H, 10-
H) ppm. 13C NMR spectroscopic data could not be obtained be-
cause of low solubility. MS: m/z = 326 [M]+ , 298, 297.
C
19H17N2O3Cl (356): calcd. C 63.96, H 4.80, N 7.85; found C
C
17H11N2O3Cl (326): calcd. C 62.49, H 3.39, N 8.57; found C
64.01, H 4.89, N 7.77.
62.44, H 3.41, N 8.51.
9-Fluoro-5,11-dimethoxy-1,4-dimethyl-1H-pyrido[3,2-b]carbazol-
9-Fluoro-1,4-dimethyl-1H-pyrido[3,2-b]carbazole-2,5,11(6H)-trione
2(6H)-one (1h): Brownish solid (30 mg, 32%), m.p. 170–172 °C. IR
(11h): Red solid (42 mg, 47%), m.p. Ͼ300 °C. IR (KBr): ν = 3500–
˜
1
(KBr): ν = 3417, 2918, 2849, 1653, 1599, 1571, 1450 cm–1. H
˜
2500, 1662, 1640 cm–1. 1H NMR (250 MHz, [D6]DMSO): δ = 2.55
(s, 3 H, 4-CH3), 3.83 (s, 3 H, 1-CH3), 6.58 (s, 1 H, 3-H), 7.43 (m,
1 H, 8-H), 7.58 (m, 1 H, 7-H), 7.69–7.72 (m, 1 H, 10-H) ppm. 13C
NMR spectroscopic data could not be obtained because of low
solubility. MS: m/z = 310 [M]+, 282, 281. C17H11N2O3F (310):
calcd. C 65.81, H 3.57, N 9.03; found C 65.90, H 3.63, N 8.99.
NMR (250 MHz, CDCl3, 25 °C): δ = 2.73 (s, 3 H, 4-CH3), 3.83 (s,
3 H, 1-CH3), 3.91 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 6.56 (s, 1
H, 3-H), 7.43–7.49 (m, 2 H, 7-H, 10-H), 7.96 (dd, J = 8.9, 2.5 Hz,
1 H, 8-H), 8.29 (br. s, 1 H, 6-H) ppm. C19H17N2O3F (340): calcd.
C 67.05, H 5.03, N 8.23; found C 67.16, H 5.05, N 8.19.
1,4-Dimethyl-1H-pyrido[3,2-b]carbazole-2,5,11(6H)-trione (11a):
6-(2-Acetoxymethylphenylamino)-1,4-dimethylquinoline-2(1H),5,8-
Red solid (64 mg, 59%), m.p. Ͼ300 °C. IR (KBr): ν = 3500–2500,
˜
trione (12): Red solid (13 mg, 59%), m.p. 254–256 °C. IR (KBr): ν
˜
1
1647 cm–1. H NMR (250 MHz, [D6]DMSO): δ = 2.56 (s, 3 H, 4-
1
= 3500–2500, 1740, 1654 cm–1. H NMR (250 MHz, CDCl3): δ =
CH3), 3.84 (s, 3 H, 1-CH3), 6.58 (s, 1 H, 3-H), 7.30–7.40 (m, 2 H,
8-H, 9-H), 7.56 (d, J = 7.5 Hz, 1 H, 7-H), 8.06 (d, J = 7.5 Hz, 1
H, 10-H), 12.94 (br. s, 1 H, 6-H) ppm. 13C NMR (63 MHz, [D6]-
DMSO): δ = 30.6, 34.5, 113.8, 114.8, 116.0, 121.8, 122.4, 123.6,
123.9, 126.4, 136.2, 137.7, 145.8, 149.1, 161.3, 177.3, 178.0 ppm.
MS: m/z = 292 [M]+, 264, 263. C17H12N2O3 (292): calcd. C 69.86,
H 4.14, N 9.58; found C 69.93, H 4.17, N 9.49.
2.16 (s, 3 H, CH3CO), 2.57 (br. s, 3 H, 4-CH3), 3.90 (s, 3 H, NCH3),
5.07 (s, 2 H, OCH2Ph), 6.01 (s, 1 H, 7-H), 6.58 (s, 1 H, 3-H), 7.25–
7.50 (m, 4 H, Ph), 8.56 (br. s, 1 H, NH) ppm. 13C NMR (63 MHz,
CDCl3, 25 °C): δ = 21.3, 23.6, 35.3, 63.6, 101.1, 115.1, 123.6, 124.5,
127.0, 127.5, 130.1, 130.4, 132.3, 136.8, 144.9, 149.9, 162.8, 171.8,
180.6, 180.9 ppm. C20H18N2O5 (366): calcd. C 65.57, H 4.95, N
7.65; found C 65.61, H 4.98, N 7.61.
1,4,8-Trimethyl-1H-pyrido[3,2-b]carbazole-2,5,11(6H)-trione (11c):
General Procedure for Preparation of Compounds 2a and 2b
Dark red solid (45 mg, 25%), m.p. Ͼ300 °C. IR (KBr): ν = 3500–
˜
1
2500, 1650 cm–1. H NMR (250 MHz, [D6]DMSO): δ = 2.36 (s, 3
Method A: A solution of the suitable compound 7 or 9 in triethyl
phosphite (1–2 mL) was heated to reflux at 160 °C for 3 h. The
reaction mixture was cooled to room temp., and the solid that pre-
cipitated was filtered and washed with ethyl ether.
H, 8-CH3), 2.56 (s, 3 H, 4-CH3), 3.83 (s, 3 H, 1-CH3), 6.57 (s, 3 H,
3-H), 7.17 (d, J = 8.8 Hz, 1 H, 9-H), 7.32 (s, 1 H, 7-H), 7.93 (d,
J = 8.8 Hz, 1 H, 10-H), 12.81 (br. s, 1 H, 1-H) ppm. 13C NMR
Eur. J. Org. Chem. 2012, 2375–2385
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2383

J. C. Menéndez et al.
FULL PAPER
Method B: A solution of the suitable compound 7 or 9 in triethyl
140.4 (C-4a), 140.6 (C-7a), 146.2 (C-1), 149.0 (C-5), 159.1 (d, J =
phosphite (1–2 mL) was heated under microwave irradiation in a
241.3 Hz, C-9), 163.0 (C-3) ppm. C18H15N2O2F (310): calcd. C
CEM Discover focused microwave reactor at 300 W and 180 °C for 69.67, H 4.87, N 9.03; found C 69.59, H 4.93, N 8.97.
25 min. The reaction mixture underwent the same workup as in
5-Methoxy-1,4-dimethyl-4,7-dihydro-3H-benzo[a]pyrido[3,2-g]carb-
azol-3-one (2aj): Yellow solid (26 mg, 40%, method A), m.p.
Method A.
5-Methoxy-1,4-dimethyl-4,7-dihydro-3H-pyrido[2,3-c]carbazol-3-
Ͼ300 °C. IR (KBr): ν = 3427, 3139, 2935, 1645, 1604, 1565, 1447,
˜
1
1381 cm–1. H NMR (250 MHz, CDCl3, 25 °C): δ = 6.82 (s, 1 H,
one (2aa): Orange solid (24 mg, 55%, method A), m.p. 223–225 °C.
IR (KBr): ν = 3420, 2960, 1648, 1600, 1553, 1453 cm–1. H NMR
1
˜
2-H), 7.35 (s, 1 H, 6-H), 7.50–7.70 (m, 2 H, 9-H, 10-H), 7.62 (d, J
= 8.2 Hz, 1 H, 12-H, overlapped with 9-H and 10-H signal), 8.00
(d, J = 8.2 Hz, 1 H, 13-H), 8.19 (d, J = 9.1 Hz, 1 H, 11-H, partially
overlapped with 8-H signal), 8.23 (d, J = 9.4 Hz, 1 H, 8-H, partially
overlapped with 11-H signal), 9.42 (br. s, 1 H, 7-H) ppm. 13C NMR
(63 MHz, [D6]DMSO, 25 °C): δ = 24.1, 36.8, 57.3, 98.3, 111.9,
118.8, 119.1, 119.2, 120.3, 121.8, 123.8, 124.0, 125.5, 125.8, 128.3,
130.1, 130.9, 136.7, 136.8, 146.8, 148.5, 162.1 ppm. C22H18N2O2
(342): calcd. C 77.17, H 5.30, N 8.18; found C 77.09, H 5.32, N
8.11.
(250 MHz, CDCl3, 25 °C): δ = 2.87 (s, 3 H, 1-CH3), 3.88 (s, 3 H,
4-CH3), 3.98 (s, 3 H, 5-OCH3), 6.73 (s, 1 H, 2-H), 7.17 (s, 1 H, 6-
H), 7.22–7.25 (m, 1 H, 10-H), 7.35–7.41 (m, 1 H, 9-H), 7.50 (d, J
= 8.1 Hz, 1 H, 8-H), 8.15 (d, J = 8.1 Hz, 1 H, 11-H), 8.87 (br. s, 1
H, 7-H) ppm. 13C NMR (63 MHz, CDCl3, 25 °C): δ = 24.6, 37.5,
56.8, 97.3, 111.2, 111.7, 119.5, 120.8, 121.6, 123.5, 124.6, 124.9,
129.5, 136.9, 140.1, 146.5, 149.6, 163.1 ppm. C18H16N2O2 (292):
calcd. C 73.95, H 5.52, N 9.58; found C 73.77, H 5.46, N 9.51.
5-Methoxy-1,4,9-trimethyl-4,7-dihydro-3H-pyrido[2,3-c]carbazol-3-
one (2ad): Yellow solid (67 mg, 53%, Method A; or 63 mg, 50%,
3,5-Dimethoxy-1-methyl-7H-pyrido[2,3-c]carbazole (2ba): Yellow
Method B), m.p. 253–255 °C. IR (KBr): ν = 3210, 2998, 1655, 1602,
˜
solid (20 mg, 45%, method B), m.p. 252–254 °C. IR (NaCl): ν =
˜
1508, 1450 cm–1. H NMR (250 MHz, CDCl3, 25 °C): δ = 2.52 (s,
1
1
3421, 3266, 1593, 1342 cm–1. H NMR (250 MHz, [D6]DMSO): δ
3 H, 9-CH3), 2.86 (s, 3 H, 1-CH3), 3.87 (s, 3 H, 4-CH3), 3.94 (s, 3
H, OCH3), 6.73 (s, 1 H, 2-H), 7.05 (dd, J = 8.5, 1.2 Hz, 1 H, 10-
H), 7.15 (s, 1 H, 6-H), 7.28 (s, 1 H, 8-H), 8.03 (d, J = 8.5 Hz, 1 H,
11-H), 8.37 (br. s, 1 H, 7-H) ppm. 13C NMR (63 MHz, [D6]DMSO,
25 °C): δ = 20.7, 23.2, 36.0, 56.0, 97.3, 109.7, 110.4, 118.3, 119.4,
119.5, 119.6, 123.5, 128.1, 132.7, 136.0, 139.7, 145.2, 147.4,
160.7 ppm. C19H18N2O2 (306): calcd. C 74.49, H 5.92, N 9.14;
found C 74.37, H 5.97, N 9.09.
= 2.51 (s, 3 H, CH3), 3.99 (s, 3 H, 5-OCH3), 4.04 (s, 3 H, 3-OCH3),
7.00 (s, 1 H, 2-H), 7.09–7.36 (m, 3 H, 6-H, 9-H, 10-H), 7.57 (d, J
= 7.9 Hz, 1 H, 8-H), 8.35 (d, J = 8.3 Hz, 1 H, 11-H), 11.74 (s, 1
H, NH) ppm. 13C NMR (63 MHz, [D6]DMSO): δ = 25.1, 52.7,
55.91, 95.9, 107.6, 111.1, 118.5, 122.6, 122.7, 123.2, 123.6, 135.5,
137.5, 138.9, 145.6, 153.6, 158.5 ppm. C18H16N2O2 (292): calcd. C
73.95, H 5.52, N 9.58; found C 74.07, H 5.57, N 9.54.
3,5-Dimethoxy-1,9-dimethyl-7H-pyrido[2,3-c]carbazole (2bd): Light
5,9-Dimethoxy-1,4-dimethyl-4,7-dihydro-3H-pyrido[2,3-c]carbazol-
3-one (2af): Yellow solid (90 mg, 51%, Method A; or 99 mg, 56%,
yellow solid (25 mg, 55%, method B), m.p. 226–228 °C. IR (NaCl):
ν = 3329, 2922, 1593, 1356 cm–1. 1H NMR (250 MHz, [D6]ace-
˜
Method B), m.p. 251–253 °C. IR (KBr): ν = 3419, 3151, 2934, 1646,
˜
tone): δ = 2.50 (s, 3 H, 9-CH3), 3.18 (d, J = 0.6 Hz, 3 H, 1-CH3),
4.05 (s, 3 H, 5-OCH3), 4.07 (s, 3 H, 3-OCH3), 6.95 (d, J = 0.7 Hz,
1 H, 2-H), 7.03 (dd, J = 8.5, 1.2 Hz, 1 H, 10-H), 7.39 (s, 2 H, 8-H,
1602, 1560, 1508 cm–1. 1H NMR (250 MHz, CDCl3, 25 °C): δ =
2.85 (s, 3 H, 1-CH3), 3.86 (s, 3 H, 4-CH3), 3.91 (s, 3 H, OCH3),
3.95 (s, 3 H, OCH3), 6.72 (s, 1 H, 2-H), 6.85 (dd, J = 9.0. 2.2 Hz,
1 H, 10-H), 6.97 (d, J = 2.2 Hz, 1 H, 8-H), 7.14 (s, 1 H, 6-H), 8.03
(d, J = 9.0 Hz, 1 H, 11-H), 8.53 (br. s, 1 H, 7-H) ppm. 13C NMR
(63 MHz, [D6]DMSO, 25 °C): δ = 24.9, 52.4, 55.0, 55.7, 94.1, 96.0,
107.6, 107.7, 112.5, 117.1, 122.1, 124.2, 135.0, 136.9, 140.2, 145.5,
152.4, 156.0, 158.1 ppm. C19H18N2O3 (322): calcd. C 70.79, H 5.63,
N 8.69; found C 70.83, H 5.59, N 8.54.
6-H), 8.30 (d, J = 8.5 Hz, 1 H, 11-H), 10.66 (s, 1 H, NH) ppm. 13
C
NMR (63 MHz, [D6]acetone): δ = 22.7, 26.9, 54.2, 57.7, 98.1,
113.0, 114.9, 122.3, 123.8, 124.9, 125.6, 134.5, 141.9, 144.6, 147.4,
147.7, 153.3, 156.1, 160.9 ppm. C19H18N2O2 (306): calcd. C 74.49,
H 5.92, N 9.14; found C 74.54, H 5.86, N 9.10.
3,5,9-Trimethoxy-1-methyl-7H-pyrido[2,3-c]carbazole (2bf): Yellow
solid (40 mg, 87%, method B), m.p. 238–240 °C. IR (NaCl): ν =
˜
9-Chloro-5-methoxy-1,4-dimethyl-4,7-dihydro-3H-pyrido[2,3-c]carb-
azol-3-one (2ag): Pale brown solid (50 mg, 30%, method A). IR
1
3341, 1699, 1683, 1457 cm–1. H NMR (250 MHz, [D6]DMSO): δ
(KBr): ν = 3426, 2923, 1645, 1601, 1556, 1455 cm–1 1H NMR
.
= 3.09 (s, 3 H, CH3), 3.86 (s, 3 H, 9-OCH3), 3.98 (s, 3 H, 5-OCH3),
4.02 (s, 3 H, 3-OCH3), 6.78 (dd, J = 9.1, 2.3 Hz, 1 H, 10-H), 6.96
(s, 1 H, 2-H), 7.06 (d, J = 2.2 Hz, 1 H, 8-H), 7.31 (s, 1 H, 6-H),
8.23 (d, J = 9.1 Hz, 1 H, 11-H), 11.58 (s, 1 H, NH) ppm. 13C NMR
(63 MHz, [D6]DMSO): δ = 25.5 (CH3-1), 52.9 (OCH3-9), 55.5
(OCH3-5), 56.2 (OCH3-3), 94.6 (C-8), 96.5 (C-6), 108.1 (C-6a),
108.3 (C-10), 112.9 (C-2), 117.6 (C-9), 122.6 (C-11c), 124.7 (C-8),
135.6 (C-5), 137.4 (C-11), 140.7 (C-11a), 145.9 (C-1), 152.9 (C-11b),
156.5 (C-8a), 158.6 (C-3) ppm. C19H18N2O3 (322): calcd. C 70.79,
H 5.63, N 8.69; found C 70.83, H 5.59, N 8.54.
˜
(250 MHz, CDCl3, 25 °C): δ = 2.83 (s, 3 H, 1-CH3), 3.87 (s, 3 H,
4-CH3), 4.00 (s, 3 H, OCH3), 6.75 (s, 1 H, 2-H), 7.14 (s, 1 H, 6-H),
7.19 (dd, J = 8.9, 1.9 Hz, 1 H, 10-H), 7.47 (d, J = 1.9 Hz, 1 H, 8-
H), 8.04 (d, J = 8.9 Hz, 1 H, 11-H), 8.43 (br. s, 1 H, 7-H) ppm. 13
C
NMR spectroscopic data could not be obtained because of low
solubility. C18H15N2O2Cl (326): calcd. C 66.16, H 4.63, N 8.57;
found C 66.23, H 4.65, N 8.46.
9-Fluoro-5-methoxy-1,4-dimethyl-4,7-dihydro-3H-pyrido[2,3-c]carb-
azol-3-one (2ah): Yellow solid (66 mg, 39%, Method A; or 95 mg,
56%, Method B), m.p. 272–274 °C. IR (KBr): ν = 3212, 2916, 1653,
9-Chloro-3,5-dimethoxy-1-methyl-7H-pyrido[2,3-c]carbazole (2bg):
˜
1
1600, 1507, 1429, 1393 cm–1. H NMR (250 MHz, CDCl3, 25 °C): Yellow solid (21 mg, 46%, method B), m.p. 133–135 °C. IR (NaCl):
δ = 2.84 (d, J = 0.7 Hz, 3 H, 1-CH3), 3.87 (s, 3 H, 4-CH3), 3.99 (s, ν = 3400, 1636 cm–1. H NMR (250 MHz, CD OD): δ = 2.94 (s, 3
1
˜
3
3 H, OCH3), 6.72 (d, J = 0.7 Hz, 1 H, 2-H) 6.96 (td, J = 9.1, H, CH3), 3.97 (s, 3 H, 5-OCH3), 4.09 (s, 3 H, 3-OCH3), 7.00 (dd,
2.5 Hz, 10-H), 7.16 (s, 1 H, 6-H), 7.17 (dd, J = 9.1, 2.5 Hz, 8-H), J = 9.0, 2.1 Hz, 1 H, 10-H), 7.06 (s, 1 H, 2-H), 7.16 (s, 1 H, 6-H),
8.07 (dd, J = 9.1, 5.4 Hz, 11-H), 8.75 (br. s, 1 H, 7-H) ppm. 13C
NMR (63 MHz, CDCl3, 25 °C): δ = 24.5 (CH3-1), 37.5 (CH3-4),
56.9 (OCH3), 97.3 (C-6), 97.6 (d, J = 25.8 Hz, C-10), 107.8 (d, J =
7.36 (d, J = 2.0 Hz, 1 H, 8-H), 8.00–8.03 (m, 2 H, NH, 11-H) ppm.
13C NMR (125 MHz, CD3OD): δ = 27.6 (CH3), 57.5 (OCH3-3),
57.8 (OCH3-5), 99.5 (C-6), 109.7 (C-11c), 112.6 (C-2), 112.7 (C-8),
23.9 Hz, C-8), 111.5 (C-11c), 120.3 (d, J = 13.0 Hz, C-11a), 121.8 121.2 (C-10), 123.4 (C-11a), 124.0 (C-6a, C-7a), 126.7 (C-11), 131.3
(C-2), 125.9 (d, J = 10.1 Hz, C-11), 130.2 (C-11b), 137.2 (C-6a), (C-11b), 140.6 (C-4a), 142.1 (C-9), 152.2 (C-5), 155.0 (C-1), 160.6
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2375–2385

Aryl Grignard Reagents in Chemodivergent N- and C-Arylations
Alonso, C. Avendaño, J. C. Menéndez, Tetrahedron Lett. 1996,
37, 6955–6958; c) J. M. Pérez, C. Avendaño, J. C. Menéndez,
Tetrahedron Lett. 1997, 38, 4717–4720; d) E. Pascual-Alfonso,
C. Avendaño, J. C. Menéndez, Synlett 2000, 205–208; e) J. M.
Pérez, P. López-Alvarado, C. Avendaño, J. C. Menéndez, Tetra-
hedron 2000, 56, 1561–1567; f) M. A. Alonso, P. López-Alva-
rado, C. Avendaño, J. C. Menéndez, Tetrahedron 2003, 59,
2821–2830; g) J. D. Sánchez, P. Cledera, S. Perumal, C. Aven-
daño, J. C. Menéndez, Synlett 2007, 2805–2808.
(C-3) ppm. C18H15N2O2Cl (326): calcd. C 66.16, H 4.63, N 8.57;
found C 66.26, H 4.65, N 8.51.
9-Fluoro-3,5-dimethoxy-1-methyl-7H-pyrido[2,3-c]carbazole (2bh):
Yellow solid (19 mg, 46%, method B), m.p. 179–181 °C. IR (KBr):
1
ν = 3410, 1733, 1506, 1457 cm–1. H NMR (250 MHz, CD OD): δ
˜
3
= 3.07 (s, 3 H, CH3), 4.02 (s, 3 H, OCH3), 4.09 (s, 3 H, OCH3),
6.86 (td, J = 9.2, 2.6 Hz, 1 H, 10-H), 7.11–7.16 (m, 2 H, 8-H, 2-
H), 7.30 (s, 1 H, 6-H), 8.18 (dd, J = 9.2, 5.2 Hz, 1 H, 11-H) ppm.
13C NMR (126 MHz, CD3OD): δ = 34.5, 62.2, 65.5, 105.5, 106.6
(d, J = 25.4 Hz), 115.9 (d, J = 23.3 Hz), 116.9, 122.5, 126.7 (d, J
= 3.7 Hz), 129.7, 131.9, 134.3 (d, J = 10.4 Hz), 145.1, 148.9 (d,
J = 12.1 Hz), 155.2, 162.9, 167.9 (d, J = 243.7 Hz), 168.1 ppm.
C18H15N2O2F (310): calcd. C 69.67, H 4.87, N 9.03; found C 69.70,
H 4.93, N 8.97.
[8] For an overview of methods for a diarylamine synthesis, see: I.
Sapountzis, P. Knochel, Angew. Chem. 2004, 116, 915; Angew.
Chem. Int. Ed. 2004, 43, 897–900.
[9] For a monograph on the reactivity of the nitro group and its
synthetic applications, see: N. Ono, The Nitro Group in Organic
Synthesis, Wiley-VCH, New York, 2001.
[10] a) I. Sapountizis, P. Knochel, J. Am. Chem. Soc. 2002, 124,
9390–9391; for a commentary on the reactions between Grig-
nard reagents and nitroarenes, see: b) A. Ricci, M. Fochi, An-
gew. Chem. 2003, 115, 1482; Angew. Chem. Int. Ed. 2003, 42,
1444–1446.
Supporting Information (see footnote on the first page of this arti-
cle): Details of the computational study of compounds 3 and 4 and
spectra.
[11] a) G. Bartoli, M. Bosco, G. Cantagalli, R. Dalpozzo, J. Chem.
Soc. Perkin Trans. 2 1985, 773; b) T. Hattori, A. Takeda, O.
Yamabe, S. Miyano, Tetrahedron 2002, 58, 233–238.
[12] R. Egris, M. Villacampa, J. C. Menéndez, Chem. Eur. J. 2009,
15, 10930–10939.
[13] For a preliminary communication of parts of the N-arylation
work and related reactions, see: J. D. Sánchez, C. Avendaño,
J. C. Menéndez, Synlett 2008, 1371–1374.
[14] For a monograph on this concept, see: J. P. Finet (Ed.), Tetra-
hedron Organic Chemistry Series, vol. 18, Ligand Coupling Re-
actions with Heteroatomic Compounds, Elsevier, Oxford, UK,
1988.
[15] For the synthesis of p-tolyllead triacetate, see: P. López-Alva-
rado, C. Avendaño, J. C. Menéndez, Heterocycles 1991, 32,
1003–1012.
Acknowledgments
Financial support from Ministerio de Ciencia e Innovación (MIC-
INN) (grant number CTQ2009-12320-BQU) and Universidad
Complutense de Madrid (UCM) (grant number GR35/10-A-
920234, Grupos de Investigación Consolidados) is gratefully ac-
knowledged. J. C. M. and S. P. also thank MICINN, Spain and the
Department of Science and Technology (DST), New Delhi for
funding the Indo-Spanish collaborative major research projects
that have made our joint work possible (grant numbers DST/INT/
SPAIN/09 and ACI2009-0956).
[16] D. H. R. Barton, D. M. X. Donnelly, J.-P. Finet, P. J. Guiry, J.
Chem. Soc. Perkin Trans. 1 1991, 2095–2102.
[17] G. Bartoli, Acc. Chem. Res. 1984, 17, 109–115.
[18] M. B. Smith, Organic Synthesis, 3rd ed., Academic Press, Wave-
function Inc., Irvine, CA, 2010, pp. 636–639.
[1] For selected reviews of carbazole alkaloids, see: a) H.-J.
Knölker, K. R. Reddy, in: The Alkaloids, vol. 65: Chemistry and
Biology of Carbazole Alkaloids (Ed.: G. A. Cordell), Academic
Press, Amsterdam, 2008, pp. 1–430; b) H.-J. Knölker, Top.
Curr. Chem. 2005, 244, 115–148; c) H.-J. Knölker, Curr. Org.
Synth. 2004, 1, 309–331; d) H.-J. Knölker, K. R. Reddy, Chem.
Rev. 2002, 102, 4303–4427.
[2] M. Stiborová, J. Sejbal, L. Borek-Dohalská, D. Aimová, J. Pol-
jaková, K. Forsterova, M. Rupertová, J. Wiesner, J. Hudecek,
M. Wiessler, E. Frei, Cancer Res. 2004, 64, 8374–8380.
[3] C. Avendaño, J. C. Menéndez, Medicinal Chemistry of Antican-
cer Drugs, Elsevier, Amsterdam, 2008, chapter 7.
[4] M. Itoigawa, Y. Kashiwada, H. Furukawa, Y. Tachibana, K. F.
Bastow, K. H. Lee, J. Nat. Prod. 2000, 63, 893–897.
[5] Q. A. Khan, J. Lu, S. M. Hecht, J. Nat. Prod. 2009, 72, 438–
442.
[6] a) X. Chen, G. D. Smith, P. W. Waring, J. Appl. Phycol. 2003,
15, 269–277; b) P. H. Bernardo, C. L. L. Chai, G. A. Heath,
P. J. Mahon, G. D. Smith, P. Waring, B. A. Wilkes, J. Med.
Chem. 2004, 47, 4958–4963.
[19] For a monograph on palladium-catalyzed intramolecular bond
formation in the context of heterocyclic synthesis, see: J. J. Li,
G. W. Gribble, Palladium in Heterocyclic Chemistry. Elsevier,
Oxford, 2000.
[20] For selected reviews of C–H activation reactions, see: a) A. R.
Dick, M. S. Sanford, Tetrahedron 2006, 62, 2439–2463; b) D.
Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174–
238; c) K. R. Campos, Chem. Soc. Rev. 2007, 36, 1069–1084;
d) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu, Chem.
Soc. Rev. 2009, 38, 3242–3472; e) I. A. I. Mkhalid, J. H. Bar-
nard, T. B. Marder, J. M. Murphy, J. F. Hartwig, Chem. Rev.
2010, 110, 890–931; f) T. W. Lyons, M. S. Sanford, Chem. Rev.
2010, 110, 1147–1169.
[21] R. J. Carroll, H. Leisch, E. Scocchera, T. Hudlicky, D. P. Cox,
Adv. Synth. Catal. 2008, 350, 2984–2992.
[22] P. P. Appukkuttan, E. Van der Eycken, W. Dehaen, Synlett
2005, 127–133.
[7] For an early review, see: a) C. Avendaño, J. C. Menéndez, Re-
cent Res. Dev. Org. Chem. 1998, 2, 69–87. For selected ad-
ditional work, see: b) J. M. Pérez, P. López-Alvarado, M. A.
Received: December 23, 2011
Published Online: March 12, 2012
Eur. J. Org. Chem. 2012, 2375–2385
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2385