Synthesis of 3,3-disubstituted-2,3-dihydroazanaphthoquinones via simultaneous alkyne oxidation and nitrile hydration of ortho- alkynylarenenitriles

Article abstract of DOI:10.1039/c4ob00852a

o-Alkynylarenenitriles when heated with Pd(OAc)₂/H ₂O/(±)-CSA in DMSO undergo simultaneous alkyne oxidation and nitrile hydration to give 3-aryl-3-hydroxy-2,3-dihydroazanaphthoquinones. Upon treatment with (±)-CSA, these compounds fo

Full text of DOI:10.1039/c4ob00852a

Organic &
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Synthesis of 3,3-disubstituted-2,3-dihydro-
azanaphthoquinones via simultaneous alkyne
oxidation and nitrile hydration of
ortho-alkynylarenenitriles†
Cite this: Org. Biomol. Chem., 2014,
12, 6440
Karuppusamy Sakthivel and Kannupal Srinivasan*
Received 25th April 2014,
Accepted 1st July 2014
o-Alkynylarenenitriles when heated with Pd(OAc)2/H2O/( )-CSA in DMSO undergo simultaneous alkyne
oxidation and nitrile hydration to give 3-aryl-3-hydroxy-2,3-dihydroazanaphthoquinones. Upon treatment
with ( )-CSA, these compounds form 3-arylazanaphthoquinones in situ, which add to electron-rich
aromatics and terminal alkene/alkyne to afford 3,3-disubstituted-2,3-dihydroazanaphthoquinones.
DOI: 10.1039/c4ob00852a
www.rsc.org/obc
Introduction
Azanaphthoquinone (A) is a structurally appealing compound
as it contains multiple functional groups: amide, imine and
ketone (Fig. 1). Given the popularity of naphthoquinones in
organic chemistry, it is surprising that only little is known
about azanaphthoquinone and its derivatives.1 This may be
correlated with the lack of a generalized method for the syn-
thesis of this type of compound. Somewhat familiar aza-
naphthoquinones are 3-aryl derivatives B, which were usually
synthesized by a thermal rearrangement of 3-azido-3-aryl-1,3-
indanediones, which in turn were prepared by a multistep pro-
cedure.1d,e Despite the limited synthetic routes, certain nucleo-
philic addition, cycloaddition and photochemical insertion
reactions of B have been studied.1e,f It is also worth noting that
Scheme 1 Proposed route to azanaphthoquinones.
these compounds may be related to 3-aryltetrahydroisoquino-
lines (C), the subunits of tetrahydroisoquinoline alkaloids.2
In continuation of our interest in the synthetic applications
of o-functionalized alkynylarenes,3 it occurred to us that in the
case of o-alkynylarenenitriles (1), if the triple bond is oxidized
to the α-diketo unit and simultaneously, the nitrile is selec-
tively hydrated to the amide group, the resulting diketoaryl-
amides
2 would undergo cyclodehydration to produce
3-substituted azanaphthoquinones 3 (Scheme 1). A variety of
reagents, including KMnO4,4 I2/DMSO,5 Fe(III) or Pd(II) com-
pounds/DMSO,6–9 MsOH/HCO2H/DMSO-HBr/H2O,10 oxone/
TFA,11 and [Ru(cymene)Cl2]2/I2/H2O2 are known for the oxi-
12
dation of alkynes to α-diketones. Likewise, numerous reagents
such
as
Ru(OH)x/Al2O3,13
TFA/H2SO4,14
Pd(OAc)2/
MeCHvNOH,15 Ag nanoparticles,16 complexes of Fe, Ru, Rh,
18
Pd, Os, Pt and Au17 and CeO2 are available for the selective
Fig. 1 Structures of azanaphthoquinone (A), 3-arylazanaphthoquinones
(B) and 3-aryltetrahydroisoquinolines (C).
hydration of nitriles to amides. But, no method exists for carry-
ing out both the transformations simultaneously in com-
pounds such as o-alkynylarenenitriles. Hence the dual
transformation would be quite useful in synthetic chemistry.
School of Chemistry, Bharathidasan University, Tiruchirappalli-620 024,
Tamil Nadu, India. E-mail: srinivasank@bdu.ac.in; Tel: +91-431-2407053-538
†Electronic supplementary information (ESI) available: Experimental procedures
and characterisation data for all products, including copies of 1H and 13C NMR
Results and discussion
spectra and X-ray structural information of 5e (CIF). CCDC 959881. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4ob00852a
We chose o-alkynylbenzonitrile 1a as a model substrate for
identifying optimal reagents and conditions for the simul-
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Table 1 Optimisation of reaction conditions for the simultaneous alkyne oxidation and nitrile hydration processa
S. No.
Reaction conditions
Yield of 4a b (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (1 equiv.), DMSO, H2O, 120 °C, 24 h
NR
65
NR
76
53
68
Pd(OAc)2 (1 equiv.), DMSO, H2O, TFA (20 mol%), 120 °C, 12 h
Pd(OAc)2 (1 equiv.), DMSO, H2O, AcOH (20 mol%), 120 °C, 12 h
Pd(OAc)2 (1 equiv.), DMSO, H2O, TfOH (20 mol%), 120 °C, 12 h
Pd(OAc)2 (1 equiv.), DMSO, H2O, MsOH (20 mol%), 120 °C, 12 h
Pd(OAc)2 (1 equiv.), DMSO, H2O, PTSA (20 mol%), 120 °C, 12 h
Pd(OAc)2 (1 equiv.), DMSO, H2O, CSA (20 mol%), 120 °C, 12 h
Pd(OAc)2 (50 mol%), DMSO, H2O, CSA (20 mol%), 120 °C, 12 h
Pd(OAc)2 (30 mol%), DMSO, H2O, CSA (20 mol%), 120 °C, 12 h
Pd(OAc)2 (1 equiv.), DMSO, H2O, CSA (10 mol%), 120 °C, 12 h
Pd(OAc)2 (1 equiv.), DMSO, H2O, CSA (30 mol%), 120 °C, 12 h
I2 (2 equiv.), DMSO, H2O, 120 °C, 24 h
87
72c
49d
60
9
10
11
12
13
14
84
55e
42 f
70g
I2 (2 equiv.), DMSO, H2O, CSA (20 mol%), 120 °C, 24 h
I2 (4 equiv.), DMSO, H2O, 150 °C, 24 h
a No reaction occurs at rt. b Isolated yield. c,d,e, f, g The corresponding alkyne oxidation product (diketobenzonitrile D) was produced as a by-
product in 7, 30, 35, 50 and 25% yields, respectively.
taneous oxidation/hydration reactions and subsequent cyclo- corresponding diketobenzonitrile D (entries 8 and 9). Redu-
dehydration to form the azanaphthoquinone 3a. Since the cing the amount of ( )-CSA to 10 mol% lowered the yield
Pd(OAc)2/CuBr2/DMSO9 system has been previously used for (entry 10) while increasing its amount to 30 mol% did not
the oxidation of alkynes and the Pd(OAc)2/MeCHvNOH15 alter the yield much (entry 11). No reaction occurred when
(H2O source) system for the hydration of nitriles, we envisaged DMSO was replaced by 1,4-dioxane and when Pd(OAc)2 was
that the Pd(OAc)2(1 equiv.)/DMSO/H2O system would be a right replaced by other catalysts such as Pd(PPh3)4, Pd(dba)3,
choice to begin with. However, with this system, 1a remained Pd(PPh3)2Cl2 and Pd(dppf)Cl2 and Ni(dppf)Cl2. Since iodine is
inert at room temperature as well as at 120 °C even after 24 h known to promote many of the transformations that palladium
(Table 1, entry 1). Larock et al. have reported the conversion of do,20 we tested the utility of I2 for the dual transformation.
nitriles to imines (subsequently, to ketones) by Pd(OAc)2/ Interestingly, when the reaction was conducted with 2 equiv.
DMSO in the presence of TFA.19 Hence, we expected that the of iodine in DMSO/H2O, 4a was produced in 55% yield along
addition of TFA to Pd(OAc)2/DMSO/H2O would promote the with D (entry 12). The inclusion of ( )-CSA reduced the yield to
dual transformation. Pleasingly, when 20 mol% of TFA was 42% (entry 13). When the reaction was conducted with
added to the reaction, it afforded the aminol 4a in 65% yield 4 equiv. of iodine at 150 °C, the yield rose to 70% (entry 14).
as the only isolable product, without undergoing further de- Based on the high yield, we selected Pd(OAc)2 (1 equiv.), H2O
hydration (entry 2). Our attempts to dehydrate/oxidize 4a to 3a (1 equiv.), and CSA (20 mol%) in DMSO at 120 °C as apt
by heating with acidic Al2O3 or DDQ (including microwave reagents and conditions for the dual transformation. If the
irradiation) did not work. Nevertheless, we thought this requirement of a sub-stoichiometric amount (1 equiv. for acti-
aminol would be as good as the respective azanaphthoquinone vating two functional groups) of expensive Pd(OAc)2 is a matter
3a with respect to its chemical reactions (see later), because of concern, inexpensive iodine may be opted with some com-
the dehydration could be effected in situ during the course of a promise in the yield (which gave 70% yield of 4a).
reaction. Hence, we proceeded with tuning the reaction con-
Using the optimized reaction conditions, the scope of the
ditions further. The reaction did not occur when AcOH was reaction was investigated for various o-alkynylarenenitriles
used instead of TFA (entry 3). However, the yield rose to 76% (Table 2). The substrates 1a–e having different aryl groups
when TfOH was used (entry 4). We tested the suitability of attached to the alkyne unit furnished the corresponding
other sulphonic acids such as MsOH, PTSA and ( )-CSA for the aminols 4a–e in 51–87% yields (entries 1–5). The yield was low
reaction (entries 5–7) and found that ( )-CSA afforded 4a in a and the reaction time was 36 h for 1d which possesses an
high yield of 87% (entry 7). With a view to reduce the amount o-anisyl group (entry 4), which may be attributed to the steric
of Pd(OAc)2 employed, we conducted the reaction with 50 and hindrance posed by the methoxy group. The reaction failed for
30 mol% of Pd(OAc)2. We found that the yields are also corres- the substrate 1f which bears an electron-deficient p-nitro-
pondingly decreased and also 4a was accompanied by the phenyl ring (entry 6) and also for 1g which bears an aliphatic
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Table 2 The scope of the dual transformationa
Entry
Product
Yieldb (%)
Nitrile
1
2
3
4
5
6
Ar = Ph, 1a
4a
4b
4c
4d
4e
87 (70)c
73 (48)c
78 (43)c
Ar = 4-MeC6H4, 1b
Ar = 4-OMeC6H4, 1c
Ar = 2-OMeC6H4, 1d
Ar = 4-ClC6H4, 1e
Ar = 4-NO2C6H4, 1f
d
51
69 (52)c
NRe
—
7
NRe
—
8
58f
9
55f
Scheme 2 Mechanism for the formation of aminol 4.
the methylenedioxy unit in the place gave a good yield of the
respective aminol 4h (entry 10).
10
78
Further, we investigated the scope of the reaction for
heterocyclic o-alkynylarenenitriles (entries 11 and 12). For the
quinoline-based nitrile 1k, only the nitrile group underwent
hydration while the triple bond did not get oxidized. The
resulting benzamide upon intramolecular hydroamination
afforded the lactam 4i (entry 11). For the tetrahydrobenzothio-
phene-based nitrile 1l, only the triple bond was oxidized while
the nitrile group remained inert to give the diketo product 4j
(entry 12).
11
12
59
81
The mechanism for the oxidation of the triple bond by
Pd(OAc)2/DMSO in the presence of an additive is known.9
Similarly, the mechanism for hydration of nitrile to amide by
Pd-catalysts has been well-documented.21 By combining the
two mechanisms, a plausible mechanism for the formation of
aminols 4 from the alkynylbenzonitriles 1 is derived as shown
in Scheme 2. A catalytically active Pd complex is generated
in situ by the replacement of acetate ligands of Pd(OAc)2 by
camphorsulphonate (RSO2O−).19,22 The complex coordinates
simultaneously to both the triple bond and the nitrile group of
1 to give P. The triple bond of P is attacked by a molecule of
a Reaction conditions: Pd(OAc)2 (1 equiv.), DMSO, H2O, CSA (20 mol
%), 120 °C, 12 h. b Isolated yield. c The number in parenthesis is the
yield obtained when the I2/H2O/DMSO system was employed. d The
reaction time was 36 h. e No reaction. f The reaction required 2 equiv.
of Pd(OAc)2 and 50 mol% of CSA and 24 h for completion.
chain instead of an aryl group (entry 7), probably due to a sig- DMSO to give Q via displacement of the RSO2O− ligand.9
nificant change in the electronic nature of the alkyne unit. We Again, another molecule of DMSO attacks Q making a mole-
also changed the substituents on the main aryl ring. When no cule of Me2S to leave, forming R. The attack of RSO2O− on R
or single methoxy group was present on the ring, the yields of regenerates a part of the catalyst and eliminates another mole-
the aminols (4f and 4g) were low (entries 8 and 9). However, cule of Me2S, giving S. Simultaneously, the nitrile group of S is
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attacked by a water molecule.15,19,21 The attack leads to iminol
T, which undergoes tautomerization to amide and regenerates
the catalyst. The resulting diketobenzamide 2 undergoes cycli-
zation to afford 4. Careful monitoring of the reactions indi-
cates that the alkyne oxidation precedes nitrile hydration
and thus, the process is, even though simultaneous, not
synchronous.
It is interesting to note that the functional group pattern
(ketone, 3° alcohol and amide functional groups in a six-mem-
bered ring) found in the aminols 4 is present in the precursor
used in the total synthesis of the alkaloid, chilenine23 and also
in the tricyclic core of secondary metabolites ugibohlin, iso-
phakellin and styloguanidine.24
To prove the point that the aminols 4 would behave like
respective azanaphthoquinones in their reactions, the nucleo-
philic addition reactions of 4a were investigated. We reasoned
that the dehydration and the nucleophilic addition would be
assisted by acid catalysts, because Nicolaou et al. have used
triflic acid in the case of 3-aryl-3-hydroxyoxindoles for generat-
ing an all-carbon quaternary center at C-3 by Friedel–Crafts
alkylation with aromatics.25 Thus we employed triflic acid
(1 equiv.) for the addition of anisole to 4a and found that the
expected nucleophilic addition product 5a was produced in
92% yield when the reaction was carried out in 1,2-DCE at
reflux for 2 h (Table 3). This suggests that the corresponding
Fig. 2 ORTEP plot of the crystal structure of 5e (at 30% probability
level).
azanaphthoquinone 3a would have formed in situ and then
undergone nucleophilic addition (however, isolation of 3a did
not materialise). To our delight, an identical yield was
obtained when ( )-CSA was used in the place of triflic acid in
the reaction. Hence we switched to ( )-CSA for subsequent
reactions due to its less corrosiveness. The scope of the reac-
tion was investigated using various nucleophilic substrates
such as 2-methylfuran, indole, 9-ethylcarbazole, styrene and
phenylacetylene (Table 3).
In all cases, the respective nucleophilic addition products
were produced in good to reasonable yields. Among the pro-
ducts 5a–f, the structure of 5e was confirmed by X-ray analysis
(Fig. 2). The addition of styrene and phenylacetylene to 4a (via
3a) deserves a comment, because the addition of terminal
alkenes/alkynes to imines, which is an effective protocol
for accessing synthetically important allylamines/propargyl-
amines, is invariably accomplished using transition metal
compounds in the literature.26 The two examples given here,
therefore, represent intriguing metal-free direct addition of the
C–H bond of terminal alkene/alkyne to a ketimine moiety.
Table 3 Nucleophilic addition reactions of 4aa
Conclusions
In summary, we have developed an efficient palladium (or
iodine)-mediated procedure for the simultaneous alkyne oxi-
dation and nitrile hydration of o-alkynylarenenitriles for acces-
sing 3-aryl-3-hydroxy-2,3-dihydroazanaphthoquinones. These
compounds might behave like respective azanaphthoquinones
in their chemical reactions as evidenced by their nucleophilic
addition reactions. With the availability of a general route to
(dihydro)azanaphthoquinones, the arena is now open for
scouting their synthetic potentials and other applications.
Experimental
General remarks
Melting points were determined using an apparatus by the
1
open capillary tube method and are uncorrected. The H and
13C NMR spectra were recorded on a 400 MHz NMR spectro-
meter. HRMS (ESI) were recorded on Q-Tof mass
spectrometers. X-ray crystallographic data were collected on a
CCD diffractometer using graphite-monochromated Mo-Kα
a Isolated yield. b Reaction time was 6 h. c Reaction time was 12 h.
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radiation. Thin layer chromatography (TLC) was performed on 126.3, 123.5, 113.4, 109.0, 107.5, 85.4, 56.1, 55.9, 55.1 ppm.
pre-coated alumina sheets and detected under UV light. Silica HRMS (ESI) calcd for C18H17NO6: 366.0954 [M + Na]+, found:
gel (100–200 mesh) was used for column chromatography.
366.0958.
3-Hydroxy-6,7-dimethoxy-3-(2-methoxyphenyl)-2,3-dihydroiso-
quinoline-1,4-dione (4d). Pale yellow solid. Yield: 26 mg
(51%). M.p.: 180–182 °C. H NMR (400 MHz, DMSO-d6): δ 8.77
General procedure for simultaneous alkyne oxidation and
nitrile hydration
1
To a solution of o-alkynylarenenitriles 1 (0.15 mmol) in DMSO (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.40 (s, 1H), 7.32
(5 mL) were added palladium(II) acetate (34 mg, 0.15 mmol) (t, J = 7.0 Hz, 1H), 7.11 (s, 1H), 7.00 (t, J = 7.4 Hz, 1H), 6.94 (d,
(67 mg, 0.30 mmol for 4f and 4g) and ( )-camphorsulphonic J = 8.0 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.37 (s, 3H). 13C NMR
acid (46 mg, 20 mol%) (116 mg, 50 mol% for 4f and 4g) and (100 MHz, DMSO-d6): δ 190.5, 160.5, 155.7, 153.6, 151.9, 130.7,
water (3 µL, 0.15 mmol) and stirred at 120 °C for 12 h (36 h for 129.4, 126.9, 126.4, 124.2, 119.9, 111.5, 109.0, 107.0, 82.0, 56.0,
4d and 24 h for 4f and 4g). The reaction mixture was then 55.9, 55.5 ppm. HRMS (ESI) calcd for C18H17NO6: 344.1134
diluted with water and extracted with EtOAc. The organic layer [M + H]+, found: 344.1132.
was dried over anhydrous Na2SO4 and concentrated under
3-(4-Chlorophenyl)-3-hydroxy-6,7-dimethoxy-2,3-dihydroiso-
reduced pressure. The crude product was purified by column quinoline-1,4-dione (4e). Off-white solid. Yield: 36 mg (69%)
1
chromatography (SiO2; EtOAc–hexane, 8 : 2 v/v) to afford the [27 mg (52%) using I2/H2O/DMSO]. M.p.:196–198 °C. H NMR
compounds 4a–j. Using I2/H2O/DMSO: To a solution of (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.60 (s, 1H), 7.46–7.41 (m,
o-alkynylarenenitriles 1 (0.15 mmol) in DMSO (5 mL) were 5H), 7.30 (s, 1H), 3.97 (s, 3H), 3.87 (s, 3H). 13C NMR (100 MHz,
added iodine (152 mg, 0.6 mmol) and water (3 µL, 0.15 mmol) DMSO-d6): δ 190.8, 161.1, 154.4, 152.3, 139.7, 133.0, 128.3,
and stirred at 150 °C for 24 h. The reaction mixture was then 128.0, 126.4, 123.3, 109.1, 107.5, 84.9, 56.1, 55.9 ppm. HRMS
quenched with aq. Na2S2O3 solution and worked up as (ESI) calcd for C17H14ClNO5: 370.0458 [M + Na]+, found:
described above.
370.0463.
3-Hydroxy-6,7-dimethoxy-3-phenyl-2,3-dihydroisoquinoline-
3-Hydroxy-3-phenyl-2,3-dihydroisoquinoline-1,4-dione (4f).
1,4-dione (4a). Pale yellow solid. Yield: 41 mg (87%) [33 mg Pale yellow solid. Yield: 22 mg (58%). M.p.: 179–181 °C (lit.1a
(70%) using I2/H2O/DMSO]. M.p. 202–204 °C. 1H NMR 181–183 °C). 1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H), 8.16
(400 MHz, DMSO-d6): δ 9.14 (s, 1H), 7.59 (s, 1H), 7.46–7.44 (m, (dd, J = 7.6, 0.8 Hz, 1H), 7.94–7.87 (m, 2H), 7.83–7.77 (m, 1H),
2H), 7.35–7.29 (m, 5H), 3.96 (s, 3H), 3.85 (s, 3H). 13C NMR 7.50–7.46 (m, 2H), 7.45 (s, 1H), 7.37–7.30 (m, 3H). 13C NMR
(100 MHz, DMSO-d6): δ 191.3, 161.1, 154.3, 152.3, 140.6, 128.2, (100 MHz, DMSO-d6): δ 192.2, 161.3, 140.1, 135.2, 133.2, 131.6,
128.0, 126.4, 126.2, 123.4, 109.1, 107.4, 85.5, 56.1, 55.9 ppm. 129.7, 128.4, 128.1, 127.7, 126.4, 126.3, 85.4 ppm. HRMS (ESI)
HRMS (ESI) calcd for C17H15NO5: 314.1028 [M + H]+, found: calcd for C15H11NO3: 276.0637 [M + Na]+, found: 276.0643.
314.1027.
3-Hydroxy-7-methoxy-3-phenyl-2,3-dihydroisoquinoline-1,4-
4,5-Dimethoxy-2-(2-oxo-2-phenyl-acetyl)-benzonitrile
(D). dione (4g). Pale yellow solid. Yield: 23 mg (55%).
Pale yellow solid. M.p.: 136–138 °C. 1H NMR (400 MHz, M.p.:164–166 °C. 1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H),
CDCl3): δ 8.02 (d, J = 8.0 Hz, 2H), 7.69 (t, J = 7.2 Hz, 1H), 7.54 7.85 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.46–7.44 (m,
(t, J = 7.6 Hz, 2H), 7.44 (s, 1H), 7.26 (s, 1H), 4.00 (s, 3H), 3.94 2H), 7.37 (s, 1H), 7.34–7.29 (m, 4H), 3.95 (s, 3H). 13C NMR
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 192.5, 190.4, 153.4, (100 MHz, DMSO-d6): δ 190.8, 164.7, 160.9, 140.5, 134.1, 129.2,
152.1, 135.1, 132.8, 130.2, 129.2, 129.1, 117.3, 116.6, 113.6, 128.2, 128.0, 126.2, 122.8, 119.7, 111.2, 85.3, 56.0 ppm.
105.6, 56.7, 56.4. HRMS (ESI) calcd for C17H13NO4: 296.0917 HRMS (ESI) calcd for C16H13NO4: 284.0923 [M + H]+, found:
[M + H]+, found: 296.0923.
284.0922.
3-Hydroxy-6,7-dimethoxy-3-(4-methylphenyl)-2,3-dihydroiso-
7-Hydroxy-7-phenyl-6,7-dihydro-[1,3]dioxolo[4,5-g]isoquino-
quinoline-1,4-dione(4b). Off-white solid. Yield: 36 mg (73%) line-5,8-dione (4h). Pale yellow solid. Yield: 35 mg (78%).
1
[23 mg (48%) using I2/H2O/DMSO]. M.p.:199–201 °C. H NMR M.p.:176–178 °C. 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H),
(400 MHz, DMSO-d6): δ 9.09 (s, 1H), 7.59 (s, 1H), 7.32 (d, J = 7.61 (s, 1H), 7.54–7.52 (m, 2H), 7.45–7.39 (m, 4H), 7.34 (s, 1H),
8.0 Hz, 2H), 7.28 (s, 1H), 7.26 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.33 (d, J = 11.2 Hz, 2H). 13C NMR (100 MHz, DMSO-d6):
3.96 (s, 3H), 3.86 (s, 3H), 2.26 (s, 3H). 13C NMR (100 MHz, δ 196.1, 166.0, 158.5, 156.7, 145.7, 134.2, 133.5, 133.3, 131.5,
DMSO-d6): δ 191.9, 161.6, 154.8, 152.7, 138.2, 138.1, 129.1, 131.0, 111.8, 110.0, 108.4, 90.5. HRMS (ESI) calcd for
126.9, 126.6, 124.0, 109.5, 107.9, 86.0, 56.6, 56.4, 21.1 ppm. C16H11NO5: 298.0715 [M + H]+, found: 298.0712.
HRMS (ESI) calcd for C18H17NO5: 328.1185 [M + H]+, found:
328.1185.
3-Phenylbenzo[b][1,6]naphthyridin-1(2H)-one
(4i). Yellow
solid. Yield: 24 mg (59%). M.p.: 260–262 °C. 1H NMR
3-Hydroxy-6,7-dimethoxy-3-(4-methoxyphenyl)-2,3-dihydroiso- (400 MHz, DMSO-d6): δ 11.71 (s, 1H), 9.34 (s, 1H), 8.31 (d, J =
quinoline-1,4-dione (4c). Pale yellow solid. Yield: 40 mg (78%) 8.0 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.01–7.93 (m, 3H),
[22 mg (43%) using I2/H2O/DMSO]. M.p.: 183–185 °C. 1H NMR 7.72–7.68 (m, 1H), 7.64–7.58 (m, 3H), 7.08 (d, J = 1.2 Hz, 1H).
(400 MHz, DMSO-d6): δ 9.08 (s, 1H), 7.58 (s, 1H), 7.35 (d, J = 13C NMR (100 MHz, DMSO-d6): δ 163.4, 153.0, 150.6, 144.4,
8.8 Hz, 2H), 7.28 (s, 1H), 7.24 (s, 1H), 6.88 (d, J = 8.8 Hz, 2H), 137.5, 133.5, 132.6, 129.9, 129.7, 128.9, 128.0, 126.9, 126.1,
3.96 (s, 3H), 3.85 (s, 3H), 3.71 (s, 3H). 13C NMR (100 MHz, 126.0, 119.6, 104.4. HRMS (ESI) calcd for C18H12N2O: 273.1028
DMSO-d6): δ 191.4, 161.2, 159.3, 154.2, 152.2, 132.5, 127.5, [M + H]+, found: 273.1026.
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2-(2-Oxo-2-phenylacetyl)-4,5,6,7-tetrahydrobenzo[b]thiophene- 128.4, 128.3, 126.0, 125.9, 125.7, 125.6, 122.8, 122.7, 120.6,
3-carbonitrile (4j). Red solid. Yield: 36 mg (81%). M.p.: 120.0, 119.2, 109.4, 108.60, 108.58, 108.2, 74.9, 56.6, 56.4, 37.6,
74–76 °C. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 7.6 Hz, 2H), 13.8 ppm. HRMS (ESI) calcd for
7.69 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 2.86–2.77 (m, [M + H]+, found: 491.1972.
C31H26N2O4: 491.1971
4H), 1.90–1.88 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 190.6,
(E)-6,7-Dimethoxy-3-phenyl-3-styryl-2,3-dihydroisoquinoline-
181.7, 149.9, 140.9, 138.6, 135.2, 132.2, 130.6, 129.0, 115.9, 1,4-dione (5e). Pale yellow solid. Yield: 27 mg (68%). M.p.:
113.5, 25.6, 24.3, 22.6, 21.6. HRMS (ESI) calcd for C17H13NO2S: 224–226 °C. 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H),
318.0565 [M + Na]+, found: 318.0565.
7.51–7.47 (m, 3H), 7.42–7.26 (m, 8H), 6.85 (d, J = 16.0 Hz, 1H),
6.75 (d, J = 16.0 Hz, 1H), 6.60 (s, 1H), 4.04 (s, 3H), 3.97 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 191.1, 162.3, 154.9, 153.1, 140.9,
135.6, 131.8, 130.0, 129.0, 128.7, 128.6, 128.5, 126.94, 126.85,
General procedure for the synthesis of dihydroazanaphtho-
quinones 5
To a solution of 4a (31 mg, 0.1 mmol) in 1,2-dichloroethane 126.0, 124.7, 109.5, 108.2, 71.8, 56.7, 56.4 ppm. HRMS (ESI)
(5 mL) were added ( )-camphor sulphonic acid (23 mg, calcd for C25H21NO4: 400.1549 [M + H]+, found: 400.1549.
0.1 mmol) and arene, alkene or alkyne (0.2 mmol) and heated
6,7-Dimethoxy-3-phenyl-3-(phenylethynyl)-2,3-dihydroisoquino-
under reflux for 2 h (6 h for 5e and 12 h for 5f). The reaction line-1,4-dione (5f). Pale orange solid. Yield: 21 mg (53%).
mixture was then diluted with water and extracted with EtOAc. M.p.:196–198 °C. 1H NMR (400 MHz, CDCl3): δ 7.77 (s, 1H),
The organic layer was dried over anhydrous Na2SO4 and con- 7.72–7.70 (m, 2H), 7.51–7.49 (m, 2H), 7.46 (s, 1H), 7.40–7.32
centrated under reduced pressure. The crude product was (m, 6H), 6.62 (brs, 1H), 4.07 (s, 3H), 3.97 (s, 3H). 13C NMR
purified by column chromatography (SiO2; EtOAc–hexane, 7 : 1 (100 MHz, CDCl3): δ 186.9, 161.6, 155.1, 153.2, 138.9, 132.0,
v/v) to afford the compounds 5a–f.
129.1, 129.0, 128.9, 128.4, 126.6, 126.0, 124.0, 121.6, 109.8,
6,7-Dimethoxy-3-(4-methoxyphenyl)-3-phenyl-2,3-dihydroiso- 108.7, 86.8, 86.3, 66.7, 56.7, 56.5 ppm. HRMS calcd for
quinoline-1,4-dione (5a). Pale orange solid. Yield: 37 mg C25H19NO4: 398.1392 [M + H]+, found: 398.1393.
1
(92%). M.p. 199–201 °C. H NMR (400 MHz, CDCl3): δ 7.65 (s,
1H), 7.46 (s, 1H), 7.32 (s, 5H), 7.24 (d, J = 8.8 Hz, 2H), 6.84 (d,
J = 8.8 Hz, 2H), 6.71 (s, 1H), 4.02 (s, 3H), 3.96 (s, 3H), 3.78 (s,
Acknowledgements
3H). 13C NMR (100 MHz, CDCl3): δ 192.2, 162.2, 159.6, 154.7,
153.0, 141.3, 133.0, 129.3, 128.6, 128.4, 128.0, 125.9, 125.5, The authors thank the Department of Science and Technology
114.0, 109.4, 108.2, 74.1, 56.6, 56.4, 55.3 ppm. HRMS (ESI) (DST) and the Council of Scientific and Industrial Research
calcd for C24H21NO5: 404.1498 [M + H]+, found: 404.1483.
(CSIR) for financial support; DST-FIST for NMR and X-ray
6,7-Dimethoxy-3-(5-methylfuran-2-yl)-3-phenyl-2,3-dihydroiso- facilities at the School of Chemistry, Bharathidasan University,
quinoline-1,4-dione (5b). Orange solid. Yield: 34 mg (90%). India.
1
M.p.: 190–192 °C. H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H),
7.47–7.44 (m, 3H), 7.37–7.32 (m, 3H), 6.76 (s, 1H), 6.23 (d, J =
3.2 Hz, 1H), 5.95–5.94 (m, 1H), 4.05 (s, 3H), 3.96 (s, 3H), 2.26
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(s, 3H). 13C NMR (100 MHz, CDCl3): δ 188.6, 162.0, 154.9,
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110.9, 109.5, 108.3, 106.3, 70.1, 56.7, 56.4, 13.7 ppm. HRMS
(ESI) calcd for C22H19NO5: 378.1341 [M + H]+, found: 378.1346.
6,7-Dimethoxy-3-(1-methyl-1H-indol-3-yl)-3-phenyl-2,3-dihydro-
isoquinoline-1,4-dione (5c). Pale orange solid. Yield: 28 mg
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(66%). M.p.:158–160 °C. H NMR (400 MHz, CDCl3): δ 7.71(s,
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hydroisoquinoline-1,4-dione (5d). Pale orange solid. Yield:
35 mg (71%). M.p.: 236–238 °C. 1H NMR (400 MHz, CDCl3):
δ 8.06 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H),
7.49 (s, 1H), 7.47–7.34 (m, 8H), 7.26 (s, 1H), 7.20 (t, J = 7.4 Hz,
1H), 6.83 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 4.01 (s, 3H), 3.95 (s,
3H), 1.41 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 192.5, 162.3, 154.6, 153.0, 142.0, 140.4, 139.7, 131.1, 128.6,
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