Iodine/water-mediated oxidation of o-alkynylaroyl compounds and application of the products of oxidation in the synthesis of nitrogen heterocycles

Article abstract of DOI:10.1002/ejoc.201300046

A facile iodine/water-mediated oxidation of the triple bond of o-alkynylaroyl compounds to furnish tricarbonyl compounds is reported. The reaction proceeds through the formation of isochromenol intermediates by the assistance of the neighbouring aroyl gro

Full text of DOI:10.1002/ejoc.201300046

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FULL PAPER
DOI: 10.1002/ejoc.201300046
Iodine/Water-Mediated Oxidation of o-Alkynylaroyl Compounds and
Application of the Products of Oxidation in the Synthesis of Nitrogen
Heterocycles
Karuppusamy Sakthivel[a] and Kannupal Srinivasan*[a]
Keywords: Synthetic methods / Oxidation / Nitrogen heterocycles / Alkynes / Neighboring-group effects
A facile iodine/water-mediated oxidation of the triple bond
alcohols, afford various heterocyclic scaffolds such as isoind-
of o-alkynylaroyl compounds to furnish tricarbonyl com- olinones, phthalazines, benzimidazoisoquinolinones, quin-
pounds is reported. The reaction proceeds through the for-
mation of isochromenol intermediates by the assistance of
the neighbouring aroyl group. The product tricarbonyl com-
pounds are versatile synthetic precursors that, upon treat-
ment with mono- and diamines, hydrazines and amino
oxalines and benzimidazole-quinoxaline hybrid compounds.
Mechanistic aspects of the formation of the above heterocy-
cles are discussed. Finally, a short synthetic route to the iso-
indolinone natural product, aristolactam BII is reported.
isochromenol B. Subsequent displacement of iodine by
water in C eventually leads to the oxidised product 2. Thus,
the neighbouring formyl group in 1 assists the oxidation of
the alkyne unit so that the reaction takes place in a facile
manner under mild conditions. By adapting this procedure,
a series of tricarbonyl analogues of 2 were prepared from
various o-alkynlarenecarbaldehydes in yields ranging from
63 to 93%.[21]
It was clear that the above oxidation methodology
should be applicable to other o-alkynylaroyl compounds
such as ketones, acids, esters and amides. The development
of these possibilities would generate a multitude of com-
pounds with a range of carbonyl groups. These compounds
could be potential precursors of a diverse array of carbo-
and heterocycles including natural products, and are thus
welcome in diversity-oriented synthesis (DOS), which con-
cerns with transformation of a set of given precursors into
a library of diverse compounds.[23]
Introduction
o-Alkynylarenecarbaldehydes are useful building blocks
in organic synthesis. They undergo cycloisomerisation in
the presence of transition-metal compounds or other elec-
trophiles to form isochromenylium intermediates.[1–10] The
addition of oxygen,[1a,1b,2b,10] nitrogen[8] or carbon nucleo-
philes[1c,3a,3b,4b,9a] to the intermediates gives various isoch-
romenes. Cycloaddition reactions of these intermediates
with suitable partners furnish naphthalenes,[2a,4a,5b,9b,9c,11]
dihydronaphthalenes[12] or polycyclic structures.[6,7,13] The
intermediates also lead to interesting carbazoles,[14] dihy-
droisoquinolines[15] and isoquinolines.[16] Furthermore, they
have been applied in the total synthesis of azaphilones,[4c,17]
fascaplysin,[18] heliophenanthrone,[5a] and (+)-ochromyci-
none.[19]
Numerous reagents have been used for the oxidation of
the C–C triple bond of internal alkynes to the correspond-
ing α-diketo derivatives.[20] We have recently reported an en-
vironmentally benign, metal-free procedure for the oxi-
dation of the triple bond of o-alkynyl arenecarbaldehydes
using an iodine/water system[21] and, more generally, molec-
ular iodine has been recognised as a valuable reagent in
organic synthesis.[22] Scheme 1 exemplifies our work. The o-
alkynylbenzaldehyde 1, upon exposure to iodine, undergoes
triple bond activation to give isochromenylium intermediate
A, which undergoes nucleophilic addition by water to form
In this article, we report the scope of our oxidation meth-
odology with respect to various o-alkynylaroyl compounds
and application of the resulting products for the synthesis
of several hetereocycles such as isoindolinones, phthalaz-
ines, benzimidazoisoquinolinones, quinoxalines and benz-
imidazole-quinoxaline hybrids, and a natural product,
aristolactam BII.
Results and Discussion
[a] School of Chemistry, Bharathidasan University,
Tiruchirappalli 620024, Tamil Nadu, India
Fax: +91-431-2407043
Oxidation of o-Alkynylarene Ketones
E-mail: srinivasank@bdu.ac.in
Homepage: www.bdu.ac.in/schools/chemistry/chemistry/
dr_k_srinivasan.php
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300046.
We began the study by applying our standard oxidation
procedure[21] to o-alkynylarene ketone 3a (Table 1, entry 1).
When 3a was stirred with iodine (2 equiv.) in water/aceto-
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Scheme 1. Oxidation of o-alkynylbenzaldehyde 1 into tricarbonyl compound 2.
Table 1. Oxidation of o-alkynylarene ketones.
[a] Isolated yield. [b] Compound 4f could not be isolated in pure form. [c] The reaction time was 20 min. [d] The isolated compound
decomposed readily.
2
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Iodine/Water-Mediated Oxidation
nitrile (1:9) at room temperature for 10 min, it smoothly cyclisation). Ester 8, for which the formation of iso-
underwent oxidation to give triketone 4a in 77% yield after chromenylium intermediate is not possible, remained inert
purification.
under the reaction conditions. Amides 9 and 10 were also
The reaction was found to be quite general, and ketones inert, probably due to the lower reactivity of the amide
3b–e, bearing a range of substituents, were also oxidised to carbonyl group under the reaction conditions.
the corresponding triketones 4b–e in good yields under the
developed conditions (Table 1, entries 2–5; the structure of
4b was confirmed by X-ray crystallographic analysis[24]).
Reactions of Tricarbonyl Compounds Derived from
However, although ketone 3f, having a nitro group on the
o-Alkynylarene Aldehydes and Ketones with Amines
aryl ring attached to the yne unit, afforded triketone 4f, the
product could not be isolated in pure form (entry 6). The
The 1,2,5-tricarbonyl compounds arising from oxidation
presence of heteroaryl groups was tolerated and ketones 3g
of o-alkynylarene aldehydes/ketones were previously un-
and 3h afforded high yields of triketones 4g and 4h, respec-
known and, hence, their reactivity patterns were not de-
scribed. In addition to showing unique reactivity as 1,2,5-
tricarbonyl compounds, they were also expected to display
reactivities of 1,2-, 1,4- or 1,5-dicarbonyl compounds. A
systematic investigation of their reactivity patterns was
therefore expected to lead to the discovery of new reactions
and materials. Thus, the tricarbonyl compounds could serve
as resourceful precursors in diversity-oriented organic syn-
tively, without giving rise to any side reactions such as cy-
cloaddition[25a] or electrophilic cyclisation[25b] (entries 7 and
8). Ketones 3i and 3j, bearing naphthyl and dibenzodioxinyl
groups, respectively, also furnished the desired triketones 4i
and 4j in good yields (entries 9 and 10). The oxidation of
diynyl ketone 3k to triketone 4k is especially interesting to
note (entry 11); in this case, the alkyne group ortho to the
carbonyl was oxidised, whereas the second alkyne group
thesis, in analogy with polyketides in natural product syn-
thesis.[26] With this idea in mind, we treated some of the
tricarbonyl compounds with a range of amines and found
that they are indeed versatile precursors for nitrogen hetero-
cycles.
para to the carbonyl moiety remained unchanged (even
when five equivalents of iodine were employed). This clearly
reveals that the reaction proceeds through formation of an
isochromenol intermediate, as proposed in the mechanism
of oxidation of o-alkynylarenecarbaldehydes (Scheme 1).
The oxidation was also successful with quinoline-based o-
alkynylarene ketone 3l, which afforded triketone 4l in 70%
yield (entry 12). Finally, the procedure was also applied to
aryl alkyl ketone 3m; in this case, the corresponding tri-
ketone 4m was isolated in 83% yield (entry 13), however,
this product was found to be unstable.
Reactions with Monoamines
Tricarbonyl compounds 2 and 4a were reacted with vari-
ous monoamines in ethanol at room temperature (Table 1).
Primary aliphatic and aryl alkylamines (n-butylamine, 4,4-
diethoxybutylamine, cyclohexylamine, benzylamine, (S)-
methyl-2-amino-3-phenylpropionate and (R)-1-phenyleth-
ylamine) were employed in the reactions. In all cases, 2 and
4a behaved as though they were 1,4-dicarbonyl (o-
phthaloyl) compounds and formed isoindolinones with the
Oxidation of Other o-Alkynylbenzoyl Compounds
We extended the oxidation methodology to other o-alk- loss of a benzoyl group. The product isoindolinones 12a–h
ynylaroyl compounds such as acids, esters and amides were obtained in 66–84% yields after purification (Table 2).
(Scheme 2). When acid 5 and ester 6[21] were subjected to The scope of the reaction was also investigated with aro-
oxidation under the usual conditions, instead of the ex- matic primary amines such as aniline, p-toluidine and p-
pected oxidation products, these substrates afforded iodo- anisidine. These reactions, however, failed to give the ex-
isochromenone 7, presumably via intermediate D (iodo- pected isoindolinones.
Scheme 2. Oxidation of various o-alkynylaroyl compounds.
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Table 2. Formation of isoindolinones.
[a] The reaction time was 20 min. [b] The reaction time was 2 h.
There have been many reports in which o-phthaloyl com- observed the other possible isoindolinone 12Ј in any of the
pounds react in a similar manner with amines and amides above reactions. Clearly, the proton or phenyl group was
to give isoindolinones.[27] Taking inspiration from these re- not eliminated from D to give EЈ, presumably owing to the
ports, we propose the mechanism depicted in Scheme 3 for difficulty of forming an sp2 carbon adjacent to the carbonyl
the formation of isoindolinones with concomitant loss of a group in EЈ.
benzoyl group in the above reactions. Thus, the reaction of
To demonstrate the versatility of the above methodology,
2 or 4a with 11 generates hemiaminal D; this compound we devised a short synthetic route to the naturally occurring
loses a benzoyl group to form hydroxy isoindole E, which, isoindolinone alkaloid (Scheme 4), aristolactam BII (16),
upon tautomerisation, affords isoindolinone 12. We never which is known to display appreciable antitumor activity.[28]
Scheme 3. Mechanism for the formation of isoindolinones 12.
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Iodine/Water-Mediated Oxidation
Scheme 4. Total synthesis of aristolactam BII.
Accordingly, tricarbonyl compound 2 was converted into form a benzimidazole derivative, which either undergoes
isoindolinone 13 by treatment with tert-butylamine in 84% cyclisation to give 17 or further cyclocondensation with an-
yield under standard conditions. Bromination of 13 in CCl4 other molecule of o-PDA to give 18. In contrast, tricarbonyl
gave bromoisoindolinone 14 in 72% yield. Adapting a ther- compounds 4b and 4c behaved like 1,2-diketones and gave
mal version of the procedure developed by Heo et al.,[29] quinoxalines 19a and 19b in 78 and 80% yields, respectively,
14 was subjected to tandem Suzuki–Miyura coupling/aldol under the same conditions.
With hydrazine, tricarbonyl compounds 2, 4b and 4c
acted as 1,4-diketones and underwent cyclocondensation to
form the phthalazine ketones 20a–c in 68–74% yields
(Scheme 6; the structure of 20b was confirmed by X-ray
crystallographic analysis[31]). Interestingly, when 2 was
treated with ethylene diamine, isoindolinone 21a was pro-
duced in 78% yield, with migration of the benzoyl group to
the terminal nitrogen. Similarly, isoindolinones 21b and 21c
condensation with (2-formylphenyl)boronic acid to give N-
protected lactam 15 in 70% yield. Removal of the protect-
ing group from 15 by treatment with trifluoroacetic acid
(TFA) furnished the target compound 16 in 90% yield (the
overall yield over four steps was 38%).
Reactions with Diamines
The tricarbonyl compounds underwent assorted trans- were obtained in very good yields when 4c was treated with
formations when treated with aliphatic and aromatic di- ethylene diamine and 1,3-diaminopropane, respectively. The
amines. Thus, tricarbonyl compound 2, when reacted with reaction, however, failed to form isoindolinone 21d when 4c
o-phenylenediamine (o-PDA), gave benzimidazo-isoquinol- was treated with 1,4-diaminobutane. This suggested to us
inone 17 in 63% yield along with the quinoxaline-benzimid- the mechanism shown in Scheme 7. Accordingly, the reac-
azole hybrid compound 18 in 10% yield (Scheme 5; the tion might proceed via tricyclic hemiaminal F. In case of
structure of 18 was confirmed by X-ray crystallographic 1,4-diaminobutane, the formation of the corresponding
analysis[30]). Clearly, o-PDA undergoes initial cycloconden- hemiaminal FЈ did not occur because it would require the
sation (and self-oxidation) with the formyl group of 2 to formation of an energetically unfavourable eight-membered
Scheme 5. Formation of benzimidazoisoquinolinones, quinoxaline-benzimidazole hybrid and quinoxalines.
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K. Sakthivel, K. Srinivasan
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Scheme 6. Formation of phthalazines and isoindolinones.
Scheme 7. Mechanism for the formation of isoindolinones 21.
C ring. Hemiaminal F then underwent opening of the C in 69 and 89% yields, respectively, with migration of the
ring to form hydroxyisoindole H, which, upon tautomeri- benzoyl group, possibly through a similar mechanistic path-
sation, gave isoindolinones 21.
way to that outlined in Scheme 7.
Reactions with Amino Alcohols
Conclusions
Finally, tricarbonyl compounds 2 and 4c were reacted
with aminoethanol (Scheme 8). As with aliphatic diamines,
these reactions also generated isoindolinones 22a and 22b
We have developed a simple, environmentally benign pro-
cedure for the oxidation of a variety of o-alkynylarene alde-
hydes and ketones into the corresponding tricarbonyl com-
pounds using an iodine/water system. The facile nature of
the reaction is attributed to the involvement of iso-
chromenol intermediates formed through intramolecular
nucleophilic attack of the neighbouring carbonyl oxygen on
the triple bond. The tricarbonyl compounds resulting from
the present oxidation methodology are potential precursors
of various nitrogen heterocycles, including isoindolinones
and a natural product, aristolactam BII. We are exploring
further synthetic potential of the tricarbonyl compounds.
Scheme 8. Formation of isoindolinones 22.
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Iodine/Water-Mediated Oxidation
NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.8 Hz, 2 H), 7.78–7.76
(m, 2 H), 7.54–7.52 (m, 1 H), 7.44–7.40 (m, 3 H), 7.01 (s, 1 H),
6.91 (d, J = 8.8 Hz, 2 H), 3.96 (s, 3 H), 3.88 (s, 3 H), 3.83 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.3, 192.5, 190.1,
164.5, 151.9, 150.7, 137.2, 134.9, 133.1, 132.9, 129.8, 128.9, 128.5,
126.3, 113.9, 113.5, 112.3, 56.4, 56.3, 55.5 ppm. HRMS: m/z calcd.
for C24H20O6 [M + H]+ 405.1333; found 405.1336.
Experimental Section
General Remarks: Melting points were determined with the open
capillary tube method and are uncorrected. 1H and 13C NMR spec-
tra were recorded with a 400 MHz NMR spectrometer. HRMS
(ESI) were recorded with a Q-Tof mass spectrometer. Low-resolu-
tion mass spectra (ESI) were recorded with an LC-MS spectrome-
ter. Elemental analyses were performed with a CHN analyzer. X-
ray crystallographic data were collected with a CCD diffractometer
using graphite-monochromated Mo-Kα radiation. Thin-layer
chromatography (TLC) was performed on pre-coated alumina
sheets and detected under UV light. Silica gel (100–200 mesh) was
used for column chromatography.
1-{[2-(2-Methylfuran-5-carbonyl)phenyl]}-2-phenylethane-1,2-dione
(4g): Yield 64 mg (81%); brown solid; m.p. 92–93 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.09 (dd, J = 8.2, 1.4 Hz, 2 H), 7.90–7.83
(m, 2 H), 7.67–7.60 (m, 3 H), 7.51–7.47 (m, 2 H), 7.10 (d, J =
3.6 Hz, 1 H), 6.19 (d, J = 3.6 Hz, 1 H), 2.36 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 191.3, 188.9, 180.2, 158.0, 149.0,
137.4, 134.6, 132.4, 131.4, 130.5, 129.9, 129.4, 128.8, 127.6, 126.8,
122.1, 107.9, 12.4 ppm. HRMS: m/z calcd. for C20H14O4
[M + H]+ 319.0965; found 319.0970.
General Procedure for the Oxidation of o-Alkynylarene Ketones: To
a solution of o-alkynylarene ketone (0.250 mmol) in acetonitrile
(9.0 mL) were added iodine (0.525 mmol) and water (1 mL) and
the mixture was stirred at room temperature for 10 min (20 min for
3k and 3l). The reaction mixture was then diluted with water and
extracted with CH2Cl2. The organic layer was washed with satd.
Na2S2O3 solution, dried with anhydrous Na2SO4 and concentrated
under reduced pressure. The crude product was purified by column
chromatography (SiO2; EtOAc/hexane, 1:9 v/v) to afford the tri-
carbonyl compound.
1-Phenyl-2-[2-(thiophene-2-carbonyl)phenyl]ethane-1,2-dione (4h):
Yield 64 mg (80 %); brown solid; m.p. 74–75 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.98–7.95 (m, 2 H), 7.86–7.84 (m, 1 H),
7.69–7.67 (m, 1 H), 7.64–7.50 (m, 5 H), 7.43–7.39 (m, 2 H), 7.07–
7.04 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 191.9, 190.0,
187.3, 142.2, 139.0, 134.4, 134.3, 133.3, 132.0, 131.5, 130.4, 129.3,
128.1, 127.5, 127.3 ppm. HRMS: m/z calcd. for C19H12O3S [M +
H]+ 321.0580; found 321.0585.
1-(2-Benzoylphenyl)-2-phenylethane-1,2-dione (4a): Yield 61 mg
(77%); brown solid; m.p. 85–86 °C. H NMR (400 MHz, CDCl3):
1
1-{[2-(2-Naphthoyl)phenyl]}-2-phenylethane-1,2-dione (4i): Yield
69 mg (76%); brown solid; m.p. 73–76 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.16 (s, 1 H), 7.92–7.89 (m, 3 H), 7.86–7.81 (m, 4 H),
7.65–7.45 (m, 6 H), 7.36–7.32 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 197.0, 193.2, 191.3, 140.7, 135.8, 135.7, 134.4, 134.3,
133.1, 132.6, 132.3, 132.2, 131.5, 131.4, 130.5, 130.0, 129.6, 128.8,
128.6, 128.4, 127.9, 126.9, 125.2 ppm. HRMS: m/z calcd. for
C25H16O3 [M + H]+ 365.1172; found 365.1177.
δ = 7.95–7.93 (m, 2 H), 7.84–7.81 (m, 1 H), 7.71–7.68 (m, 2 H),
7.60–7.46 (m, 5 H), 7.40–7.33 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 197.1, 193.2, 191.2, 140.4, 136.8, 135.9, 134.4, 133.2,
133.1, 132.4, 131.4, 130.5, 129.91, 129.89, 128.6, 128.5 ppm.
HRMS: m/z calcd. for C21H14O3 [M + Na]+ 337.0835; found
337.0841.
1-[2-(4-Methylbenzoyl)phenyl]-2-phenylethane-1,2-dione (4b): Yield
68 mg (83%); yellow solid; m.p. 101–102 °C. H NMR (400 MHz,
1
1-[2-(Dibenzo[1,4]dioxine-2-carbonyl)phenyl]-2-phenylethane-1,2-
dione (4j): Yield 78 mg (74%); yellow solid; m.p. 101–102 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.03–8.01 (m, 2 H), 7.94–7.91 (m, 1
H), 7.70–7.57 (m, 4 H), 7.50–7.46 (m, 2 H), 7.35 (dd, J = 8.4,
2.0 Hz, 1 H), 7.31 (d, J = 2.0 Hz, 1 H), 6.94–6.81 (m, 5 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 194.8, 193.0, 191.3, 146.6, 142.1,
141.6, 141.3, 140.4, 135.3, 134.4, 132.8, 132.6, 131.5, 131.2, 130.4,
129.4, 128.6, 126.8, 124.6, 124.2, 118.0, 116.5, 116.3 ppm. MS
(ESI): m/z = 421 [M + H]+. C27H16O5: calcd. C 77.14, H 3.84;
found C 77.36, H 3.76.
CDCl3): δ = 7.94–7.91 (dd, J = 8.2, 1.0 Hz, 2 H), 7.82–7.80 (m, 1
H), 7.60–7.46 (m, 6 H), 7.38–7.34 (m, 2 H), 7.14 (d, J = 8.0 Hz, 2
H), 2.30 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.7,
193.3, 191.2, 144.3, 140.7, 135.8, 134.4, 134.3, 133.1, 132.4, 131.33,
131.30, 130.5, 130.2, 129.8, 129.3, 128.6, 21.7 ppm. MS (ESI): m/z
= 329 [M + H]+. C22H16O3: calcd. C 80.47, H 4.91; found C 80.60,
H 4.85. Single crystals suitable for X-ray studies were grown from
a solution of 4b in chloroform.
1-[2-(4-Methoxybenzoyl)phenyl]-2-phenylethane-1,2-dione
(4c):
1-[2-(4-Methoxybenzoyl)-5-(2-phenylethynyl)phenyl]-2-phenyl-
Yield 71 mg (83%); brownish-yellow solid; m.p. 125–126 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.01 (dd, J = 8.2, 1.0 Hz, 2 H), 7.92–
7.89 (m, 1 H), 7.69 (d, J = 8.8 Hz, 2 H), 7.65–7.61 (m, 2 H), 7.59–
7.55 (m, 2 H), 7.48–7.44 (m, 2 H), 6.90 (d, J = 8.8 Hz, 2 H), 3.83
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 195.6, 193.2,
191.3, 163.8, 141.0, 135.5, 134.3, 133.1, 132.5, 132.4, 131.4, 131.0,
130.4, 129.7, 129.5, 128.6, 113.8, 55.5 ppm. HRMS: m/z calcd. for
C22H16O4 [M + H]+ 345.1121; found 345.1127.
ethane-1,2-dione (4k): Yield 78 mg (70%); brown solid; m.p. 81–
1
83 °C. H NMR (400 MHz, CDCl3): δ = 8.00 (dd, J = 8.2, 1.0 Hz,
2 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.82–7.75 (m, 3 H), 7.68 (d, J =
1.6 Hz, 1 H), 7.64–7.60 (m, 1 H), 7.55–7.53 (m, 2 H), 7.50–7.46 (m,
2 H), 7.38–7.36 (m, 3 H), 6.95 (d, J = 8.8 Hz, 2 H), 3.89 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.8, 192.4, 191.2,
164.0, 141.4, 134.4, 134.3, 133.5, 133.0, 132.5, 132.1, 131.9, 131.5,
130.5, 129.5, 129.2, 128.6, 128.5, 128.0, 122.2, 114.0, 93.9, 87.9,
55.6 ppm. HRMS: m/z calcd. for C30H20O4 [M + H]+ 445.1434;
found 445.1441.
1-[2-(4-Isopropylbenzoyl)phenyl]-2-phenylethane-1,2-dione
(4d):
Yield 72 mg (81%); yellow solid; m.p. 100–101 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.03 (d, J = 7.6 Hz, 2 H), 7.93–7.91 (m, 1
H), 7.72 (d, J = 8.0 Hz, 2 H), 7.68–7.59 (m, 4 H), 7.49–7.46 (m, 2
H), 7.30 (d, J = 8.4 Hz, 2 H), 2.96 (sept., J = 6.8 Hz, 1 H), 1.27
(d, J = 7.2 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.7,
193.3, 191.2, 154.9, 140.6, 135.9, 134.6, 134.3, 133.2, 132.3, 131.3,
130.5, 130.3, 129.9, 128.6, 126.7, 34.3, 23.7 ppm. HRMS: m/z calcd.
for C24H20O3 [M + H]+ 357.1485; found 357.1509.
1-(3-Benzoylquinolin-2-yl)-2-phenylethane-1,2-dione (4l): Yield
64 mg (70 %); pale-yellow solid; m.p. 120–121 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.14 (s, 1 H), 8.17 (d, J = 8.6 Hz, 1 H),
8.03–8.01 (m, 2 H), 7.94 (d, J = 8.2 Hz, 1 H), 7.89–7.86 (m, 2 H),
7.85–7.82 (m, 1 H), 7.76–7.72 (m, 1 H), 7.65–7.59 (m, 2 H), 7.52–
7.48 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 195.0, 193.4,
192.6, 151.5, 147.4, 137.8, 136.7, 134.5, 133.6, 133.2, 132.6, 131.8,
1-[(2-Benzoyl-4,5-dimethoxyphenyl)]-2-(4-methoxyphenyl)ethane- 130.7, 130.1, 130.0, 129.6, 128.8, 128.7, 128.3, 127.9 ppm. HRMS:
1
1,2-dione (4e): Yield 86 mg (85%); yellow solid; m.p. 89–90 °C. H
m/z calcd. for C24H15NO3 [M + H]+ 366.1125; found 366.1130.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O30046
/KAP1
Date: 08-04-13 17:10:50
Pages: 12
K. Sakthivel, K. Srinivasan
FULL PAPER
1-(4,5-Dimethoxy-2-pentanoylphenyl)-2-phenylethane-1,2-dione
(4m): Yield 78 mg (83%); pale-orange solid; m.p. 100–101 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.22–8.20 (m, 2 H),7.65–7.61 (m, 1
H), 7.55–51 (m, 2 H), 7.28 (s, 1 H), 7.20 (s, 1 H), 4.01 (s, 3 H), 3.98
(s, 3 H), 2.81 (t, J = 7.4 Hz, 2 H), 1.58–1.54 (m, 2 H), 1.33–1.25
CDCl3): δ = 7.95–7.93 (m, 1 H), 7.46–7.43 (m, 2 H), 7.37–7.34 (m,
3 H), 7.29–7.25 (m, 3 H), 7.19–7.17 (m, 2 H), 7.17–7.06 (m, 3 H),
5.40 (d, J = 14.8 Hz, 1 H), 5.24 (s, 1 H), 3.73 (d, J = 14.8 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.5, 146.4, 137.1,
136.8, 131.8, 131.4, 129.1, 128.7, 128.5, 128.3, 127.8, 127.6, 123.8,
(m, 2 H), 0.87 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, 123.2, 63.6, 43.8 ppm.
CDCl3): δ = 201.6, 193.5, 189.7, 152.5, 150.9, 133.7, 133.6, 131.9,
(S)-Methyl 2-(5,6-Dimethoxy-1-oxoisoindolin-2-yl)-3-phenylpro-
131.7, 130.7,128.4, 112.9, 110.9, 56.4, 38.7, 26.4, 22.3, 13.8 ppm.
No satisfactory mass/elemental analysis data could be obtained due
to the instability of the compound.
panoate (12g): Yield 51 mg (72%); pale-yellow solid; m.p. 76–77 °C
1
(ref.[27e] 138–139 °C). H NMR (400 MHz, CDCl3): δ = 7.27 (s, 1
H), 7.26–7.15 (m, 5 H), 6.86 (s, 1 H), 5.37 (dd, J = 10.4, 6.0 Hz, 1
H), 4.43 (d, J = 16.4 Hz, 1 H), 4.24 (d, J = 16.4 Hz, 1 H), 3.92 (s,
3 H), 3.91 (s, 3 H), 3.72 (s, 3 H), 3.48 (dd, J = 14.8, 5.8 Hz, 1 H),
3.18 (dd, J = 14.8, 10.4 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.5, 169.2, 152.8, 149.7, 136.5, 135.3, 128.7, 128.5,
126.9, 124.1, 105.5, 105.0, 56.21, 56.19, 54.7, 52.4, 47.2, 35.9 ppm.
HRMS: m/z calcd. for C20H21NO5 [M + Na]+ 378.1312; found
378.1283.
General Procedure for the Synthesis of Isoindolinones 12a–h and 13:
To a solution of tricarbonyl compounds 2 or 4a (0.20 mmol) in
ethanol (5 mL) was added amine 11 (0.4 mmol; for 12g, 0.40 mmol
of NaOAc was also included) and the mixture was stirred at room
temperature for 5 min (20 min for 12b and 12f, and 2 h for 12g).
The mixture was diluted with water and extracted with ethyl acet-
ate. The combined organic layers were dried with NaSO4, filtered
and the solvents evaporated. The crude product was purified by
column chromatography on silica gel (EtOAc/hexane, 1:1 v/v).
(R)-5,6-Dimethoxy-2-(1-phenylethyl)isoindolin-1-one (12h): Yield
46 mg (78 %); pale-orange solid; m.p. 113–114 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.34–7.31 (m, 5 H), 7.28–7.24 (m, 1 H),
6.84 (s, 1 H), 5.76 (q, J = 7.0 Hz, 1 H), 4.24 (d, J = 16.8 Hz, 1 H),
3.93 (s, 4 H), 3.89 (s, 3 H), 1.67 (d, J = 7.2 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.5, 152.5, 149.7, 140.9, 134.9,
128.6, 127.5, 127.1, 125.1, 105.5, 105.1, 56.23, 56.20, 49.2, 45.3,
17.4 ppm. HRMS: m/z calcd. for C18H19NO3 [M + Na]+ 320.1257;
found 320.1231.
2-Butyl-5,6-dimethoxyisoindolin-1-one (12a): Yield 64 mg (75%);
1
white semi-solid. H NMR (400 MHz, CDCl3): δ = 7.31 (s, 1 H),
6.92 (s, 1 H), 4.29 (s, 2 H), 3.94 (s, 3 H), 3.935 (s, 3 H), 3.59 (t, J
= 7.2 Hz, 2 H), 1.67–1.60 (m, 2 H), 1.43–1.35 (m, 2 H), 0.96 (t, J
= 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.8,
152.3, 149.6, 134.6, 125.4, 105.4, 105.0, 56.2, 49.6, 42.2, 30.6, 20.1,
13.8 ppm. MS (ESI): m/z = 250 [M + H]+. C14H19NO3 (249.31):
calcd. C 67.45, H 7.68, N 5.62; found C 67.66, H 7.76, N 5.77.
2-tert-Butyl-5,6-dimethoxyisoindolin-1-one (13): Yield 42 mg (84%);
pale-yellow solid; m.p. 104–105 °C. H NMR (400 MHz, CDCl3):
2-Butyl-3-phenylisoindolin-1-one (12b): Yield 35 mg (66%); white
solid; m.p. 87–89 °C. H NMR (400 MHz, CDCl3): δ = 7.90–7.88
1
1
δ = 7.26 (s, 1 H), 6.88 (s, 1 H), 4.37 (s, 2 H), 3.93 (s, 3 H), 3.92 (s,
3 H), 1.56 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.2,
152.3, 149.6, 134.1, 126.8, 104.9, 104.7, 56.21, 56.15, 54.3, 48.1,
28.1 ppm. HRMS: m/z calcd. for C14H19NO3 [M + Na]+ 272.1257;
found 272.1236.
(m, 1 H), 7.47–7.44 (m, 2 H), 7.37–7.33 (m, 3 H), 7.17–7.12 (m, 3
H), 5.45 (s, 1 H), 3.95–3.93 (m, 1 H), 2.88–2.84 (m, 1 H), 1.54–1.50
(m, 2 H), 1.34–1.26 (m, 2 H), 0.89 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.6, 146.3, 137.2, 131.8, 131.6,
129.1, 128.6, 128.3, 127.6, 123.5, 123.0, 64.4, 39.9, 30.4, 20.1,
13.7 ppm. HRMS: m/z calcd. for C18H19NO [M + H]+ 266.1539;
found 266.1545.
4-Bromo-2-tert-butyl-5,6-dimethoxyisoindolin-1-one (14): To a
stirred solution of 13 (125 mg, 0.5 mmol) in CCl4 (15 mL) was
added bromine (321 mg, 2.0 mmol) in CCl4 (5 mL) over 5 min. The
reaction mixture was stirred at room temperature for 3 h, then
quenched with a 10% aq. Na2S2O5 solution to remove excess bro-
mine. The organic layer was separated, washed with brine, dried
with Na2SO4, filtered, and concentrated in vacuo to give a pale-
brown solid. The crude product was purified by column
chromatography (EtOAc/hexane). Yield 118 mg (72%); m.p.100–
2-(4,4-Diethoxybutyl)-5,6-dimethoxyisoindolin-1-one (12c): Yield
52 mg (78%); yellow solid; m.p. 64–65 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.31 (s, 1 H), 6.92 (s, 1 H), 4.52 (t, J = 5.6 Hz, 1 H),
4.30 (s, 2 H), 3.94 (s, 3 H), 3.937 (s, 3 H), 3.67–3.60 (m, 4 H), 3.51–
3.45 (m, 2 H), 1.77–1.68 (m, 4 H), 1.17 (t, J = 7.2 Hz, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 168.9, 152.5, 149.7, 134.7, 125.3,
105.4, 105.1, 102.6, 61.5, 56.24, 56.21, 49.6, 42.2, 31.0, 23.7,
15.3 ppm. HRMS: m/z calcd. for C18H27NO5 [M + Na]+ 360.1781;
found 360.1787.
1
101 °C. H NMR (400 MHz, CDCl3): δ = 7.27 (s, 1 H), 4.29 (s, 2
H), 3.92 (s, 3 H), 3.90 (s, 3 H), 1.57 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.1, 154.2, 149.2, 134.1, 130.9, 112.3,
105.5, 60.9, 56.4, 54.7, 48.8, 28.0 ppm. HRMS: m/z calcd. for
C14H18BrNO3 [M + H]+ 328.0543; found 328.0548.
2-Cyclohexyl-5,6-dimethoxyisoindolin-1-one (12d): Yield 44 mg
(80%); white solid; m.p. 135–136 °C (ref.[27e] 136–138 °C). 1H NMR
(400 MHz, CDCl3): δ = 7.32 (s, 1 H), 6.93 (s, 1 H), 4.26 (s, 2 H),
4.23–4.17 (m, 1 H), 3.94 (s, 6 H), 1.87–1.84 (m, 4 H), 1.74–1.71
(m, 1 H), 1.51–1.40 (m, 4 H), 1.21–1.18 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.2, 152.2, 149.6, 134.8, 125.7, 105.3,
105.0, 56.2, 50.6, 45.7, 31.5, 25.6, 25.5 ppm.
5-tert-Butyl-1,2-dimethoxy-5H-dibenzo[cd,f]indol-4-one (15): To a
stirred solution of 14 (99 mg, 0.30 mmol) in toluene/EtOH (10 mL/
5 mL), were added 2-formylboronic acid (54 mg, 0.36 mmol),
[Pd(PPh3)4] (14 mg, 4 mol-%), and Cs2CO3 (88 mg, 0.9 mmol). The
reaction mixture was heated at reflux for 4 h, then cooled to room
temperature and filtered through a Celite pad. The solution was
diluted with EtOAc and the mixture was concentrated under re-
duced pressure and purified by column chromatography (EtOAc/
hexane) to give 15. Yield 70 mg (70 %); yellow solid; m.p. 134–
135 °C. 1H NMR (400 MHz, CDCl3): δ = 9.22–9.18 (m, 1 H), 7.80–
7.76 (m, 1 H), 7.72 (s, 1 H), 7.57–7.51 (m, 2 H), 7.41 (s, 1 H), 4.09
(s, 3 H), 4.05 (s, 3 H), 1.88 (s, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.1, 154.2, 151.0, 137.2, 134.9, 129.4, 127.4, 127.2,
126.4, 126.0, 123.3, 122.1, 120.9, 109.2, 108.6, 60.3, 58.4, 56.9,
2-Benzyl-5,6-dimethoxyisoindolin-1-one (12e): Yield 47 mg (84%);
yellow solid; m.p. 99–100 °C. 1H NMR (400 MHz, CDCl3): δ =
7.35 (s, 1 H), 7.34–7.24 (m, 5 H), 6.85 (s, 1 H), 4.77 (s, 2 H), 4.17
(s, 2 H), 3.94 (s, 3 H), 3.90 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 168.9, 152.6, 149.7, 137.3, 134.8, 128.8, 128.0, 127.6,
124.8, 105.5, 105.1, 56.2, 49.1, 46.4 ppm. HRMS: m/z calcd. for
C17H17NO3 [M + H]+ 284.1281; found 284.1286.
2-Benzyl-3-phenylisoindolin-1-one (12f): Yield 42 mg (70%); white
solid; m.p. 135–136 °C (ref.[27f] 136 °C). 1H NMR (400 MHz,
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30046
/KAP1
Date: 08-04-13 17:10:50
Pages: 12
Iodine/Water-Mediated Oxidation
29.8 ppm. HRMS: m/z calcd. for C21H21NO3 [M + Na]+ 358.1414; (4-Methoxyphenyl)[2-(3-phenylquinoxalin-2-yl)phenyl]methanone
found 358.1419.
(19b): Obtained from 4c (69 mg) and o-phenylenediamine (24 mg).
Yield 66 mg (80 %); brown semi-solid. 1H NMR (400 MHz,
CDCl3): δ = 8.13–8.11 (m, 1 H), 7.99–7.97 (m, 1 H), 7.74–7.52 (m,
4 H), 7.47–7.42 (m, 6 H), 7.26–7.21 (m, 1 H), 7.18–7.14 (m, 2 H),
6.79–6.76 (m, 2 H), 3.85 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 195.1, 163.2, 153.8, 153.4, 141.3, 141.0, 140.7, 139.3,
138.5, 132.4, 131.4, 130.8, 130.2, 130.0, 129.8, 129.6, 129.3, 129.1,
128.7, 128.1, 127.8, 113.2, 55.4 ppm. HRMS: m/z calcd. for
C28H20N2O2 [M + H]+ 417.1598; found 417.1625.
Aristolacatam BII (16): To solution of 15 (67 mg, 0.2 mmol) in 1,2-
dichloroethane (5 mL) was added TFA (1.6 mL, 2.0 mmol). The
reaction mixture was heated to reflux for 18 h, then the solvent was
removed under vacuum. The residue was diluted with dichloro-
methane (10 mL), and triethylamine (1 mL) and water (2 mL) were
added with stirring. The organic layer was separated, washed with
brine, dried with Na2SO4 and concentrated to give a residue that
was purified by column chromatography (EtOAc/hexane) to give
16. Yield 50 mg (90%); pale-yellow solid; m.p. 253–254 °C (ref.[29]
254 °C). 1H NMR (400 MHz, [D6]DMSO): δ = 10.85 (s, 1 H), 9.09
(d, J = 7.6 Hz, 1 H), 7.91 (d, J = 9.2 Hz, 1 H), 7.82 (s, 1 H), 7.58–
7.54 (m, 2 H), 7.15 (s, 1 H), 4.012 (s, 3 H), 4.005 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.6, 154.2, 150.5, 134.9, 134.7,
129.1, 127.6, 126.8, 125.9, 125.7, 123.2, 121.3, 119.9, 109.8, 105.0,
60.0, 56.9 ppm.
(6,7-Dimethoxyphthalazin-1-yl)(phenyl)methanone (20a): Obtained
from 2 (53 mg) and hydrazine hydrate (11 mg). Yield 40 mg (68%);
white solid; m.p.142–144 °C. 1H NMR (400 MHz, CDCl3): δ = 9.47
(s, 1 H), 8.07–8.04 (m, 2 H), 7.66–7.62 (m, 1 H), 7.59 (s, 1 H), 7.52–
7.48 (m, 2 H), 7.27 (s, 1 H), 4.10 (s, 3 H), 4.02 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 193.7, 155.0, 154.5, 150.2, 136.5,
134.0, 131.2, 128.5, 121.9, 104.7, 103.4, 56.52, 56.49 ppm. HRMS:
m/z calcd. for C17H14N2O3 [M + H]+ 295.1077; found 295.1082.
General Procedure for the Condensation of Tricarbonyl Compounds
with Diamines/Aminoethanol: To a solution of 2, 4b or 4c
(0.2 mmol) in EtOH (5 mL), diamine (0.22 mmol; for 21a–c,
0.42 mmol was used) or amino ethanol (0.42 mmol) was added.
The reaction mixture was stirred at room temperature for 5–30 min,
then diluted with water and extracted with ethyl acetate. The com-
bined organic extracts were washed with water, dried with Na2SO4,
filtered and the solvents evaporated. The crude product was puri-
fied by column chromatography on silica gel (EtOAc/hexane, 1:1 v/
v).
Phenyl(4-p-tolylphthalazin-1-yl)methanone (20b): Obtained from 4b
(66 mg) and hydrazine hydrate (11 mg). Yield 46 mg (70%); pale-
yellow solid; m.p. 131–132 °C. 1H NMR (400 MHz, CDCl3): δ =
8.28–8.20 (m, 2 H), 8.12 (d, J = 7.2 Hz, 2 H), 7.92–7.87 (m, 2 H),
7.73 (d, J = 8.0 Hz, 2 H), 7.63 (t, J = 7.4 Hz, 1 H), 7.50 (t, J =
7.6 Hz, 2 H), 7.41 (d, J = 7.6 Hz, 2 H), 2.49 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 193.2, 160.9, 155.0, 140.0, 136.3,
134.1, 133.0, 132.8, 132.7, 131.1, 130.3, 129.4, 128.6, 126.9, 126.0,
125.5, 125.4, 21.5 ppm. HRMS: m/z calcd. for C22H16N2O [M +
H]+ 325.1341; found 325.1371. Single crystals suitable for X-ray
studies were grown from a solution of 20b in dichloromethane.
6-Hydroxy-2,3-dimethoxy-6-phenylbenzo[4,5]imidazo[2,1-a]iso-
quinolin-5-one (17) and 2-[2-(1H-Benzo[d]imidazol-2-yl)-4,5-dimeth-
oxyphenyl]-3-phenylquinoxaline (18): From 2 (53.2 mg) and o-phen-
ylenediamine (24 mg), the products 17 and 18 were obtained as
yellow solids.
[4-(4-Methoxyphenyl)phthalazin-1-yl](phenyl)methanone (20c): Ob-
tained from 4c (69 mg) and hydrazine hydrate (11 mg). Yield 50 mg
(74%); pale-yellow solid; m.p. 130–132 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.31–8.24 (m, 2 H), 8.14–8.12 (m, 2 H), 7.93–7.91 (m,
2 H), 7.83–7.80 (m, 2 H), 7.67–7.64 (m, 1 H), 7.51 (t, J = 7.8 Hz,
2 H), 7.14 (d, J = 8.4 Hz, 2 H), 3.94 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 193.2, 161.0, 160.4, 154.8, 136.3, 134.1,
132.8, 132.7, 131.8, 131.1, 128.6, 128.2, 126.9, 125.9, 125.6, 125.4,
114.2, 55.5 ppm. MS (ESI): m/z = 341 [M + H]+. C22H16N2O2: C
77.63, H 4.74, N 8.23; found C 77.84, H 4.89, N 8.38.
Compound 17: Yield 48 mg (63 %); m.p. 215–216 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.32 (s, 1 H), 7.98 (s, 1 H), 7.82 (d, J
= 8.0 Hz, 1 H), 7.45 (s, 1 H), 7.37–7.22 (m, 7 H), 7.18–7.16 (m, 1
H), 4.14 (s, 3 H), 3.94 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 191.0, 155.2, 151.2, 145.5, 143.7, 138.7, 134.4, 128.8,
128.7, 125.4, 124.5, 123.1, 122.8, 120.4, 119.5, 113.4, 108.7, 106.6,
87.9, 56.3, 55.8 ppm. MS (ESI): m/z = 387 [M + H]+. C23H18N2O4:
C 71.49, H 4.70, N 7.25; found C 71.68, H 4.60, N 7.39.
5,6-Dimethoxy-2-(N-benzoylaminoethyl)-2,3-dihydroisoindol-1-one
(21a): Obtained from 2 (53 mg) and 1,2-diaminoethane (25 mg).
Yield 53 mg (78 %); yellow solid; m.p. 204–205 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.84–7.82 (m, 2 H), 7.61 (br. s, 1 H), 7.47–
7.39 (m, 3 H), 7.24 (s, 1 H), 6.90 (s, 1 H), 4.41 (s, 2 H), 3.93 (s, 3
H), 3.90 (s, 3 H), 3.89–3.87 (m, 2 H), 3.77–3.74 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.6, 167.7, 152.8, 149.8, 135.1,
134.0, 131.4, 128.5, 127.1, 124.4, 105.2, 105.0, 56.24, 56.21, 50.7,
42.4, 40.4 ppm. HRMS: m/z calcd. for C19H20N2O4 [M + H]+
341.1496; found 341.1501.
Compound 18: Yield 9 mg (10 %); m.p. 242–243 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.09 (d, J = 8.4 Hz, 1 H), 7.66–7.62 (m, 1
H), 7.52 (br. s, 1 H), 7.38–7.19 (m, 7 H), 7.02–6.98 (m, 3 H), 6.73
(d, J = 7.6 Hz, 2 H), 6.57 (s, 1 H), 3.92 (s, 3 H), 2.96 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 155.6, 153.2, 151.2, 149.7, 149.5,
141.5, 139.8, 137.2, 130.5, 130.2, 129.7, 129.0, 128.4, 128.1, 128.0,
125.9, 124.3, 122.5, 113.8, 112.7, 56.0, 55.2 ppm. MS (ESI): m/z =
481 [M + Na]+. C29H22N4O2: C 75.97, H 4.84, N 12.22; found C
76.18, H 4.92, N 12.35. Single crystals suitable for X-ray studies
were grown from a solution of 18 in ethanol/ethyl acetate (1:1).
3-(4-Methoxyphenyl)-2-(N-benzoylaminoethyl)-2,3-dihydroisoindol-
1-one (21b): Obtained from 4c (69 mg) and 1,2-diaminoethane
(25 mg). Yield 70 mg (91 %); orange oil. 1H NMR (400 MHz,
CDCl3): δ = 7.86–7.80 (m, 3 H), 7.70 (br. s, 1 H), 7.49–7.37 (m, 5
H), 7.16 (d, J = 7.6 Hz, 1 H), 7.07 (d, J = 8.8 Hz, 2 H), 6.87 (d, J
= 8.8 Hz, 2 H), 5.55 (s, 1 H), 4.02–3.97 (m, 1 H), 3.81 (s, 3 H),
3.79–3.74 (m, 1 H), 3.42–3.32 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.4, 167.7, 160.1, 146.8, 134.0, 132.2, 131.4, 131.0,
129.1, 128.5, 128.4, 128.1, 127.1, 123.4, 123.3, 114.7, 65.0, 55.3,
40.24, 40.18 ppm. HRMS: m/z calcd. for C24H22N2O3 [M + Na]+
409.1523; found 409.1516.
[2-(3-Phenylquinoxalin-2-yl)phenyl](p-tolyl)methanone (19a): Ob-
tained from 4b (66 mg) and o-phenylenediamine (24 mg). Yield
63 mg (78%); white solid; m.p. 119–120 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.13–8.11 (m, 1 H), 8.01–7.98 (m, 1 H), 7.71–7.67 (m,
2 H), 7.60–7.54 (m, 2 H), 7.46–7.34 (m, 6 H), 7.25–7.22 (m, 1 H),
7.18–7.14 (m, 2 H), 7.09–7.07 (m, 2 H), 2.35 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 196.2, 153.8, 153.4, 143.3, 141.3,
141.0, 140.8, 139.1, 138.5, 134.5, 131.4, 130.9, 130.19, 130.15,
130.05, 129.8, 129.6, 129.2, 129.1, 128.7, 128.6, 128.1, 127.8,
21.6 ppm. MS (ESI): m/z = 402 [M + 2 H]2+. C28H20N2O: C 83.98,
H 5.03, N 7.00; found C 84.27, H 5.18, N 7.21.
3-(4-Methoxyphenyl)-2-(N-benzoylaminopropyl)-2,3-dihydroiso-
indol-1-one (21c): Obtained from 4c (69 mg) and 1,2-diaminopro-
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pane (31 mg). Yield 66 mg (83%); orange oil. 1H NMR (400 MHz,
CDCl3): δ = 7.99–7.89 (m, 4 H), 7.51–7.42 (m, 5 H), 7.20–7.18 (m,
1 H), 7.04 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 5.43 (s,
1 H), 3.88–3.86 (m, 1 H), 3.79 (s, 3 H), 3.70–3.65 (m, 1 H), 3.21–
3.10 (m, 2 H), 1.73–1.61 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.8, 167.2, 160.1, 146.6, 134.4, 132.1, 131.3, 131.1,
129.0, 128.5, 128.2, 127.1, 123.5, 123.3, 114.6, 64.5, 55.3, 37.2, 35.8,
27.5 ppm. HRMS: m/z calcd. for C25H24N2O3 [M + H]+ 401.1860;
found 401.1872.
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5,6-Dimethoxy-2-(benzoyloxyethyl)-2,3-dihydroisoindol-1-one (22a):
Obtained from 2 (53 mg) and 2-aminoethanol (26 mg). Yield 47 mg
(69%); pale-yellow solid; m.p. 106–107 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.04–8.02 (m, 2 H), 7.59–7.55 (m, 1 H), 7.47–7.43 (m,
2 H), 7.32 (s, 1 H), 6.91 (s, 1 H), 4.57 (t, J = 5.4 Hz, 2 H), 4.44 (s,
2 H), 4.01 (t, J = 5.4 Hz, 2 H), 3.93 (s, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.1, 166.4, 152.6, 149.7, 134.9, 133.2,
129.8, 129.6, 128.5, 124.6, 105.4, 105.0, 63.5, 56.2, 50.7, 41.7 ppm.
HRMS: m/z calcd. for C19H19NO5 [M + Na]+ 364.1155; found
364.1161.
[10]
[11]
3-(4-Methoxyphenyl)-2-(benzoyloxyethyl)-2,3-dihydroisoindol-1-
one (22b): Obtained from 4c (69 mg) and 2-aminoethanol (26 mg).
1
Yield 69 mg (89%); pale-brown solid; m.p. 113–114 °C. H NMR
(400 MHz, CDCl3): δ = 8.01–7.98 (m, 2 H), 7.91–7.89 (m, 1 H),
7.58–7.54 (m, 1 H), 7.48–7.41 (m, 4 H), 7.16–7.14 (m, 1 H), 7.01
(d, J = 8.4 Hz, 2 H), 6.83 (d, J = 8.8 Hz, 2 H), 5.56 (s, 1 H), 4.58–
4.52 (m, 1 H), 4.42–4.36 (m, 1 H), 4.33–4.27 (m, 1 H), 3.77 (s, 3
H), 3.33–3.28 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
168.8, 166.3, 160.0, 146.7, 133.1, 131.9, 131.2, 129.9, 129.7, 128.9,
128.5, 128.4, 128.3, 123.6, 123.2, 114.6, 64.7, 62.9, 55.3, 39.2 ppm.
HRMS: m/z calcd. for C24H21NO4 [M + H]+ 388.1543; found
388.1549.
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Iodine/Water-Mediated Oxidation
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Received: January 11, 2013
Published Online: ᭿
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Date: 08-04-13 17:10:50
Pages: 12
K. Sakthivel, K. Srinivasan
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Nitrogen Heterocycles
K. Sakthivel, K. Srinivasan* ............ 1–12
Iodine/Water-Mediated Oxidation of o-
Alkynylaroyl Compounds and Application
of the Products of Oxidation in the Syn-
thesis of Nitrogen Heterocycles
Tricarbonyl compounds obtained from the
oxidation of o-alkynylaroyl compounds
using an iodine/water system act as useful
precursors for the synthesis of a diverse
range of heterocycles, including a natural
product.
Keywords: Synthetic methods / Oxidation /
Nitrogen heterocycles / Alkynes / Neigh-
boring-group effects
12
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