Aryl-free radical-mediated oxidative arylation of naphthoquinones using o-iodoxybenzoic acid and phenylhydrazines and its application toward the synthesis of benzocarbazoledione

Article abstract of DOI:10.1021/jo500131h

Oxidative arylation of naphthoquinones has been developed through combination of o-iodoxybenzoic acid with arylhydrazines under mild conditions at open atmosphere. Arylated naphthoquinones with different electronic properties were obtained in moderate to good yields. The postulated radical mediated mechanism is supported by radical trapping experiments. Developed protocol for direct arylation of naphthoquinones has been extended toward short, high yielding, and an effective synthesis of antitumor-antibiotic precursor such as benzocarbazoledione.

Full text of DOI:10.1021/jo500131h

Note
pubs.acs.org/joc
Aryl-Free Radical-Mediated Oxidative Arylation of Naphthoquinones
Using o‑Iodoxybenzoic Acid and Phenylhydrazines and Its
Application toward the Synthesis of Benzocarbazoledione
Pravin Patil, Abhay Nimonkar, and Krishnacharya G. Akamanchi*
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400019, India
S
* Supporting Information
ABSTRACT: Oxidative arylation of naphthoquinones has
been developed through combination of o-iodoxybenzoic acid
with arylhydrazines under mild conditions at open atmos-
phere. Arylated naphthoquinones with different electronic
properties were obtained in moderate to good yields. The
postulated radical mediated mechanism is supported by radical
trapping experiments. Developed protocol for direct arylation
of naphthoquinones has been extended toward short, high
yielding, and an effective synthesis of antitumor−antibiotic
precursor such as benzocarbazoledione.
aphthoquinones are ubiquitous in nature and play
significant roles in biological systems due to their
iodonium intermediates.13 There are few reports14 available on
arylboronic acid mediated arylation in the presence of various
oxidants.
N
electron and proton transfer properties. It articulates the
spectrum of wide-ranging biological activities such as
antibacterial, antifungal, anti-inflammatory, antithrombotic,
antiplatelet, antibiotic, antiallergic, and apoptosis.1 1,4-
Naphthoquinone derivatives have also been proven to be
human DNA topoisomerase I and II inhibitors.2 1,4-Naphtho-
quinones and arylated naphthoquinones constitute an imperi-
ous class of natural products and found embedded in crisamicin
A, microphyllaquinone, conocurvone and angelmicin B, δ-
rubromycin, and in some other natural products.3 Naphtho-
quinones have important applications in cosmetics,4 dyes,5 and
pharmaceutical industries.6 There are several drugs possessing
wide-ranging activity such as parvaquone (antiprotozal),
atovaquone (antimalerial), lapachol (antiproliferative), mena-
dione (anticancer), and plumbagin (anticancer) constitute
functionalized naphthoquinone as the basic core in them.
Eventually, the applicability of naphthoquinones toward natural
and synthetic materials has attracted the attention of
researchers in preparative chemistry.
Despite pervasiveness of arylated naphthoquinones in several
fields of science, they can be obtained by a few general methods
such as oxidation of corresponding aromatics,7 using a
cycloaddition ring construction approach,8 radical coupling
reactions,9 and by transition metal catalyzed coupling reactions
through C−H bond activation. Out of these pathways, arylation
via transition metal mediated cross-coupling has broader scope.
Arylation of naphthoquinones can be accomplished by
palladium(II) acetate mediated coupling of naphthoquinone
to an arene with cosolvent,10 palladium catalyzed coupling
reaction of stannanes with naphthoquinones11a and naphtho-
quinone triflates,11b coupling of aryl chlorides with naphtho-
quinones using HgCl2/LiPdCl2,12 and arylation via zwitterionic
The common limitations of most of these methods are
inevitability of transition metals which possess high cost and
toxicity, necessity of prefunctionalization of C−H bond at 2 or
3 positions of the starting naphthoquinones with a halogen or
triflate group, use of expensive arylating counterparts such as
boronic acid and stannanes, elevated temperature, and longer
reaction time. Radical coupling of naphthoquinones can be
accessed through aryldiazonium salts1,9 which are difficult to
synthesize, unstable, and give very poor yield with formation of
azoproducts9d and known as explosive under certain circum-
stances. With the background of these inadequacies, the
development of an adaptable method for arylation of
naphthoquinones which is free from transition metal, relatively
inexpensive, having short reaction time under mild reaction
conditions is still a significant challenge.
o-Iodoxybenzoic acid (IBX) is an imperative part of
hypervalent iodine(V) reagents. Due to its chemoselectivity
and mild oxidizing properties, its attractiveness is cumulative
among synthetic chemists and it can be arbitrated from recent
reports.15 In persistence of our research contribution16 toward
exploring new-fangled applications of IBX, we recently
discovered a new method for generation of arylating species
for N-arylation of amines through combination of IBX and
arylhydrazines.17 Inspired by this outcome and considering the
essential reactivity of naphthoquinones with nucleophilic
species, it was of great interest to generate the same arylating
species through combination of IBX and arylhydrazines as
Received: January 20, 2014
Published: February 10, 2014
© 2014 American Chemical Society
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arylating counterparts to react with electrophiles such as
naphthoquinones.
Table 1. Arylation of Substituted Naphthoquinones Using
IBX
a
To verify our hypothesis, we choose 1,4-naphthoquinone and
phenylhydrazine as standard substrates as examples. When to a
solution of 1,4-naphthoquinone 1a and IBX in acetonitrile was
added phenylhydrazine 2a dropwise at room temperature,
evolution of gas bubbles was observed during the course of the
reaction. We surmised that the gas could be nitrogen generated
by oxidation of phenylhydrazine 2a by IBX. After completion of
the reaction, products were analyzed and found as a mixture of
2-phenyl-1,4-naphthoquinone 3a and 2,3-biphenyl-1,4-
naphthoquinone 3h in 60 and 15%, respectively (Scheme 1).
Scheme 1. Arylation of 1,4-Naphthoquinone Using IBX and
Phenylhydrazine
a
Reaction conditions: naphthoquinones (1 equiv), phenylhydrazine 2a
(1.2 equiv), IBX (2 equiv) in 20 mL of acetonitrile at room
temperature. Isolated yield mentioned after column chromatography
(silica gel 60-120 mesh size and ethyl acetate/hexane as eluent).
To reduce the possibility of formation of diarylated product,
reaction was carried out by using monosubstituted naphtho-
quinone. When 2-amino-1,4-naphthoquinone 1e was subjected
to the same reaction conditions, 2-amino-3-phenyl-1,4-
naphthoquinone 3e was obtained in good yield of 78%.
Further optimization was done with respect to feasibility of
other hypervalent iodine(V) reagents, solvents, and mole ratio
of reactants by keeping 2-amino-1,4-naphthoquinone 1e as a
constant substrate. Hypervalent iodine(V) reagents such as
Dess-Martin periodinane (DMP) and iodic acid (HIO3) were
tested against IBX under the same set of reaction conditions.
DMP and HIO3 gave arylated naphthoquinones in 67 and 56%,
respectively, in comparison with 78% by IBX. Among the listed
solvents such as ACN, DMSO, THF, CHCl3, and toluene,
ACN was found to be the best solvent for the arylation. The
reaction in DMSO was found to be vigorous and resulted in
multiple side products with exothermicity. The inferior yield
was observed with toluene (38%), and this might be due to the
poor solubility of IBX in it. The best result was obtained with
1.2 equiv of phenylhydrazine and 2.0 equiv of IBX. Further
exploration was carried out under optimized reaction
conditions.
Table 2. Reaction of 2-Amino-1,4-naphthoquinone with
a
Substituted Arylhydrazines
To demonstrate the substrate scope, a series of 1,4-
naphthoquinones having different electronic properties were
subjected to arylation and results are depicted in Table 1.
Most arylated naphthoquinones with different electronic
properties were obtained in moderate to good yields. The best
result was obtained with 2-amino-1,4-naphthoquinone 1e, while
reaction with 2-phenyl-1,4-naphthoquinone 1h was found to be
slower, and this may be due to steric hindrance caused by the
phenyl ring present at the C-2 position. Although the substrate
scope did not explicate decent chemoselectivity, the results with
hydroxy and amino substituted naphthoquinones 1d and 1e,
respectively, were encouraging while considering the radical
quenching nature of hydroxy and amino groups. To illustrate
the reactivity of differently substituted arylhydrazines, they were
reacted with 2-amino-1,4-naphthoquinones. The reactions went
smoothly, and the results are summarized in Table 2.
a
Reaction conditions: 2-amino-1,4-naphthoquinone 1e (1 equiv),
substituted arylhydrazine (2b−g) (1.2 equiv), IBX (2 equiv) in 20 mL
of acetonitrile at room temperature. Isolated yield mentioned after
column chromatography (silica gel 60-120 mesh size and ethyl
acetate/hexane as eluent).
naphthoquinones 4a−f. We hypothesized that oxidative
arylation of naphthoquinone could proceed through the
intermediary of an aryl radical generated through oxidation of
arylhydrazine by IBX. The plausible radical-mediated mecha-
nism is shown in Scheme 2.
Phenylhydrazine 2a may be attracted toward IBX due to the
electrophilic nature of the iodine atom, and subsequent
Reactions of 2-amino-1,4-naphthoquinone with differently
substituted arylhydrazines provided 59−69% of arylated
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Scheme 2. Postulated Radical-Mediated Mechanism for the Arylation of Naphthoquinones
oxidation ensues, leading to loss of a water molecule from
intermediate A to produce phenyldiazine 5 and o-iodoso-
benzoic acid (IBA). Being nucleophilic in nature, phenyldiazine
would react with another molecule of IBX and form
intermediate B, which undergoes oxidative cleavage through
single electron transfer (SET) to form phenyl radical C along
with species D. The characteristic SET mechanism by IBX was
supported by literature.18 Due to nucleophilic nature of the
phenyl radical, it would be attracted to the electrophilic C-2 or
C-3 positions of naphthoquinone, and subsequently, through
the intermediate E, it would produce arylated naphthoquinones
3 along with another molecule of IBA and water. The reaction
was carried out in open atmosphere and considered to tolerate
a lower percentage of water molecules formed during the
progress of the reaction. To understand the further role of IBA
in the reaction sequence, a separate experiment was carried out
on 2-amino-1,4-naphthoquinone 1e under optimized reaction
conditions but using IBA (prepared by literature method)19
instead of IBX. It was found that the reaction between IBA and
phenylhydrazine 2a was slow and gave only 30% yield of
corresponding arylated compound 3e after 8 h. Based on this
result, IBA would be considered to contribute a least partially to
oxidation of arylhydrazine. To support the plausible radical
mediated mechanism for arylation of naphthoquinones,
experimental evidence was developed (Scheme 3).
Scheme 3. Phenyl Radical Trapping Experiments
biphenyl 8 to the extent of 30% along with a small percentage
of azobenzene and benzene (Scheme 3c). Formation of 6, 7,
and 8 along with small percentages of azobenzene and benzene
in corresponding radical trapping experiments strongly
supports the presence of a phenyl radical as the reactive
species in the reaction sequence.
Radical trapping experiment was carried out by using 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO). When phenyl-
hydrazine 2a was oxidized with IBX in the presence of
TEMPO, it produced 1-(2,2,6,6-tetramethylpiperidinyloxy)-
benzene 6 in 30% yield (Scheme 3a). When oxidation of
phenylhydrazine was carried out using IBX in a mixture of
solvents such as acetonitrile and CCl4, it produced
chlorobenzene 7 in 25% yield along with traces of biphenyl 8
and benzene (Scheme 3b). Formation of chlorobenzene 7
could be expected from abstraction of a Cl radical by a phenyl
radical present in the reaction mixture. In another experiment,
when phenylhydrazine 2a was oxidized with IBX in acetonitrile
in the absence of naphthoquinone, 1a showed formation of
The results obtained during arylation of naphthoquinones
particularly with 2-amino-1,4-naphthoquinone 1e were found
potentially applicable toward synthesis of benzocarbazoledione.
Benzocarbazolediones are important precursors of anticancer
and antibiotic molecules due to the “2-phenylnaphthalene-type”
structural pattern.20 The reported methods for the synthesis of
these analogues have common scarcities such as multistep
synthesis, use of hazardous reagents, and side product
formation.21 By applying newly developed protocols toward
the synthesis of benzocarbazoledione, these limitations were
effectively excluded.
When 2-amino-1,4-naphthoquinone 1e was reacted with 2-
bromophenylhydrazine 2g in the presences of IBX, inter-
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Note
133.8, 133.3, 132.4, 132.0, 130.5, 130.0, 128.4, 127.6, 125.9; FT-IR (ν)
3059, 1663, 1596, 1490, 1448, 758, and 696 cm−1.
mediate 4f was produced in 59% yield (Table 2), which
underwent cyclization in the presence of 5% Pd(OAc)2 in DMF
and gave 9 in 90% yield (Scheme 4).
2-Chloro-3-phenyl-1,4-naphthoquinone 3b. Following the general
procedure, the crude product was purified over a silica gel column
using a hexane/EtOAc system (7:3) to give a yellowish solid (174 mg,
65% yield): mp 108−110 °C; 1H NMR (300 MHz, CDCl3) δ 8.22 (d,
J = 4.0 Hz, 1H), 8.15 (d, J = 4.0 Hz, 1H), 7.79 (t, J = 4.5 Hz, 2H), 7.48
(m, 3H), 7.37 (d, J = 4.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
182.1, 178.2, 145.9, 143.0, 134.4, 134.0, 131.7, 131.6, 131.2, 130.4,
129.5, 129.4, 128.0, 127.5, 127.3, 127.1; FT-IR (ν) 3060, 1671, 1594,
1491, 1443, 755, and 706 cm−1. Anal. Calcd for C16H9ClO2: C, 71.52;
H, 3.38. Found: C, 71.68; H, 3.51.
Scheme 4. Synthesis of Benzocarbazoledione
2-Bromo-3-phenyl-1,4-naphthoquinone 3c.23 Following the
general procedure, the crude product was purified over a silica gel
column using a hexane/EtOAc system (7:3) to give a yellowish orange
solid (184 mg, 59% yield): mp 82−84 °C; 1H NMR (300 MHz,
CDCl3) δ 8.23 (dd, J = 8.7 and 4.8 Hz, 1H), 8.16 (dd, J = 8.7 and 4.8
Hz, 1H), 7.80 (t, J = 4.5 Hz, 2H), 7.49 (t, J = 4.0 Hz, 3H), 7.33 (t, J =
4.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 178.3, 173.8, 149.7, 145.7,
134.4, 134.1, 134.0, 131.5, 131.1, 130.5, 129.7, 129.3, 129.1, 128.0,
127.6, 127.3; FT-IR (ν) 3058, 1661, 1593, 1491, 1443, 755, and 700
cm−1. Anal. Calcd for C16H9BrO2: C, 61.37; H, 2.90. Found: C, 61.53;
H, 3.08.
In conclusion, we demonstrated a new method for radical
mediated arylation of naphthoquinones using the combination
of IBX with arylhydrazines. It does not require transition metal
catalysis and prefunctionalization on the naphthoquinone
moiety. The reactions occurred under mild conditions in
open atmosphere. Further, both 2-hydroxy and 2-amino groups
were found to be tolerated under optimized reaction
conditions. This fact could be attributed to rapid reaction
between IBX and phenylhydrazine. A postulated radical
mediated mechanism was supported by radical trapping
experiments. Developed protocols were successfully extended
toward an effective, short and high yielding synthesis of
benzocarbazoledione. IBX-mediated developed protocols for
arylation could open a new field in quinone chemistry as well as
in the development of new procedures for arylation of electron-
deficient molecules in the near future.
2-Hydroxy-3-phenyl-1,4-naphthoquinone 3d.24 Following the
general procedure, the crude product was purified over a silica gel
column using a hexane/EtOAc system (7:3) to give an orange red
1
solid (157 mg, 63% yield): mp 142−144 °C; H NMR (300 MHz,
CDCl3) δ 8.21−8.14 (m, 2H), 7.81−7.73 (m, 2H), 7.50−7.44 (m,
5H), 5.35 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 183.70, 181.8,
152.1, 135.2, 133.1, 132.7, 130.5, 129.8, 129.2, 128.6, 127.9, 127.2,
126.1; FT-IR (ν) 3289, 3071, 1674, 1600, 1562, 1512, 1441, 1256,
1162, 730, and 698 cm−1.
2-Amino-3-phenyl-1,4-naphthoquinone 3e.25 Following the
general procedure, the crude product was purified over a silica gel
column using a hexane/EtOAc system (7:3) to give an orange red
EXPERIMENTAL SECTION
■
1
1
General Methods. H and 13C NMR spectra were recorded on
solid (194 mg, 78% yield): mp 172−174 °C; H NMR (300 MHz,
CDCl3) δ 8.12 (dd, J = 16.0 and 6.6 Hz, 2H), 7.70 (dt, J = 12.0 and 8.0
Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.41−7.22 (m, 3H), 5.20 (s br, 2H);
13C NMR (75 MHz, CDCl3) δ 181.7, 181.6, 145.0, 134.7, 134.6, 133.1,
132.4, 132.1, 130.4, 129.9, 128.9, 128.1, 126.6, 125.8, 116.8; FT-IR (ν)
3351, 3060, 1658, 1593, 1492, 1460, 1366, 1283, 757, and 693 cm−1.
2-Methylamino-3-phenyl-1,4-naphthoquinone 3f.26 Following
the general procedure, the crude product was purified over a silica
gel column using a hexane/EtOAc system (7:3) to give a reddish solid
(181 mg, 69% yield): mp 160−162 °C; 1H NMR (300 MHz, CDCl3)
δ 8.10 (dd, J = 16.0 and 7.5 Hz, 2H), 7.72 (t, J = 7.2 Hz, 1H), 7.62 (t, J
= 7.2 Hz, 1H), 7.36−7.26 (m, 5H), 6.06 (s br, 1H), 2.43 (d, J = 5.7
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 182.8, 182.3, 145.1, 134.7,
134.1, 133.4, 131.9, 131.5, 130.1, 127.4, 126.5, 126.0, 114.9, 32.5; FT-
IR (ν) 3284, 3060, 1673, 1599, 1555, 1482, 1397, 755, and 697 cm−1.
2-Ethylamino-3-phenyl-1,4-naphthoquinone 3g. Following the
general procedure, the crude product was purified over a silica gel
column using a hexane/EtOAc system (7:3) to give a reddish solid
(182 mg, 66% yield): mp 134−136 °C; 1H NMR (300 MHz, CDCl3)
δ 8.10 (dd, J = 7.5 and 3.75 Hz, 1H), 8.07 (dd, J = 7.5 and 3.75 Hz,
1H), 7.72 (t, J = 10.5 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.38−7.29 (m,
5H), 5.84 (s, 1H), 2.63 (q, J = 6.6 and 6.0 Hz, 2H), 1.03 (t, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 182.8, 182.3, 144.2, 134.7, 134.3,
133.4, 131.8, 131.2, 130.1, 127.5, 127.4, 126.4, 125.9, 114.9, 39.8, 15.1;
FT-IR (ν) 3288, 3060, 1674, 1602, 1564, 1511, 1415, 1345, 728, and
693 cm−1. Anal. Calcd for C18H15NO2: C, 77.96; H, 5.45; N, 5.05.
Found: C, 77.79; H, 5.63; N, 5.27.
300 and 75 MHz spectrometers, respectively. Chemical shifts are
reported as δ values relative to internal chloroform (δ 7.26 for H
1
NMR and 77.0 for 13C NMR), DMSO (δ 2.50 for 1H NMR and 39.52
for 13C NMR) in parts per million (ppm). The following abbreviations
are used for the multiplicities: s, singlet; d, doublet; dd, doublet of
doublet; ddd, doublet of doublet of doublet; t, triplet; q, quadruplet;
m, multiplet; dt, doublet of triplet; br, broad; for proton spectra,
coupling constants (J) are reported in hertz (Hz). Infrared spectra
were recorded on an IR spectrometer, and absorption frequencies were
reported in reciprocal centimeters (cm−1).
Typical Procedure for Arylation of Naphthoquinones. To a
stirred slurry of o-iodoxybenzoic acid (2 mmol) in 10 mL of
acetonitrile was added naphthoquinones 1 (1 mmol) and stirred for 5
min. To this solution was slowly added a solution of phenylhydrazines
2 (1.2 mmol) dissolved in 10 mL of acetonitrile over a period of 30
min, and stirring was continued at room temperature for 2.2−4.5 h.
Evolution of nitrogen gas bubbles was observed during the course of
the reaction, and intensity of the same was decreased as the reaction
proceeded. Progress of the reaction was monitored by TLC using
hexane/EtOAc as a mobile phase. After completion of the reaction,
acetonitrile was evaporated under vacuum to obtain residue. To this
residue were added ethyl acetate (15 mL) and water (15 mL),
followed by saturated sodium bicarbonate solution (10 mL). Separated
organic layer was dried over anhydrous sodium sulfate and evaporated
under vacuum to obtain a yellow-orange residue, which was
chromatographed on silica gel column using hexane/ethyl acetate
mobile phase to afford the corresponding pure arylated naphtho-
quinones 3 and 4.
2,3-Diphenyl-1,4-naphthoquinone 3h.27 Following the general
procedure, the crude product was purified over a silica gel column
using a hexane/EtOAc system (7:3) to give a yellowish solid (179 mg,
58% yield): mp 134−137 °C; 1H NMR (300 MHz, CDCl3) δ 8.18 (t, J
= 3.3 Hz, 2H), 7.78 (t, J = 3.3 Hz, 2H), 7.22 (m, 6H), 7.08 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 184.7, 145.6, 133.8, 133.1, 132.0, 130.4,
128.1, 127.5, 126.5; FT-IR (ν) 3060, 1671, 1593, 1491, 1443, 1284,
755, and 700 cm−1.
2-Phenyl-1,4-naphthoquinone 3a.22 Following the general
procedure, the crude product was purified over a silica gel column
using a hexane/EtOAc mobile phase (9:1) to give a yellowish solid
(140 mg, 60% yield): mp 107−109 °C; 1H NMR (300 MHz, CDCl3)
δ 8.18−8.10 (m, 2H), 7.86−7.75 (m, 2H), 7.56−7.48 (m, 5H), 7.07 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 185.2, 185.1, 148.1, 135.2, 133.9,
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2-Amino-3-(2-toluyl)-1,4-naphthoquinone 4a. Following the
general procedure, the crude product was purified over a silica gel
column using a hexane/EtOAc system (7:3) to give an orange solid
(173 mg, 66% yield): mp 148−150 °C; 1H NMR (300 MHz, CDCl3)
δ 8.12 (t, J = 8.0 Hz, 2H), 7.70 (dt, J = 10.5 and 7.5 Hz, 2H), 7.32−
7.15 (m, 4H), 4.97 (s br, 2H), 2.19 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 181.7, 181.5, 145.2, 137.3, 134.6, 133.2, 132.1, 131.7, 130.7,
130.5, 129.9, 128.6, 126.6, 126.4, 125.9, 117.2, 19.6; FT-IR (ν) 3449,
3338, 2928, 2854, 3052, 1680, 1601, 1560, 1383, 1280,758 and 721
cm−1. Anal. Calcd for C17H13NO2: C, 77.55; H, 4.98; N, 5.32. Found:
C, 77.71; H, 5.10; N, 5.53.
2-Amino-3-(4-toluyl)-1,4-naphthoquinone 4b. Following the
general procedure, the crude product was purified over a silica gel
column using a hexane/EtOAc system (7:3) to give a dark red solid
(163 mg, 62% yield): mp 208−210 °C; 1H NMR (300 MHz, CDCl3)
δ 8.11 (dd, J = 7.5 Hz, 2H), 7.69 (dt, J = 11.1 and 7.5 Hz, 2H), 7.27
(dd, J = 7.8 Hz, 4H), 5.19 (s br, 2H), 2.39 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 187.1, 181.8, 145.0, 137.9, 134.5, 133.1, 132.1, 130.4,
129.8, 129.6, 129.3, 126.6, 125.8, 116.9, 21.3; FT-IR (ν) 3455, 3341,
3060, 2926, 2853, 1673, 1598, 1565, 1513, 1386, 1346, 1307, and 724
cm−1. Anal. Calcd for C17H13NO2: C, 77.55; H, 4.98; N, 5.32. Found:
C, 77.69; H, 5.16; N, 5.58.
2-Amino-3-(2-ethylphenyl)-1,4-naphthoquinone 4c. Following
the general procedure, the crude product was purified over a silica
gel column using a hexane/EtOAc system (7:3) to give an orange solid
(180 mg, 65% yield): mp 136−139 °C; 1H NMR (300 MHz, CDCl3)
δ 8.12 (t, J = 8.4 Hz, 2H), 7.70 (dt, J = 7.0 Hz, 2H), 7.37−7.26 (m,
3H), 7.13 (d, J = 9.0 Hz, 1H), 4.95 (s br, 2H), 2.50 (q, J = 4.2 and 3.0
Hz, 2H), 1.12 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
181.8, 181.7, 145.5, 143.4, 134.6, 133.2, 132.1, 131.1, 130.5, 130.0,
128.9, 128.8, 126.6, 126.5, 125.9, 117.4, 26.4, 15.2; FT-IR (ν) 3414,
3303, 3063, 2964, 2926, 1682, 1596, 1560, 1479, 1397, 1351, 1226,
998, 758, and 723 cm−1. Anal. Calcd for C18H15NO2: C, 77.96; H,
5.45; N, 5.05. Found: C, 77.83; H, 5.61; N, 5.23.
2-Amino-3-(4-fluorophenyl)-1,4-naphthoquinone 4d. Following
the general procedure, the crude product was purified over a silica gel
column using a hexane/EtOAc system (7:3) to give a reddish solid
(170 mg, 64% yield): mp 134−137 °C; 1H NMR (300 MHz, CDCl3)
δ 8.12 (dd, J = 7.5 and 6.6 Hz, 2H), 7.70 (dt, J = 12.6 and 7.5 Hz, 2H),
7.38−7.16 (m, 4H), 5.20 (s br, 2H); 13C NMR (75 MHz, CDCl3) δ
181.3, 181.0, 145.6, 134.7, 133.1, 132.3, 132.1, 132.0, 130.5, 130.4,
126.7, 126.0, 124.6, 124.5, 116.4, 116.1; FT-IR (ν) 3426, 3305, 3061,
1677, 1596, 1561, 1489, 1446, 1398, 1351, 1225, 1000, 759, and 721
cm−1. Anal. Calcd for C16H10FNO2: C, 71.91; H, 3.77; N, 5.24. Found:
C, 71.70; H, 3.95; N, 5.09.
reaction mixture was partitioned between EtOAc (30 mL) and H2O
(30 mL). Separated aqueous phase was extracted with EtOAc (2 × 25
mL) and combined with the previous fraction. The combined organic
extracts washed with brine (25 mL), dried (Na2SO4), and filtered. The
solvents were evaporated. The obtained residue was purified by
column chromatography to afford an orange solid (222 mg, 90%
1
yield): mp 311−313 °C; H NMR (300 MHz, DMSO-d6) δ 13.09 (s,
1H), 8.22 (d, J = 8.0 Hz, 1H), 8.14−8.10 (m, 2H), 7.89−7.81 (m,
2H), 7.61 (d, J = 8.0 Hz, 1H), 7.46 (ddd, J = 8.0 Hz, 1H), 7.38 (ddd, J
= 8.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 184.1, 181.7, 144.1,
135.03, 134.6, 133.1, 132.6, 130.5, 130.4, 127.8, 126.7, 126.2, 123.1,
104.4; FT-IR (ν) 3307, 3038, 1672, 1620, 1589, 1531, 1343, and 739
cm−1.
Preparation of Starting Compounds. Compounds 1,4-naphtho-
quinone 1a and 2-hydroxy-1,4-naphthoquinone 1d were purchased
from commercial sources and used as received. 2-Phenyl-1,4-
naphthoquinone 1h was synthesized by the method described in this
paper and used as a starting material after characterization. Remaining
starting compounds were synthesized using literature procedures.
2-Chloro-1,4-naphthoquinone 1b:29 Yellowish solid (83% yield);
mp 114−116 °C; 1H NMR (300 MHz, CDCl3) δ 8.18 (t, J = 4.8 Hz,
1H), 8.09 (t, J = 4.8 Hz, 1H), 7.79 (t, J = 4.5 Hz, 2H), 7.23 (s, 1H);
FT-IR (ν) 1678, 1654, 1585, 1559, 1273, and 701 cm−1.
2-Bromo-1,4-naphthoquinone 1c:30 Brown solid (78% yield); mp
1
130−133 °C; H NMR (300 MHz, CDCl3) δ 8.20−8.17 (m, 1H),
8.10−8.08 (m, 1H), 7.81−7.75 (m, 2H), 7.53 (s, 1H); FT-IR (ν)
1678, 1658, 1589, 1569, 1292, 1244, and 694 cm−1.
2-Amino-1,4-naphthoquinone 1e:31 Reddish solid (68% yield);
1
mp 205−206 °C; H NMR (300 MHz, DMSO-d6) δ 7.96 (t, J = 7.8
Hz, 2H), 7.74 (t, J = 7.2 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 6.94 (s br,
2H), 5.89 (s, 1H); FT-IR (ν) 3410, 3178, 1612, 1557, 1495, 1418,
1269, 984, and 723 cm−1.
2-Methylamino-1,4-naphthoquinone 1f:32 Reddish solid (65%
yield); mp 232−234 °C; 1H NMR (300 MHz, CDCl3) δ 8.07 (dd, J =
12.3 and 7.5 Hz, 2H), 7.73 (t, J = 7.2 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H),
5.95 (s, 1H), 5.72 (s, 1H), 2.93 (d, J = 5.1 Hz, 3H). FT-IR (ν) 3380,
2856, 1613, 1598, 1586, and 1420 cm−1.
2-Ethylamino-1,4-naphthoquinone 1g:33 Reddish solid (72%
1
yield); mp 140−142 °C; H NMR (300 MHz, CDCl3) δ 8.07 (dd, J
= 10.2 and 7.5 Hz, 2H), 7.72 (t, J = 7.5 Hz, 1H), 7.61 (t, J = 7.5 Hz,
1H), 5.84 (s, 1H), 5.73 (s, 1H), 3.27−3.18 (m, 2H), 1.34 (t, J = 7.5
Hz, 3H); FT-IR (ν) 3378, 2928, 2859, 1623, 1608, 1578, and 1450
cm−1.
ASSOCIATED CONTENT
■
2-Amino-3-(2-chlorophenyl)-1,4-naphthoquinone 4e. Following
the general procedure, the crude product was purified over a silica gel
column using a hexane/EtOAc system (7:3) to give an orange solid
(195 mg, 69% yield): mp 182−185 °C; 1H NMR (300 MHz, CDCl3)
δ 8.13 (dd, J = 7.8 and 3.6 Hz, 2H), 7.71 (dt, J = 11.4 and 7.5 Hz, 2H),
7.53 (t, J = 6.3 Hz, 2H), 7.38−7.28 (m, 2H), 5.06 (s br, 2H); 13C
NMR (75 MHz, CDCl3) δ 181.5, 181.0, 145.4, 145.3, 134.7, 133.1,
132.3, 132.0, 131.3, 130.4, 130.1, 129.9, 127.4, 126.7, 126.0, 117.4; FT-
IR (ν) 3476, 3331, 3083, 1684, 1607, 1565, 1472, 1398, 844, 792, 757,
and 726 cm−1. Anal. Calcd for C16H10ClNO2: C, 67.74; H, 3.55; N,
4.94. Found: C, 67.53; H, 3.63; N, 5.06.
S
* Supporting Information
Copies of 1H and 13C NMR spectra for all of the products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kgap@rediffmail.com; kg.akamanchi@ictmumbai.edu.
■
in.
Notes
2-Amino-3-(2-bromophenyl)-1,4-naphthoquinone 4f. Following
the general procedure, the crude product was purified over a silica gel
column using a hexane/EtOAc system (7:3) to give an orange-brown
The authors declare no competing financial interest.
1
ACKNOWLEDGMENTS
solid (192 mg, 59% yield): mp 196−199 °C; H NMR (300 MHz,
■
CDCl3) δ 8.13−8.07 (m, 2H), 7.75−7.74 (m, 2H), 7.49−7.34 (m,
4H), 5.21 (s br, 2H); 13C NMR (75 MHz, CDCl3) δ 181.5, 180.9,
145.0, 134.9, 134.7, 133.6, 133.3, 132.7, 132.3, 131.9, 130.1, 128.0,
127.2, 126.7, 126.0, 116.9. FT-IR (ν) 3339, 1683, 1605, 1571, 1458,
1399, 1351, 1276, 757, and 721 cm−1. Anal. Calcd for C16H10BrNO2:
C, 58.56; H, 3.07; N, 4.27. Found: C, 58.43; H, 3.19; N, 4.42.
5H-Benzo[b]carbazole-6,11-dione 9.28 A mixture of 4f (1.0
mmol), Pd (OAc)2 (0.05 mmol), Ph3P (0.1 mmol), and K2CO3 (3.0
mmol) in dry DMF (15 mL) under N2 atmosphere was heated to 120
°C for 4 h. Reaction mixture was cooled to room temperature. The
We are grateful to the TEQIP (P.P.) and CSIR (A.N.) for
financial support of this research. We are also thankful to M/s
Omkar Speciality Chemicals Ltd., Badlapur, Mumbai, for the
generous gift of IBX.
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