An efficient route for the synthesis of isochromenocarbazolones through palladium-catalyzed intramolecular ortho -arylation

Article abstract of DOI:10.1055/s-0030-1260162

A new efficient protocol for the synthesis f isochromeno[3,4-b]-, [4,3-a]-, -[4,3-b]-, and -[3,4-c]carbazolones has been successfully established via palladium-catalyzed intramolecular ortho-arylation of C-H bond under ligand-free conditions. Georg Thieme

Full text of DOI:10.1055/s-0030-1260162

PAPER
3195
An Efficient Route for the Synthesis of Isochromenocarbazolones through
Palladium-Catalyzed Intramolecular ortho-Arylation
S
ynthesis of Isoch
e
r
omenocarb
v
azolones anga K. Sreenivas, Rajagopal Nagarajan*
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
E-mail: rnsc@uohyd.ernet.in
Received 13 May 2011; revised 20 June 2011
synthesis of pyranocarbazole alkaloids and their deriva-
tives, very little attention has been paid to the synthesis of
its isomers and fused with other biologically important
molecules.
Abstract: A new efficient protocol for the synthesis of isochro-
meno[3,4-b]-, [4,3-a]-, -[4,3-b]-, and -[3,4-c]carbazolones has been
successfully established via palladium-catalyzed intramolecular
ortho-arylation of C–H bond under ligand-free conditions.
Key words: isochromenocarbazolones, intramolecular arylation, In recent years, transition-metal-catalyzed coupling reac-
carbazolyl iodobenzoates
tions have become one of the most successful and direct
methods for the construction of ring systems as they offer
efficient entry from relatively simple precursors to cyclic
compounds.9 In particular, palladium-catalyzed intramo-
lecular direct arylation of the C–H bond of a heteroaro-
matic compound is of considerable interest due to its
significant utility in organic synthesis.10 In the present
work, we wish to demonstrate the synthesis of iso-
chromenocarbazolones by intramolecular palladium-cata-
lyzed ortho-arylation starting from various derivatives of
carbazolyl iodobenzoates (Scheme 1).
Carbazole and its fused derivatives1 such as pyrano-
carbazoles2 have attracted great attention from medicinal
and synthetic chemists due to their wide range of biologi-
cal applications. Glycoborinine, euchrestifoline, and
clausamines are some of the important pyranocarbazole
alkaloids3 (Figure 1). Among these, clausamines A–C and
D, E4 isolated from Clausena anisata and Clausena exca-
vate respectively, possess various biological activity, such
as antitumor,5 anti-oxidative, and anti-inflammatory,6 and
they also potently inhibit Epstein–Barr virus early antigen
(EBV-EA) activation induced by 12-O-tetrade-
canoylphorbol-13-acetate (TPA) in Raji cells.7
9-Ethyl-9H-carbazol-3-yl 2-iodobenzoate (3a), which
was synthesized from 9-ethyl-3-hydroxy-9H-carbazole
and 2-iodobenzoyl chloride, was used as the prototype
substrate to optimize the reaction conditions. The initial
screenings with various solvents like toluene, 1,4-diox-
ane, 1,2-dichlorobenzene were unsuccessful, recovering
the starting material in all cases (Table 1, entries 1–3).
When a mixture of solvents, such as N,N-dimethylform-
amide–N,N-dimethylacetamide (DMA), was used, two re-
gioisomeric products 4a and 5a were obtained in poor
yields (entry 5). The influence of catalyst, ligand, addi-
tive, and temperature in the reaction outcome were exam-
ined as shown in Table 1. By examining various catalysts,
we found that palladium(II) acetate was a suitable cata-
lyst. The effect of the base on the reaction was studied,
different bases such as triethylamine, DABCO, pyridine,
and cesium carbonate were not effective but sodium ace-
tate and potassium acetate were most effective. N,N-Di-
methylacetamide was the best solvent compared to other
solvents. Ligand and additives had no effect on the reac-
tion, without ligand and additive the reaction proceeded
well within four hours (entry 16). No reaction was found
to occur at or below 110 °C.
O
O
N
HO
H
N
H
O
glycoborinine
euchrestifoline
HO
OH
O
O
O
O
O
O
N
N
N
H
H
H
OR
OR
HO
R = H, clausamine A R = H, clausevatine D
R = Me, clausamine B R = Me, clausamine C
clausevatine G
Figure 1 Pyranocarbazole alkaloids
The syntheses of euchrestifoline, eustifoline D, and glyco-
maurrol were reported by Knölker and co-workers using
an elegant cross-coupling strategy to assemble the carba-
zole core of the targets.8 Despite the great interest in the
After all these optimization assays, the best optimized
conditions were found to involve palladium(II) acetate
(10 mol%) in N,N-dimethylacetamide with sodium ace-
tate (2.5 equiv) as a base at 140 °C. At these optimized
conditions, 3a was converted to give a mixture of products
4a and 5a in 85% yield, which on column chromatogra-
phy over silica gel provided 4a and 5a in 58% and 27%
yields respectively, within four hours (entry 16). The for-
SYNTHESIS 2011, No. 19, pp 3195–3203
x
x.
x
x
.
2
0
1
1
Advanced online publication: 08.08.2011
DOI: 10.1055/s-0030-1260162; Art ID: T50611SS
© Georg Thieme Verlag Stuttgart · New York

3196
D. K. Sreenivas, R. Nagarajan
PAPER
O
R5
R5
I
O
R2
I
OH
R2
O
Cl
pyridine, CH2Cl2
+
0 °C, 15 min
r.t., 2–10 h
N
R1
N
R1
R3
R3
R4
R4
if R3, R5 = H
if R3, R5 = Me
Pd(OAc)2, NaOAc
DMA, 140 °C
Pd(OAc)2, KOAc
DMA, 140 °C
R4
O
O
O
R2
O
R2
O
R2
O
+
R4
R4
N
R1
N
R1
N
R1
major
minor
Scheme 1 Schematic representation of work
mation of two isomers 4a and 5a is due to the two reactive substituted derivatives 4d and 5d were characterized by
ortho positions of 3a; 4a is formed as the major and 5a as single crystal X-ray analysis (Figure 2).11 The structure of
the minor product.
4b was also confirmed by single crystal X-ray analysis
(Figure 3).11
The two regioisomers 4a and 5a were characterized by
1
their H NMR spectra (see Supporting Information). In By employing similar conditions, we synthesized iso-
the 1H NMR spectrum of 4a, two doublets were observed chromeno[3,4-b]- and -[4,3-a]carbazolones from 9H-car-
at d = 8.94 and 8.56 ppm whereas for 5a clearly two sin- bazol-2-yl 2-iodobenzoate 3e to afford a mixture of
glets at d = 8.04 and 7.98 ppm were observed.
products 4e and 5e in 80% yield, which on chromato-
graphed over basic alumina gave 4e and 5e in 60% and
20% yields, respectively (Scheme 3). The two isomers 4e
and 5e were distinguished by their 1H NMR spectra (see
By employing the above optimized conditions, various
isochromenocarbazolone derivatives were synthesized.
Carbazolyl benzoates 3a–d were subjected to cyclization
to provide isomeric products 4a–d and 5a–d in good
yields (Scheme 2, Table 2). The regioisomers of methyl-
1
Supporting Information). From H NMR of 4e, two sin-
glets were observed at d = 9.20 and 7.43 ppm, whereas in
O
I
O
R2
R2
OH
O
R4
pyridine, CH2Cl2
Cl
+
I
0 °C, 15 min
r.t., 2–10 h
N
R1
N
R1
R4
1a–d
1 = Et, Bn
2 = Me, H
2a,b
R4 = H, NO2
3a–d
R
R
Pd(OAc)2, NaOAc
DMA,140 °C
R4
O
O
R2
O
R2
O
+
R4
N
N
R1
R1
4a–d
major
5a–d
minor
Scheme 2 Synthesis of isochromenocarbazolone derivatives
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PAPER
Synthesis of Isochromenocarbazolones
3197
Table 1 Optimization Conditions for the Conversion of 3a into 4a and 5aa
O
O
O
O
I
O
O
+
N
N
Et
3a
N
Et
5a
minor
Et
4a
major
Entry
1
Catalyst
Ligand
Ph3P
Additive
Base
Solvent
toluene
1,4-dioxane
DMF
Temp (°C)
120
120
110
140
140
140
140
120
130
130
130
130
130
130
140
140
130
140
140
140
130
140
120
Time (h)
Yieldb (%)
c
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PPh3)2
CuIe
K2CO3
KOAc
–
c
2
Ph3P
TBAB
TBAB
24
24
12
12
16
16
16
12
10
24
10
10
10
8
–
c
3
KOAc
–
4
Ph3P
Cy3P
NaOAc
NaOAc
KOH
DMF
35
35
78
5
DMF–DMAd
DMSO
DMSO
TEG
6
c
7
TBAB
TBAB
TBAB
TBAB
K2CO3
NaOAc
NaHCO3
NaOAc
DABCO
K2CO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
KOAc
–
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ph3P
Ph3P
Ph3P
Cy3P
Cy3P
53
9
DMA
75
10
11
12
13
14
15
16
17
18
19
20
21
22
23
DMA
80 (52:22)
c
DMA
–
SDSf
DMA
58
TBAB
DMA
80 (52:22)
80 (52:22)
85 (58:27)g
85 (58:27)g
80 (58:22)
60 (25:15)
44
Ph3P
DMA
DMA
h
Pd(OAc)2
DMA
4
PdCl2(PPh3)2
PdCl2
DMA
10
10
16
10
8
DMA
Pd/Ci
DMA
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2/H2Oj
Pd(OAc)2
DMA
85 (58:27)
68
NaOAc·3H2O
KOAc
DMA
c
DMA
16
–
NaOAc
DMA
24k
a Unless otherwise stated, all reactions were carried out in a sealed tube using catalyst (0.05 equiv), ligand (0.2 equiv), additive (1.0 equiv), base
(2.5 equiv), solvent (2.0 mL).
b Combined yield of 4a + 5a.
c No reaction.
d DMF–DMA in the ratio 1:1.
e CuI (10 mol%).
f SDS (1.5 equiv).
g Isolated yields of regioisomers 4a and 5a.
h Pd(OAc)2 (10 mol%).
i Pd/C (20 mol%).
j Activated.
k In domestic microwave at temperature 120 °C for 10 min.
Synthesis 2011, No. 19, 3195–3203 © Thieme Stuttgart · New York

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D. K. Sreenivas, R. Nagarajan
PAPER
I
O
I
pyridine, CH2Cl2
O
Cl
O
+
OH
0 °C, 15 min
r.t., 8 h
N
H
N
H
1e
85%
2a
3e
Pd(OAc)2, NaOAc
DMA, 140 °C
O
+
N
H
O
O
O
N
H
4e, 60%
major
5e, 20%
minor
Scheme 3 Synthesis of isochromeno[3,4-b]- and -[4,3-a]carbazolones
O
O
I
O
OH
pyridine, CH2Cl2
Cl
R4
+
I
0 °C, 15 min
r.t., 2–10 h
62–82%
N
R1
N
R1
R4
1f–h
1 = Et, Bn
2a–c
R4 = H, Cl
3f–h
R
Pd(OAc)2, KOAc
DMA, 140 °C
O
O
R4
N
R1
5f R1 = Et, R4 = H 75%
5g R1 = Bn, R4 = H 82%
5h R1 = Et, R4 = Cl 62%
Scheme 4 Synthesis of dimethylisochromeno[4,3-b]carbazolone derivatives
isomer 5e two doublets were observed at d = 8.79 and 7.91 A variety of dimethylisochromeno[4,3-b]carbazolone de-
ppm.
rivatives 5f–h were prepared in 62–82% yields (Scheme
4). Among these, derivative 5f was also confirmed by its
single crystal X-ray analysis (Figure 4).11
Employing similar conditions, we obtained a 45% yield of
cyclized product 5f. To improve the yield, changing the
base from sodium acetate to potassium acetate at 140 °C In conclusion, we have developed an efficient route for
and using palladium(II) acetate (10 mol%) in N,N-dimeth- the construction of new classes of isochromeno[3,4-b]-,
ylacetamide gave 5f in 75% yield.
-[4,3-a]-, -[4,3-b]-, and -[3,4-c]carbazolones via palladi-
um-catalyzed intramolecular arylation of C–H bonds un-
der ligand-free conditions.
Table 2 Yields and Product Distribution of 3a–d, 4a–d, and 5a–d
Entry R1
R2
H
R4
H
ProductYield (%)Products Yielda (%)
The procedures do not require an inert atmosphere. All the products
obtained were purified by column chromatography using basic alu-
mina and silica gel (100–200 mesh). Hexane was used as a co-elu-
1
2
3
4
Et
Bn
Et
Et
3a
3b
65
68
78
62
4a + 5a 58 + 27
4b + 5b 55 +25
4c + 5c 58 + 18
4d + 5d 55 + 24
H
H
1
ent. H and 13C NMR spectra were recorded at 400 MHz and 100
1
H
NO2 3c
3d
MHz, respectively, relative to TMS (d = 0 ppm) for H NMR and
the central CDCl3 resonance (d = 77.0 ppm) and DMSO-d6
(d = 39.51 ppm) for 13C NMR. IR spectra were recorded on FT/IR-
5300.
Me
H
a Yields after separation and isolation by column chromatography.
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Synthesis of Isochromenocarbazolones
3199
Figure 4 ORTEP diagram of 5f
The X-ray diffraction measurements were carried out at 298 K on
an automated diffractometer using graphite monochromated, Mo-
Ka (l = 0.71073 Å) radiation with CAD4 software or the X-ray in-
tensity data were measured at 298 K equipped with a graphite
monochromator and a Mo-Ka fine-focus sealed tube (l = 0.71073
Å). Elemental analyses were recorded on a Thermo Finnigan Flash
EA 1112 analyzer in School of Chemistry at University of Hydera-
bad. Mass spectra were recorded on either VG7070H mass spec-
trometer using EI technique or Shimadzu-LCMS-2010A mass
spectrometer. Melting points were measured in open capillary tubes
and are uncorrected.
9-Ethyl-9H-carbazol-3-yl 2-Iodobenzoate (3a); Typical Proce-
dure
To 1a (0.5 g, 2.1 mmol) in CH2Cl2 (10 mL), pyridine (0.42 mL, 4.3
mmol) was added and the mixture was stirred at r.t. for 15 min. Then
the mixture was cooled in an ice bath and freshly prepared 2a (0.7
mL, 2.6 mmol) (prepared from 2-iodobenzoic acid and SOCl2) was
added in dropwise. After stirring for 15 min, the mixture was
brought to r.t. and stirring was continued for up to 6 h. The solvent
was evaporated in vacuo, and the crude product was chromato-
graphed (alumina, 12% EtOAc–hexanes) to give pure 3a as a white
solid; yield: 65%; mp 89 °C.
Figure 2 ORTEP diagrams of 4d and 5d
IR (KBr): 3059, 2930, 1732, 1689, 1577, 1462, 1244, 1080, 1037,
891, 744 cm–1.
1H NMR (400 MHz, TMS, CDCl3): d = 8.16–8.11 (m, 3 H), 8.02 (s,
1 H), 7.55–7.51 (m, 2 H), 7.45 (q, J = 4.0 Hz, 2 H), 7.41–7.38 (dd,
J1 = 2.0 Hz, J2 = 2.0 Hz, 1 H), 7.29–7.24 (m, 2 H), 4.40 (q, J = 7.2
Hz, 2 H, NCH2CH3), 1.47 (t, J = 7.2 Hz, 3 H, NCH2CH3).
13C NMR (100 MHz, TMS, CDCl3): d = 165.8, 143.5, 141.6, 140.6,
137.8, 134.7, 133.8, 128.1, 126.1, 123.3, 122.6, 120.7, 119.2, 118.9,
113.0, 108.8, 108.7, 94.6, 37.7, 13.8.
LC-MS (+-mode): m/z = 441 [M + H]+.
Anal. Calcd for C21H16INO2: C, 57.16; H, 3.65; N, 3.17. Found: C,
57.28; H, 3.71; N, 3.22.
9-Benzyl-9H-carbazol-3-yl 2-Iodobenzoate (3b)
White solid; yield: 68%; mp 48 °C.
IR (KBr): 3418, 3061, 1734, 1693, 1583, 1466, 1242, 1014, 891,
794, 680 cm–1.
1H NMR (400 MHz, TMS, CDCl3): d = 8.09–8.04 (m, 4 H), 8.02–
8.00 (m, 2 H), 7.51–7.47 (m, 1 H), 7.43 (t, J = 6.0 Hz, 3 H), 7.37–
7.35 (m, 2 H), 7.24 (s, 1 H), 7.20–7.17 (ddd, J1 = 1.2 Hz, J2 = 1.2
Hz, J3 = 1.2 Hz, 1 H), 7.13 (d, J = 5.6 Hz, 2 H), 5.51 (s, 2 H).
Figure 3 ORTEP diagram of 4b
13C NMR (100 MHz, TMS, CDCl3): d = 165.8, 141.9, 141.6, 141.3,
138.5, 136.9, 133.5, 133.1, 132.0, 131.5, 128.9, 128.0, 126.4, 126.3,
Synthesis 2011, No. 19, 3195–3203 © Thieme Stuttgart · New York

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D. K. Sreenivas, R. Nagarajan
PAPER
123.4, 122.7, 120.7, 118.8, 119.4, 119.3, 113.0, 109.3, 109.1, 94.7,
46.7.
(q, J = 8.0 Hz, 2 H, NCH2CH3), 2.83 (s, 3 H), 2.74 (s, 3 H), 1.43 (t,
J = 8.0 Hz, 3 H, NCH2CH3).
LC-MS (+-mode): m/z = 504 [M + H]+.
13C NMR (100 MHz, TMS, CDCl3): d = 165.7, 141.7, 141.3, 141.2,
136.7, 134.4, 133.1, 131.5, 128.1, 125.2, 123.9, 122.9, 122.7, 122.4,
118.9, 118.1, 108.1, 94.7, 39.3, 20.1, 15.5, 13.6.
Anal. Calcd for C26H18INO2: C, 62.04; H, 3.60; N, 2.78. Found: C,
62.15; H, 3.72; N, 2.71.
LC-MS (+-mode): m/z = 470 [M + H]+.
9-Ethyl-9H-carbazol-3-yl 2-Iodo-5-nitrobenzoate (3c)
Red solid; yield: 78%; mp 98 °C.
IR (KBr): 3057, 2970, 1745, 1569, 1317, 1016, 829 cm–1.
Anal. Calcd for C23H20INO2: C, 58.86; H, 4.30; N, 2.98. Found: C,
58.75; H, 4.36; N, 2.91.
9-Benzyl-1,4-dimethyl-9H-carbazol-3-yl 2-Iodobenzoate (3g)
White solid; yield: 72%; mp 122–124 °C.
1H NMR (400 MHz, TMS, CDCl3): d = 8.91 (s, 1 H), 8.28 (d,
J = 8.8 Hz, 1 H), 8.09–8.0 (m, 3 H), 7.52 (d, J = 7.6 Hz, 1 H), 7.49–
7.43 (m, 2 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.24 (d, J = 7.2 Hz, 1 H),
4.4 (q, J = 7.2 Hz, 2 H, NCH2CH3), 1.46 (t, J = 6.8 Hz, 3 H,
NCH2CH3).
13C NMR (100 MHz, TMS, CDCl3): d = 164.0, 143.1, 143.0, 140.6,
138.0, 135.9, 126.7, 126.3, 125.9, 123.3, 122.5, 120.7, 119.0, 118.8,
112.8, 108.9, 103.1, 37.7, 13.8.
IR (KBr): 2922, 1739, 1682, 1579, 1508, 1396, 1165, 1014, 885,
796 cm–1.
1H NMR (400 MHz, TMS, CDCl3): d = 8.29–8.17 (m, 1 H), 8.15–
8.09 (m, 2 H), 7.52 (q, J = 8.0 Hz, 1 H), 7.32 (s, 1 H), 7.30–7.22 (m,
5 H), 7.10 (d, J = 8.0 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 6.95 (d,
J = 8.0 Hz, 1 H), 5.80 (s, 2 H), 2.80 (s, 3 H), 2.64 (s, 3 H).
LC-MS (+-mode): m/z = 487 [M + H]+.
13C NMR (100 MHz, TMS, CDCl3): d = 165.8, 143.9, 141.6, 140.0,
139.3, 138.5, 134.6, 133.1, 131.5, 129.4, 128.9, 128.1, 127.3, 125.5,
124.0, 122.6, 122.4, 121.9, 121.2, 119.4, 118.8, 117.8, 115.0, 109.1,
94.6, 48.3.
Anal. Calcd for C21H15IN2O4: C, 51.87; H, 3.11; N, 5.76. Found: C,
51.73; H, 3.18; N, 5.71.
9-Ethyl-6-methyl-9H-carbazol-3-yl 2-Iodobenzoate (3d)
LC-MS (–-mode): m/z = 530 [M – H].
White solid; yield: 62%; mp 74 °C.
Anal. Calcd for C28H22INO2: C, 63.29; H, 4.17; N, 2.64. Found: C,
63.15; H, 4.22; N, 2.58.
IR (KBr): 2962, 1738, 1577, 1458, 1344, 1302, 1182, 1141, 1068,
891, 640, 607 cm–1.
9-Ethyl-1,4-dimethyl-9H-carbazol-3-yl 5-Chloro-2-iodoben-
zoate (3h)
White solid; yield: 65%; mp 84 °C.
IR (KBr): 2994, 1736, 1608, 1504, 1180, 1010, 804, 615 cm–1.
1H NMR (400 MHz, TMS, CDCl3): d = 8.21 (d, J = 8.0 Hz, 1 H),
8.12 (d, J = 2.8 Hz, 1 H), 8.0 (d, J = 8.8 Hz, 1 H), 7.50–7.43 (m, 2
H), 7.24–7.21 (m, 2 H), 7.03 (s, 1 H), 4.60 (q, J = 7.2 Hz, 2 H,
NCH2CH3), 2.81 (s, 3 H), 2.72 (s, 3 H), 1.42 (t, J = 8.0 Hz, 3 H,
NCH2CH3).
13C NMR (100 MHz, TMS, CDCl3): d = 164.5, 142.8, 141.1, 136.8,
135.8, 134.7, 133.2, 131.4, 128.3, 125.3, 123.9, 122.9, 122.5, 122.2,
121.9, 119.0, 118.2, 108.6, 91.9, 39.3, 20.1, 15.5, 13.7.
1H NMR (400 MHz, TMS, CDCl3): d = 8.15–8.11 (m, 2 H), 7.93 (d,
J = 2.4 Hz, 1 H), 7.90 (s, 1 H), 7.55–7.51 (m, 1 H), 7.44 (s, 1 H),
7.41 (s, 1 H), 7.38 (d, J = 2.4 Hz, 2 H), 7.28–7.24 (m, 1 H), 4.37 (q,
J = 7.2 Hz, 2 H, NCH2CH3), 2.57 (s, 3 H, CH3), 1.45 (t, J = 7.2 Hz,
3 H, NCH2CH3).
13C NMR (100 MHz, TMS, CDCl3): d = 165.9, 143.3, 141.6, 138.9,
138.0, 134.7, 133.0, 131.5, 128.2, 128.0, 127.5, 123.0, 122.7, 120.6,
119.0, 112.9, 108.7, 108.4, 94.6, 37.7, 21.4, 13.8.
LC-MS (+-mode): m/z = 456 [M + H]+.
Anal. Calcd for C22H18INO2: C, 58.04; H, 3.98; N, 3.08. Found: C,
58.12; H, 3.91; N, 3.15.
9H-Carbazol-2-yl 2-Iodobenzoate (3e)
LC-MS (+-mode): m/z = 504 [M + H]+, 506 [M + 2].
White solid; yield: 85%; mp 179 °C.
Anal. Calcd for C23H19ClINO2: C, 54.84; H, 3.80; N, 2.78. Found:
C, 54.75; H, 3.86; N, 2.71.
IR (KBr): 3396, 1728, 1601, 1458, 1325, 1251, 1138, 1012, 802,
742 cm–1.
9-Ethylisochromeno[3,4-c]carbazol-5(9H)-one (4a) and 12-Eth-
ylisochromeno[4,3-b]carbazol-5(12H)-one (5a); Typical Proce-
dure
1H NMR (400 MHz, TMS, DMSO-d6): d = 11.41 (s, 1 H), 8.18 (d,
J = 8.4 Hz, 1 H), 8.11 (t, J = 9.2 Hz, 2 H), 8.01 (d, J = 8.0 Hz, 1 H),
7.61 (t, J = 6.8 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.42 (s, 1 H), 7.36
(d, J = 6.8 Hz, 2 H), 7.18 (t, J = 7.2 Hz, 1 H), 7.09 (d, J = 6.8 Hz, 1
H).
13C NMR (100 MHz, TMS, DMSO-d6): d = 166.0, 149.0, 141.2,
140.8, 135.5, 133.9, 131.4, 128.9, 126.0, 122.4, 121.2, 121.0, 120.6,
119.4, 113.0, 111.5, 104.5, 95.2.
A mixture of 3a (0.15 g, 0.34 mmol), anhyd NaOAc (0.07 g, 0.85
mmol), and Pd(OAc)2 (0.007 g, 10 mol%) in DMA (3.0 mL) was
added to a sealed tube and heated at 140 °C for 4 h with continuous
stirring. After completion of the reaction (TLC monitoring), the
mixture was cooled and poured into cold H2O (10 mL). A solid pre-
cipitate was formed was extracted with CHCl3 or CH2Cl2 (3 × 20
mL). The combined organic extracts were washed with H2O (3 × 20
mL) and brine (20 mL) and dried (Na2SO4). Evaporation of solvent
gave crude material that was purified by column chromatography
(silica gel, 100–200 mesh, 14% EtOAc–hexanes) to give 4a and 5a.
Compounds 4b–d, 5b–d, and 5f–h were obtained using the same
procedure. Compounds 4e and 5e were chromatographed on basic
alumina using 35% EtOAc in hexanes as eluent. For 5f–h, anhyd
KOAc (2.5 equiv) was used as base.
LC-MS (+-mode): m/z = 414 [M + H]+.
Anal. Calcd for C19H12INO2: C, 55.23; H, 2.93; N, 3.39. Found: C,
55.42; H, 2.86; N, 3.31.
9-Ethyl-1,4-dimethyl-9H-carbazol-3-yl 2-Iodobenzoate (3f)
White solid; yield: 70%; mp 108 °C.
IR (KBr): 2964, 2924, 1745, 1601, 1456, 1280, 1176, 1101, 869,
748 cm–1.
9-Ethylisochromeno[3,4-c]carbazol-5(9H)-one (4a)
White solid; yield: 58%; mp 189–191 °C.
IR (KBr): 3248, 3057, 2970, 1645, 1469, 1327, 1012, 800 cm–1.
1H NMR (400 MHz, TMS, CDCl3): d = 8.23 (d, J = 8.0 Hz, 1 H),
8.18–8.16 (dd, J1 = 1.6 Hz, J2 = 1.2 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1
H), 7.54–7.44 (m, 3 H), 7.24 (t, J = 6.4 Hz, 2 H), 7.07 (s, 1 H), 4.64
Synthesis 2011, No. 19, 3195–3203 © Thieme Stuttgart · New York

PAPER
Synthesis of Isochromenocarbazolones
3201
1H NMR (400 MHz, TMS, CDCl3): d = 8.94 (d, J = 8.4 Hz, 1 H),
8.56 (d, J = 8.4 Hz, 1 H), 8.49–8.47 (dd, J1 = 1.2 Hz, J2 = 1.2 Hz, 1
H), 7.91–7.87 (m, 1 H), 7.67–7.63 (m, 1 H), 7.57–7.48 (m, 4 H),
7.24–7.20 (ddd, J1 = 4.0 Hz, J2 = 4.0 Hz, J3 = 4.0 Hz, 1 H), 4.46 (q,
J = 8.0 Hz, 2 H, NCH2CH3), 1.48 (t, J = 8.0 Hz, 3 H, NCH2CH3).
13C NMR (100 MHz, TMS, CDCl3): d = 161.8, 146.4, 140.7, 137.7,
135.2, 133.5, 130.2, 128.6, 126.3, 126.2, 123.2, 122.0, 118.3, 117.1,
115.5, 114.2, 111.0, 109.2, 37.7, 13.8.
9-Ethyl-3-nitroisochromeno[3,4-c]carbazol-5(9H)-one (4c)
Red solid; yield: 58%; mp 182 °C.
IR (KBr): 2922, 2852, 1714, 1614, 1469, 1332, 1114, 1020, 866,
690 cm–1.
1H NMR (400 MHz, TMS, CDCl3): d = 9.28 (s, 1 H), 9.09 (d,
J = 8.0 Hz, 1 H), 8.69–8.66 (dd, J1 = 4.0 Hz, J2 = 4.0 Hz, 1 H), 8.45
(d, J = 8.0 Hz, 1 H), 7.71 (d, J = 12.0 Hz, 1 H), 7.60–7.53 (m, 3 H),
7.30–7.26 (dd, J1 = 4.0 Hz, J2 = 2.0 Hz, 1 H), 4.52 (q, J = 8.0 Hz, 2
H), 1.52 (t, J = 8.0 Hz, 3 H).
LC-MS (+-mode): m/z = 314 [M + H]+.
Anal. Calcd for C21H15NO2: C, 80.49; H, 4.82; N, 4.47. Found: C,
80.32; H, 4.75; N, 4.41.
13C NMR (100 MHz, TMS, CDCl3): d = 159.8, 147.3, 146.7, 140.9,
140.1, 137.6, 127.5, 127.1, 126.9, 125.7, 122.8, 122.2, 121.3, 118.9,
117.1, 115.5, 113.5, 112.4, 109.7, 37.8, 13.9.
12-Ethylisochromeno[4,3-b]carbazol-5(12H)-one (5a)
White solid; yield: 27%; mp 122 °C.
IR (KBr): 3491, 2916, 1720, 1601, 1442, 1302, 798, 765 cm–1.
LC-MS (+-mode): m/z = 359 [M + H]+.
Anal. Calcd for C21H14N2O4: C, 70.39; H, 3.94; N, 7.82. Found: C,
70.28; H, 4.02; N, 7.75.
1H NMR (400 MHz, TMS, CDCl3): d = 8.46–8.44 (dd, J1 = 0.8 Hz,
J2 = 1.2 Hz, 1 H), 8.30 (d, J = 8.0 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1
H), 8.04 (s, 1 H), 7.98 (s, 1 H), 7.88–7.44 (m, 1 H), 7.60–7.51 (m, 2
H), 7.43 (d, J = 8.0 Hz, 1 H), 7.28–7.24 (m, 1 H), 4.46 (q, J = 8.0
Hz, 2 H, NCH2CH3), 1.50 (t, J = 8.0 Hz, 3 H, NCH2CH3).
13C NMR (100 MHz, TMS, CDCl3): d = 161.7, 145.3, 141.6, 137.1,
135.6, 134.5, 130.7, 128.3, 127.2, 125.0, 122.1, 121.6, 121.2, 121.0,
119.2, 116.1, 108.7, 108.4, 100.7, 37.7, 13.7.
12-Ethyl-3-nitroisochromeno[4,3-b]carbazol-5(12H)-one (5c)
Red solid; yield: 18%; mp 216 °C.
IR (KBr): 3057, 2916, 1714, 1595, 1485, 1329, 1086, 744 cm–1.
1H NMR (400 MHz, TMS, DMSO-d6): d = 9.06 (d, J = 8.8 Hz, 1
H), 8.96 (s, 1 H), 8.84 (d, J = 8.8 Hz, 1 H), 8.48 (t, J = 8.4 Hz, 1 H),
8.13–8.07 (dd, J1 = 0.8 Hz, J2 = 0.4 Hz, 1 H), 7.85 (d, J = 8.0 Hz, 1
H), 7.67 (s, 1 H), 7.64 (s, 1 H), 7.31 (t, J = 8.0 Hz, 1 H), 4.62 (q,
J = 24.0 Hz, 2 H), 1.41 (t, J = 8.0 Hz, 3 H).
LC-MS (+-mode): m/z = 314 [M + H]+.
Anal. Calcd for C21H15NO2: C, 80.49; H, 4.82; N, 4.47. Found: C,
80.35; H, 4.91; N, 4.42.
13C NMR (100 MHz, TMS, DMSO-d6): d = 160.0, 147.8, 143.5,
143.0, 140.6, 138.0, 137.0, 127.4, 126.7, 125.3, 122.8, 122.2, 121.1,
119.8, 119.3, 113.5, 110.1, 109.9, 108.5, 37.6, 14.1.
9-Benzylisochromeno[3,4-c]carbazol-5(9H)-one (4b)
Compound was recrystallized (50% MeOH–MeCN); white solid;
yield: 55%; mp 136 °C.
LC-MS (+-mode): m/z = 360 [M + H]+.
Anal. Calcd for C21H14N2O4: C, 70.39; H, 3.94; N, 7.82. Found: C,
70.31; H, 3.98; N, 7.76.
IR (KBr): 2924, 1714, 1602, 1446, 1302, 1176, 1084, 800, 692
cm–1.
9-Ethyl-12-methylisochromeno[3,4-c]carbazol-5(9H)-one (4d)
Compound was recrystallized (10% EtOAc–hexane); white solid;
yield: 55%; mp 140 °C.
1H NMR (400 MHz, TMS, CDCl3): d = 8.99 (d, J = 8.0 Hz, 1 H),
8.64–8.61 (dd, J1 = 4.0 Hz, J2 = 4.0 Hz, 1 H), 8.52–8.50 (dd,
J1 = 1.2 Hz, J2 = 1.2 Hz, 1 H), 7.95–791 (m, 1 H), 7.70–7.66 (m, 1
H), 7.53–7.45 (m, 4 H), 7.33–7.25 (m, 4 H), 7.15 (d, J = 8.0 Hz, 2
H), 5.63 (s, 2 H).
13C NMR (100 MHz, TMS, CDCl3): d = 161.7, 146.6, 141.5, 138.4,
136.5, 135.1, 133.6, 130.2, 128.9, 128.7, 126.5, 126.2, 123.2, 122.0,
118.8, 117.3, 115.8, 114.3, 111.5, 109.7, 46.6.
IR (KBr): 2922, 2852, 1712, 1605, 1514, 1461, 1322, 1014, 1020,
766, 690 cm–1.
1H NMR (400 MHz, TMS, CDCl3): d = 8.94 (d, J = 8.0 Hz, 1 H),
8.48 (d, J = 8.0 Hz, 1 H), 8.35 (s, 1 H), 7.89 (t, J = 8.0 Hz, 1 H), 7.63
(t, J = 8.0 Hz, 1 H), 7.54–7.35 (m, 3 H), 7.20–7.10 (dd, J1 = 4.0 Hz,
J2 = 4.0 Hz, 1 H), 4.46 (q, J = 8.0 Hz, 2 H, NCH2CH3), 2.54 (s, 3 H),
1.46 (t, J = 8.0 Hz, 3 H, NCH2CH3).
LC-MS (+-mode): m/z = 376 [M + H]+.
Anal. Calcd for C26H17NO2: C, 83.18; H, 4.56; N, 3.73. Found: C,
83.65; H, 4.72; N, 3.81.
13C NMR (100 MHz, TMS, CDCl3): d = 161.9, 146.2, 139.1, 137.9,
135.3, 133.4, 130.1, 128.5, 127.7, 126.2, 123.1, 122.1, 121.9, 116.8,
115.3, 114.1, 111.0, 108.9, 37.7, 21.7, 13.8.
12-Benzylisochromeno[4,3-b]carbazol-5(12H)-one (5b)
White solid; yield: 25%; mp 112 °C.
LC-MS (+-mode): m/z = 328 [M + H]+.
Anal. Calcd for C22H17NO2: C, 80.71; H, 5.23; N, 4.28. Found: C,
80.65; H, 5.18; N, 4.36.
IR (KBr): 2949, 1710, 1602, 1530, 1456, 1392, 1278, 1142, 1084,
789 cm–1.
1H NMR (400 MHz, TMS, CDCl3): d = 8.41 (d, J = 4.0 Hz, 1 H),
8.14 (t, J = 12.0 Hz, 2 H), 8.05 (s, 1 H), 7.90 (s, 1 H), 7.97 (t, J = 8.0
Hz, 1 H), 7.56–7.48 (m, 2 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.34 (d,
J = 4.0 Hz, 4 H), 7.17 (d, J = 4.0 Hz, 2 H), 5.59 (s, 2 H).
13C NMR (100 MHz, TMS, CDCl3): d = 161.6, 145.6, 142.4,
137.9,136.6, 135.5, 134.6, 130.7, 128.9, 128.4, 127.7, 127.5, 126.2,
125.1, 122.2, 121.6, 121.2, 120.9, 119.7, 116.3, 109.1, 108.5, 101.3,
46.7.
12-Ethyl-9-methylisochromeno[4,3-b]carbazol-5(12H)-one (5d)
Compound was recrystallized (10% EtOAc–hexane); white solid;
yield: 24%; mp 122 °C.
IR (KBr): 3057, 2962, 1714, 1595, 1485, 1261, 1086, 800, 694
cm–1.
1H NMR (400 MHz, TMS, CDCl3): d = 8.42 (d, J = 8.0 Hz, 1 H),
8.25 (d, J = 8.0 Hz, 1 H), 7.96 (s, 1 H), 7.90 (s, 1 H), 7.88 (s, 1 H),
7.84 (t, J = 8.0 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.0
Hz, 1 H), 7.29 (t, J = 8.0 Hz, 1 H), 4.41 (q, J = 8.0 Hz, 2 H,
NCH2CH3), 2.54 (s, 3 H), 1.47 (t, J = 8.0 Hz, 3 H, NCH2CH3).
LC-MS (+-mode): m/z = 376 [M + H]+.
Anal. Calcd for C26H17NO2: C, 83.18; H, 4.56; N, 3.73. Found: C,
83.84; H, 4.72; N, 3.81.
Synthesis 2011, No. 19, 3195–3203 © Thieme Stuttgart · New York

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D. K. Sreenivas, R. Nagarajan
PAPER
13C NMR (100 MHz, TMS, CDCl3): d = 161.7, 145.1, 139.6, 134.5,
133.3, 130.6, 128.6, 128.5, 127.7, 126.2, 123.1, 122.8, 121.5, 121.0,
115.2, 110.9, 108.9, 108.2, 100.6, 37.5, 21.2, 13.9.
12-Benzyl-7,13-dimethylisochromeno[4,3-b]carbazol-5(12H)-
one (5g)
White solid; yield: 82%; mp 177 °C.
LC-MS (+-mode): m/z = 328 [M + H]+.
IR (KBr): 3018, 2918, 1724, 1602, 1564, 1494, 1460, 1311, 1242,
1155, 1126, 1026, 987, 746 cm–1.
Anal. Calcd for C22H17NO2: C, 80.71; H, 5.23; N, 4.28. Found: C,
80.62; H, 5.32; N, 4.21.
1H NMR (400 MHz, TMS, CDCl3): d = 8.47–8.45 (dd, J1 = 0.8 Hz,
J2 = 1.2 Hz, 1 H), 8.32 (d, J = 6.0 Hz, 1 H), 8.1 (d, J = 6.0 Hz, 1 H),
7.78–7.43 (m, 1 H), 7.54 (t, J = 5.6 Hz, 1 H), 7.47 (t, J = 5.6 Hz, 1
H), 7.35 (q, J = 6.8 Hz, 2 H), 7.29 (t, J = 5.2 Hz, 3 H), 7.21 (d,
J = 5.6 Hz, 2 H), 5.71 (s, 2 H), 3.02 (s, 3 H), 2.97 (s, 3 H).
Isochromeno[3,4-b]carbazol-5(8H)-one (4e)
Chromatographed on basic alumina (35% EtOAc–hexanes); white
solid; yield: 60%; mp 232 °C.
IR (KBr): 3418, 1770, 1608, 1460, 1412, 1373, 1201, 1014, 750,
678 cm–1.
1H NMR (400 MHz, TMS, DMSO-d6): d = 11.55 (s, 1 H, NH), 9.20
(s, 1 H), 8.59 (d, J = 6.8 Hz, 1 H), 8.25 (t, J = 10.4 Hz, 2 H), 7.96 (t,
J = 5.2 Hz, 1 H), 7.59 (t, J = 6.8 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H),
7.43 (s, 1 H), 7.30–7.13 (m, 2 H).
13C NMR (100 MHz, TMS, DMSO-d6): d = 160.8, 141.8, 141.2,
140.0, 135.9, 134.2, 131.1, 129.7, 128.8, 125.1, 123.0, 121.2, 120.8,
120.1, 119.3, 112.5, 109.5, 108.7.
13C NMR (100 MHz, TMS, CDCl3): d = 161.8, 144.6, 144.1, 139.6,
138.3, 136.4, 133.2, 130.3, 128.9, 127.6, 127.5, 127.3, 126.8, 125.7,
125.4, 124.1, 123.8, 123.3, 122.3, 120.0, 118.1, 117.3, 114.9, 110.5,
109.7, 50.3, 20.7, 12.8.
LC-MS (–-mode): m/z = 402 [M – H].
Anal. Calcd for C28H21NO2: C, 83.35; H, 5.25; N, 3.47. Found: C,
83.28; H, 5.18; N, 3.41.
3-Chloro-12-ethyl-7,13-dimethylisochromeno[4,3-b]carbazol-
5(12H)-one (5h)
Yellow solid; yield: 62%; mp 224–226 °C.
LC-MS (–-mode): m/z = 284 [M – H].
Anal. Calcd for C19H11NO2: C, 79.99; H, 3.89; N, 4.91. Found: C,
79.86; H, 3.94; N, 4.85.
IR (KBr): 3012, 1708, 1622, 1589, 1464, 1332, 1260, 1089, 742
cm–1.
Isochromeno[4,3-a]carbazol-5(13H)-one (5e)
Chromatographed on basic alumina (35% EtOAc–hexanes); white
solid; yield: 20%; mp 182 °C.
1H NMR (400 MHz, TMS, CDCl3): d = 8.46 (s, 1 H), 8.29 (d,
J = 8.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 7.77–7.74 (dd, J1 = 2.4
Hz, J2 = 4.0 Hz, 1 H), 7.57–7.48 (m, 2 H), 7.29 (t, J = 8.0 Hz, 1 H),
4.59 (q, J = 4.0 Hz, 2 H, NCH2CH3), 3.13 (s, 3 H), 3.0 (s, 3 H), 1.46
(t, J = 4.0 Hz, 3 H, NCH2CH3).
13C NMR (100 MHz, TMS, CDCl3): d = 160.0, 143.9, 142.3, 142.2,
137.9, 136.8, 135.8, 134.3, 132.5, 129.4, 126.4, 125.0, 124.0,
123.8, 123.2, 120.1, 119.3, 109.7, 40.4, 21.1, 16.6, 14.7.
IR (KBr): 3424, 2920, 1762, 1638, 1501, 1492, 1358, 1019, 823,
725 cm–1.
1H NMR (400 MHz, TMS, DMSO-d6): d = 11.7 (s, 1 H), 8.79 (d,
J = 8.0 Hz, 1 H), 8.41–8.39 (dd, J1 = 1.2 Hz, J2 = 1.2 Hz, 1 H), 8.19
(d, J = 7.6 Hz, 1 H), 8.10 (t, J = 6.8 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 1
H), 7.84 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 16.0 Hz, 1 H), 7.25–7.21
(m, 1 H), 7.08–7.04 (ddd, J1 = 0.8 Hz, J2 = 0.8 Hz, J3 = 1.2 Hz, 1 H),
6.81 (d, J = 2.0 Hz, 1 H).
13C NMR (100 MHz, TMS, DMSO-d6): d = 156.8, 150.5, 141.2,
140.0, 135.9, 133.3, 130.6, 129.0, 126.0, 124.1, 123.4, 122.3, 121.1,
120.5, 118.7, 112.5, 110.8, 103.8, 96.7.
LC-MS (+-mode): m/z = 376 [M + H]+, 378 [M + 2].
Anal. Calcd for C23H18ClNO2: C, 73.50; H, 4.83; N, 3.73. Found: C,
73.25; H, 4.51; N, 3.69.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
LC-MS (+-mode): m/z = 286 [M + H]+.
Anal. Calcd for C19H11NO2: C, 79.99; H, 3.89; N, 4.91. Found: C,
79.85; H, 3.84; N, 5.07.
Acknowledgment
We gratefully acknowledge DST for financial assistance (Project
number: SR/S1/OC-70/2008) and for providing single-crystal X-
ray diffractometer facility in our school. D.K.S. thanks CSIR for a
Senior Research Fellowship. D.K.S. also thanks to Rambabu for
helping in crystal studies.
12-Ethyl-7,13-dimethylisochromeno[4,3-b]carbazol-5(12H)-
one (5f)
Compound was recrystallized (15% EtOAc–hexane); yellow solid;
yield: 75%; mp 159 °C.
IR (KBr): 2978, 2916, 1712, 1599, 1562, 1448, 1269, 1101, 744,
692 cm–1.
References
1H NMR (400 MHz, TMS, CDCl3): d = 8.49 (d, J = 8.0 Hz, 1 H),
8.29 (d, J = 8.0 Hz, 1 H), 8.22 (d, J = 8.0 Hz, 1 H), 7.81 (t, J = 8.0
Hz, 1 H), 7.59–7.48 (m, 3 H), 7.29 (d, J = 4.0 Hz, 1 H), 4.60 (q,
J = 8.0 Hz, 2 H, NCH2CH3), 3.15 (s, 3 H), 3.0 (s, 3 H), 1.46 (t,
J = 8.0 Hz, 3 H, NCH2CH3).
13C NMR (100 MHz, TMS, CDCl3): d = 161.9, 143.9, 138.9, 136.4,
134.4, 133.2, 130.3, 127.7, 127.4, 126.5, 124.2, 124.1, 123.4, 122.3,
119.6, 117.9, 117.1, 114.7, 109.5, 41.1, 20.7, 14.9, 12.7.
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80.85; H, 5.68; N, 4.21.
Synthesis 2011, No. 19, 3195–3203 © Thieme Stuttgart · New York

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formula: C26H15NO2; unit cell parameters: a = 8.2147(7),
b = 9.9766(7), c = 12.2199(11), a = 88.285(6),
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63, 893. (b) Wu, T.-S.; Wang, M.-L.; Wu, P.-L.
b = 87.066(7), g = 67.350(7); space group P1. The CCDC
deposition number for compound 4d is 824502; formula:
C22H17NO2; unit cell parameters: a = 7.5580(5),
b = 19.9905(8), c = 10.6520(6); space group Pna21. The
CCDC deposition number for compound 5d is 823152;
formula: C22H17NO2; unit cell parameters: a = 8.5988(6),
b = 15.5481(14), c = 14.6529(12), b = 122.242(6); space
group P21/c. The CCDC deposition number for compound
5f is 824503; formula: C23H19NO2; unit cell parameters:
a = 7.5027(6), b = 9.1436(12), c = 12.7349(13),
Phytochemistry 1996, 43, 785.
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Nishino, H.; Furukawa, H. J. Nat. Prod. 2000, 63, 125.
(b) Ito, C.; Itoigawa, M.; Katsuno, S.; Omura, M.; Tokuda,
H.; Nishino, H.; Furukawa, H. J. Nat. Prod. 2000, 63, 1218.
a = 100.156(0), b = 101.632(8), g = 92.456(9); space group
P1.
Synthesis 2011, No. 19, 3195–3203 © Thieme Stuttgart · New York