C-N bond formation via Cu-catalyzed cross-coupling with boronic acids leading to methyl carbazole-3-carboxylate: Synthesis of carbazole alkaloids

Article abstract of DOI:10.1039/c3ra44903c

Copper promoted N-arylation of methyl 4-amino-3-iodobenzoate with boronic acids followed by Pd-catalyzed intramolecular C-H arylation provides an efficient route to methyl carbazole-3-carboxylate derivatives. This methodology was implemented in the synthe

Full text of DOI:10.1039/c3ra44903c

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C–N bond formation via Cu-catalyzed cross-
coupling with boronic acids leading to methyl
carbazole-3-carboxylate: synthesis of carbazole
alkaloids†‡
Cite this: RSC Adv., 2014, 4, 4960
ab
ab
ab
b
Sk. Rasheed, D. Nageswar Rao, K. Ranjith Reddy, S. Aravinda,
b
ab
Ram A. Vishwakarma and Parthasarathi Das*
Copper promoted N-arylation of methyl 4-amino-3-iodobenzoate with boronic acids followed by
Pd-catalyzed intramolecular C–H arylation provides an efficient route to methyl carbazole-3-carboxylate
derivatives. This methodology was implemented in the synthesis of naturally occurring carbazole
alkaloids clausine C, clausine H, clausine L, clausenalene, glycozoline, glycozolidine, glycozolidal and
sansoakamine.
Received 5th September 2013
Accepted 22nd October 2013
DOI: 10.1039/c3ra44903c
www.rsc.org/advances
alkaloids (Fig. 1). Methyl carbazole-3-carboxylate (2a) and
methyl 6-methoxycarbazole-3-carboxylate (2c) have been iso-
Introduction
6
Carbazoles have attracted considerable attention both in bio- lated from the roots of Clausena lansium.
logical and material sciences as ubiquitous structural motif due
7a
Wu et al. reported the isolation of clausine C (2b), clau-
to their medicinal, photophysical and optoelectronic applica- sine H (2k), clausine M from the root bark of Clausena
1
2
7b
7c
3
tion. Naturally occurring carbazomycin and ellipticine are well excavata. Clausine L (2j) and mukonidine both isolated by Wu
known for their antibacterial and anticancer properties and co-workers form the Chinese medicinal plant Clausena
4
8
respectively. Carbazole containing carveidilol and carazolol are excavata. Recently, 2,6-dioxygenated sansoakamine (6) was
9
used for the treatment of hypertension, ischemic heart disease isolated from the stem of Clausena excavata. In 2012
and congestive heart failure. Carbazoles having –CO Me group Laphookhieo et al. reported the isolation and biological
5
2
at 3-position represent a wide class of naturally occurring activity of methyl carbazole-3-carboxylate (clausine C, clausine
H, clausine L and mukonidine) and during the evaluation of
antibacterial properties, mukonidine showed weak activity
ꢀ
1
against MRSA (MIC 64 mg mL ) and moderate activity against
Gram-negative pathogen S. typhimurium with an MIC value
ꢀ
1
10
of 32 mg mL
5
.
Further the anti-plasmodial activity (IC50
ꢀ
1
11
.5–8.2 mg mL ) of clausine H has been reported. For
structure–activity relationships (SAR) study, the diversity in
carbazole synthesis, especially the regiospecic installation of
substituent's onto each of the nine positions of the carbazole
skeleton, is challenging from synthetic point. Thus, the
development of a mild, efficient and regio-controlled diversi-

ed method for the preparation of carbazole remains of high
interest.
Transition metal-catalyzed N-arylation has been extensively
Fig. 1 Naturally occurring methyl carbazole-3-carboxylate alkaloids.
12
studied over the past decade. The discovery of Pd- or Cu-
catalyzed amination reactions pioneered by Buchwald and
a
13,14
Academy of Scientic and Innovative Research (AcSIR), India
Hartwig is a hallmark reaction in this eld.
Despite these
b
Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal
signicant progresses in improvements of the reaction condi-
tions, limitation exists in terms of functional group tolerability
and high cost of palladium. In 1998 independent publications
Road, Jammu-180001, India. E-mail: partha@iiim.ac.in; Fax: +91-191-2569019
†
Electronic supplementary information (ESI) available: Experimental details and
spectroscopic data for all compounds. CCDC 909569. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3ra44903c
15
16
17
by Chan, Evans and Lam revolutionized the copper
mediated heteroatom arylation reaction for the formation of
‡
IIIM communication no. 1565.
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N-aryl and O-aryl bonds using boronic acids. Later discovery by to 40% conversion in the rst 5–6 h and then catalytic activity
18
Collman
rendered catalytic for the arylation of imidazoles when wald have previously reported similar observations and they
Cu(OH)$TMEDA] Cl is used as a copper source. In the course modied the conditions by using 2,6-lutidine as a base,
has demonstrated that this reaction can be diminished over the next 20 h. J. C. Antilla and S. L. Buch-
27
[
2
2
of time the Chan–Lam type coupling became a useful synthetic myristic acid as an additive and toluene the preferred solvent.
tool due to the mild reaction conditions employed e.g. room To our delight, when we subjected methyl 4-amino-3-iodo-
temperature, weak base, ambient atmosphere (open-ask benzoate to the N-arylation conditions with phenylboronic
19–21
chemistry).
2
acid by using catalytic Cu(OAc) (10 mol%), 2,6-lutidine in
Many different approaches for construction of carbazoles toluene under air the reaction proceed smoothly with 70%
22,23
have been studied.
Among them the approaches involving isolated yield (1a). In this reaction condition we used n-dec-
transition metal-catalyzed intramolecular C–C bond forma- anoic acid (20 mol%) as an additive. The use of molecular
tion in diarylamines via C–H activation provide an excellent oxygen did not have any further improvement with the iso-
22
access to these important class of natural product. While lated yield. By using this optimized condition a series of
the direct synthesis of carbazoles by cascade Buchwald– N-arylated methyl 4-amino-3-iodobenzoate have been synthe-
Hartwig N-arylation followed by C–H arylation using o-hal- sized (Table 1). Methoxy substituted phenylboronic acids
24
oanilines has been reported. The main drawback of these became our rst choice as coupling partner so that naturally
reactions are use of expensive ligand, strong base and high occurring carbazoles can be synthesized in subsequent cycli-
reaction temperature. It is well precedented that oxidative zation process (Table 2). We were pleased to nd that
insertion into a C–X bond is most facile for aryl iodides, so methoxy substitution of phenylboronic acids both at m- and
use of aryl iodides as coupling partner can give easy access to p-position gave satisfactory coupling products (1b and 1c).
25
the desired arylated product.
The versatility of this reaction protocol has been demon-
Keeping this in mind, we decided to use o-iodoanilines as strated by further using different boronic acids as coupling
substrate for cross-coupling reaction. Thus to nd a mild reac- partner (Table 1). Three more p-substituted boronic acids
tion conditions for carbazole synthesis here we wish to report our have been used to synthesize the corresponding N-arylated
study on Cu-catalyzed N-arylation of methyl 4-amino-3-iodo- product (1d–f) in good yield. Phenylboronic acids containing
26
benzoate with boronic acid at room temperature under air fol- electron withdrawing group (EWG) also resulted (1g–h) in
lowed by Pd-catalyzed intramolecular cyclization (Scheme 1). satisfactory yield (65–66%) under this cross-coupling condi-
This protocol is general and culminated in the synthesis of tions. Bicyclic benzo[d][1,3]dioxol-5-ylboronic acid also gave
several naturally occurring carbazoles including rst total clean coupled product with 72% isolated yield (1i). To nd
synthesis of sansoakamine.
the generality and substrate scope of this methodology we
further explore the N-arylation of 2-methoxy derivative of
methyl 4-amino-3-iodobenzoate with different boronic acids.
Phenyl boronic acid works satisfactorily to yield 1j in 70%.
Results and discussion
For N-arylation of methyl 4-amino-3-iodobenzoate, we rst
11
16
use the protocol as reported by Chan and Evans for O-
arylation of o-iodophenol. Our initial experiment starts with
N-arylation of methyl 4-amino-3-iodobenzoate with phenyl-
Table 1 Cu-catalyzed coupling of methyl 4-amino-3-iodobenzoate
with boronic acids
a
2 3
boronic acid by using Cu(OAc) (1 equiv.) and Et N (2 equiv.)
in DCM under air and room temperature. But this reaction
ended with poor conversion (only 40%) of the starting
material even aer 48 h. Screening of different solvents,
copper salts and base frustrated us with poor yield (see ESI†
for details of optimization protocol). Interestingly, the reac-
tion also have only 40% conversion under catalytic (10 mol%)
use of Cu(OAc) . Careful observation on the progress of this
2
reaction, revealed that the reaction proceed smoothly with 30
a
Methyl 4-amino-3-iodobenzoate (1 equiv.), boronic acids (1.5 equiv.),
Cu(OAc)
2
(10 mol%), n-decanoic acid (20 mol%), 2,6-lutidine
Scheme 1 Synthesis of methyl carbazole-3-carboxylate.
(2 equiv.), toluene (5 mL), rt, air, 24 h.
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Table 2 Pd-catalyzed C–H arylation of methyl 3-iodo-4-(phenyl-
a
amino)benzoate
Scheme 2 Synthesis of glycozoline (3), glycozolidine (4), clausenaline
ꢁ
(
5): (a) LiAlH
4
(2 equiv.), THF, 65 C, 1 h.
C–H arylation process. Methyl 6-propyl-9H-carbazole-3-carbox-
ylate (2f) has been synthesized under this Pd-catalyzed cycliza-
tion condition and the structure has been conrmed by X-ray
32
crystal structure analysis (Fig. 2).
Methyl group at C-3 position remains one of the common
structural features for many carbazole alkaloids. Thus to
synthesize more naturally occurring carbazoles we pay our
a
attention to the functional transformation of the 3-CO Me
group. We rst consider methyl 6-methoxycarbazole-3-carbox-
ylate (2c) and it is obvious that carbazole 2c can serve as
Methyl-3-iodo-4-(phenylamino)benzoate (1 equiv.), Pd(OAc)
2
(10 mol%),
2
ꢁ
K
CO
2 3
(2 equiv.), DMSO (5 mL), sealed tube, 130 C.
3
3
precursor for glycozoline (3). Thus reduction of –CO
group of 2c with LiAlH gave glycozoline (3) in 75% yield
Scheme 2). By following the same reduction condition we
2
Me
4
Both m- and p-substituted methoxyboronic acid gave the cross
coupled product (1k–l) in 72% and 70% yield respectively.
Aer successful completion of the synthesis of diverse N-
arylated product (1a–l), these 2-iodo diarylamine derivatives
were used for intramolecular cyclization to obtain different
carbazole alkaloids. To achieve the intramolecular C–H aryla-
tion of N-phenyl-2-iodoaniline derivatives, we rst performed
the reaction with methyl 3-iodo-4-(phenylamino)benzoate by
34
(
35
successfully synthesized glycozolidine (4) from carbazole 2l
in 65% yield and methylenedioxy carbazole clausenalene (5)
36
form 2i in 72% yield. Synthesized glycozoline, glycozolidine
and clausenalene have been fully characterized by spectro-
scopic data which are in good agreement with those reported
for natural product.
With the readily available 2,6-dioxygenated carbazole 2l in
hand we envisaged direct access to sansoakamine and glyco-
2 2 3
using Pd(OAc) (10 mol%) as catalyst, K CO as base and DMSO
ꢁ
28
as solvent in sealed tube at 130 C. To our expectation the
reaction proceeded smoothly with complete conversion of
starting material in 3 h to give methyl carbazole-3-carboxylate
3
zolidal. BBr mediated cleavage of both the methyl ether groups
of 2l afforded sansoakamine (6) in 76% yield (Scheme 3). The
spectroscopic data of the synthesized carbazole was in good
29
(2a) with 92% isolated yield (Table 2). This Pd-catalyzed reac-
9
agreement with the reported data. To the best of our knowledge
tion is very clean and works well without NH-protection. By
following same reaction conditions naturally occurring carba-
zoles clausine C
have been synthesized successfully. Clausine C can be con-
verted to 7-hydroxy derivative, clausine M as reported by
Kn ¨o lker.
this is the rst report of total synthesis of sansoakamine. The
methyl ester group of 2l was reduced directly into aldehyde
30a,b,e
30c,d
30a,f
(2b), clausine L
(2j), clausine H
(2k)
37
group (Scheme 3) by DIBAL-H to produce another natural
alkaloid glycozolidal (7), which was structurally conrmed by its
35b
spectroscopic data.
30b
Clausine H (2i) can be considered as crucial
precursor for several 2,7-dioxygenated carbazoles particularly
30a
for clausine K and clausine O. Chloro and uoro derivatives
of N-arylated methyl 4-amino-3-iodobenzoate smoothly cyclized
under this catalytic condition to give halogenated carbazoles
(
2g–h). Another naturally occurring carbazole methyl 6-
31
methoxycarbazole-3-carboxylate (2c)
synthesized in this
process can be used as precursor for glycozoline (Scheme 2). 2,6-
Dioxygenated carbazole (2l) and methylenedioxy carbazole (2i)
synthesized by this route can be used as precursor for the
synthesis of different carbazole alkaloids (Schemes 2 & 3).
Two more new 6-oxygenated carbazoles 2d (85%) and 2e
Scheme 3 Synthesis of sansoakamine (6), glycozolidal (7): (a) BBr
3
ꢁ
ꢁ
(
2 equiv.), CH
2
ꢁ
Cl
2
, ꢀ78 C to ꢀ20 C, 24 h, 76%; (b) DIBAL-H (1 equiv.),
(
80%) have also been synthesized by using this intramolecular toluene, ꢀ78 C, 1 h, 86%.
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open air. The reaction mixture was diluted with ethyl acetate
(10 mL) and ltered through Whatman lter paper. The
organic layer was washed with water (2 ꢂ 10 mL) and dried
over Na SO . Then ltered and the solvent was removed
2
4
under reduce pressure. The crude reaction mixture was
puried by column chromatography on silica gel by using
ethyl acetate–hexanes (2 : 8) as eluent to give 1a (92 mg,
1
7
1
7
8
0%). Colourless gel; H NMR (400 MHz, CDCl
3
) d 8.43 (s,
H), 7.82 (dd, J ¼ 8.6, 1.8 Hz, 1H), 7.38 (t, J ¼ 7.9 Hz, 2H),
.21 (d, J ¼ 8.4 Hz, 2H), 7.16 (t, J ¼ 8.1 Hz, 1H), 7.04 (d, J ¼
1
3
.7 Hz, 1H), 6.32 (br s, 1H), 3.87 (s, 3H); C NMR (125 MHz,
Fig. 2 Molecular structure of methyl 6-propyl-9H-carbazole-3-car-
baxylate (2f) in crystal.
CDCl ) d 167.0, 148.1, 140.8, 138.4, 131.5, 129.5, 123.1, 121.1,
3
+
1
20.4, 114.5, 96.6, 51.8; MS (ESI): m/z ¼ 354 [M + H] ; HRMS
+
2
(ESI): m/z calcd for C14H12INO [M + H] : 353.9986; found:
353.9988.
The following compounds 1b–l were prepared according to
this procedure.
Conclusion
The Cu-catalyzed N-arylation and subsequent Pd-catalyzed
intramolecular C–H arylation protocol has been successfully
utilized in synthesizing various methyl carbazole-3-carboxylate
derivatives. This two-step reaction sequence resulted in the
direct synthesis of clausine C, clausine L and clausine H. This
exercise also resulted in rst total synthesis of 2,6-dioxygenated
carbazole sansoakamine in four steps with 40% overall yield.
Considering the availability of starting material and mild
reaction conditions the procedure involved, we have demon-
strated that this can be general methodology for synthesis of
this family of compounds. Further studies including biological
activity of these derivatives are presently being carried out in
our laboratory.
Methyl 3-iodo-4-(3-methoxyphenylamino)benzoate (1b). The
reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36
mmol), 3-methoxyphenylboronic acid (82 mg, 0.54 mmol),
Cu(OAc)
.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene
5 mL) gave 1b (102 mg, 74%); eluent: ethyl acetate–hexanes
2
(6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg,
0
(
(
7
8
1
1
2 : 8); colourless gel; H NMR (400 MHz, CDCl
3
) d 8.43 (s, 1H),
.83 (dd, J ¼ 8.6, 1.9 Hz, 1H), 7.26 (d, J ¼ 8.8 Hz, 1H), 7.10 (d, J ¼
.5 Hz, 1H), 6.80 (d, J ¼ 8.5 Hz, 1H), 6.75 (s, 1H), 6.70 (d, J ¼ 8.4,
1
3
H) 6.30 (br s, 1H), 3.85 (s, 3H), 3.79 (s, 3H); C NMR (125 MHz,
CDCl ) d 167.0, 157.5, 153.1, 148.8, 136.1, 131.5, 129.8, 129.7,
3
1
23.1, 120.1, 118.4, 113.8, 96.4, 55.0, 51.7; MS (ESI): m/z ¼ 384
+
+
[
M + H] ; HRMS (ESI): m/z calcd for C15
84.0091; found: 384.0100.
Methyl 3-iodo-4-(4-methoxyphenylamino)benzoate (1c). The
3
H14INO [M + H] :
3
Experimental
General information
reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36
mmol), 4-methoxyphenylboronic acid (82 mg, 0.54 mmol),
Cu(OAc)2 (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg,
Analytical thin layer chromatography (TLC) was performed on
pre-coated silica gel plates (60 F254; MERCK). TLC plates were
visualized by exposing UV light or by iodine vapours or
0.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene
(
(
5 mL) gave 1c (91 mg, 70%), eluent: ethyl acetate–hexanes
1
1
2 : 8); colourless gel; H NMR (400 MHz, CDCl
3
) d 8.41 (s, 1H),
immersion in ninhydrin followed by heating on hot plate. H
1
3
7
.78 (dd, J ¼ 8.7, 1.4 Hz, 1H), 7.15 (d, J ¼ 8.7 Hz, 2H), 6.94 (dd,
and C NMR spectra were recorded with BRUKER 500 and 400
MHz NMR instruments. All the NMR spectra were processed in
MestReNova. Mass spectra were recorded with VARIAN GC-MS
instrument. HRMS spectra were recorded with LCMS-QTOF
Module no. G6540 A (UHD) instrument. IR spectra were recor-
ded on Jasco FT/IR-5300 spectrophotometer. Melting points
were measured in open capillary tubes and are uncorrected.
Unless otherwise indicated, chemicals and solvents were
purchased from commercial suppliers.
J ¼ 8.8, 1.3 Hz, 2H), 6.75 (dd, J ¼ 8.7, 1.3 Hz, 1H), 6.22 (br s,
1
3
1
1
1
3
H), 3.86 (s, 3H), 3.84 (s, 3H); C NMR (125 MHz, CDCl ) d
67.1, 156.5, 149.8, 138.4, 133.4, 131.5, 124.4, 119.9, 114.8,
13.2, 96.1, 55.5, 51.6; MS (ESI): m/z ¼ 384 [M + H] ; HRMS
+
+
(ESI): m/z calcd for C H INO [M + H] : 384.0091; found:
15 14
3
384.0100.
Methyl 3-iodo-4-(4-phenoxyphenylamino)benzoate (1d). The
reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36
mmol), 4-phenoxyphenylboronic acid (115.5 mg, 0.54 mmol),
2
Cu(OAc) (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0. 072
mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene (5 mL)
General procedure for N-arylation of amine with boronic acids
(
1a–l)
gave 1d (105 mg, 65%). Eluent: ethyl acetate–hexanes (2 : 8);
1
Methyl 3-iodo-4-(phenylamino)benzoate (1a). To a solution colourless gel; H NMR (500 MHz, CDCl
) d 8.42 (s, 1H), 7.82
3
of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 mmol) in (dd, J ¼ 8.9, 1.9 Hz, 1H), 7.35 (m, 2H), 7.18 (dd, J ¼ 8.6, 1.9 Hz,
toluene (5 mL) was added phenylboronic acid (66 mg, 2H), 7.12 (m, 1H), 7.03 (m, 3H), 7.00 (dd, J ¼ 7.1, 2.1 Hz, 1H),
1
3
0
.54 mmol), Cu(OAc) (6.5 mg, 0.036 mmol), n-decanoic acid 6.90 (d, J ¼ 8.7 Hz, 1H), 6.26 (br s, 1H), 3.86 (s, 3H); C NMR
2
(12.4 mg, 0.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) (125 MHz, CDCl
3
) d 167.0, 160.7, 147.8, 142.2, 138.2, 135.2,
and was stirred vigorously for 24 h at room temperature in 131.4, 130.2, 121.3, 115.0, 112.5, 108.3, 106.0, 89.2, 51.7; MS
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+
+
(
[
ESI): m/z ¼ 446 [M + H] ; HRMS (ESI): m/z calcd for C15
H11NO
4
2
(ESI): m/z calcd for C14H11IFNO [M + H] : 371.9891; found:
371.9886.
+
M + H] : 446.0248; found: 446.0249.
Methyl 4-(4-butoxyphenylamino)-3-iodobenzoate (1e). The
Methyl-4-(benzo[d][1,3]dioxol-5-ylamino)-3-iodobenzoate (1i).
reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 The reaction of methyl 4-amino-3-iodobenzoate (100 mg,
mmol), 4-butoxyphenylboronic acid (105 mg, 0.54 mmol), 0.36 mmol), benzo[d][1,3]dioxol-5-ylboronic acid (89 mg,
Cu(OAc)
.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in (12.4 mg, 0.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol)
toluene (5 mL) gave 1e (106 mg, 70%). Eluent: ethyl acetate– in toluene (5 mL) gave 1i (105 mg, 72%). Eluent: ethyl acetate–
2 2
(6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0.54 mmol), Cu(OAc) (6.5 mg, 0.036 mmol), n-decanoic acid
0
1
1
hexanes (2 : 8); colourless gel; H NMR (500 MHz, CDCl
.39 (s, 1H), 7.76 (d, J ¼ 8.6 Hz, 1H), 7.13 (dd, J ¼ 6.5, 2.1 8.40 (s, 1H), 7.79 (dd, J ¼ 8.6, 1.7 Hz, 1H), 6.81 (dd, J ¼ 8.4,
Hz, 2H), 6.92 (dd, J ¼ 8.4, 2.2 Hz, 2H), 6.74 (d, J ¼ 8.6 Hz, 7.2 Hz, 2H), 6.73 (d, J ¼ 2.1 Hz, 1H), 6.68 (dd, J ¼ 8.2, 1.8 Hz,
3 3
) d hexanes (3 : 7); colourless gel; H NMR (400 MHz, CDCl ) d
8
1
3
1
H), 6.20 (br s, 1H), 3.97 (t, J ¼ 6.4 Hz, 2H), 3.85 (s, 3H), 1.77 1H), 6.18 (br s, 1H), 6.00 (s, 2H), 3.86 (s, 3H); C NMR (125
dd, J ¼ 14.3, 6.6 Hz, 2H), 1.51 (dd, J ¼ 14.8, 7.4 Hz, 2H), MHz, CDCl ) d 179.9, 167.1, 149.4, 148.3, 144.3, 134.7, 131.5,
) d 167.1, 120.2, 115.7, 113.5, 108.6, 104.6, 101.3, 96.7, 51.7; MS (ESI): m/
(
3
1
3
0
1
9
.99 (t, J ¼ 7.3 Hz, 3H); C NMR (125 MHz, CDCl
3
+
56.2, 149.9, 138.4, 133.2, 131.5, 124.4, 119.9, 115.4, 113.2, z ¼ 398 [M + H] ; HRMS (ESI): m/z calcd for C15
4
H12INO [M +
+
6.3, 68.1, 51.6, 29.2, 19.2, 13.7; MS (ESI): m/z ¼ 426 [M + H] : 397.9884; found: 397.9883.
+
+
H] ; HRMS (ESI): m/z calcd for C18
H
20INO
3
[M + H] :
Methyl 5-iodo-2-methoxy-4-(phenylamino)benzoate (1j). The
426.0561; found: 426.0554.
reaction of methyl 4-amino-5-iodo-2-methoxybenzoate (100
Methyl 3-iodo-4-(4-propylphenylamino)benzoate (1f). The mg, 0.32 mmol), phenylboronic acid (58.5 mg, 0.48 mmol),
reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 Cu(OAc)2 (5.8 mg, 0.032 mmol), n-decanoic acid (11 mg,
mmol), 4-n-propylphenylboronic acid (88 mg, 0.54 mmol), 0.064 mmol), 2,6-lutidine (68.5 mg, 0.64 mmol) in toluene (5
Cu(OAc)
mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene (5 mL) (1 : 9); colourless gel; H NMR (400 MHz, CDCl
gave 1f (90 mg, 68%). Eluent: ethyl acetate–hexanes (2 : 8); col- 1H), 7.79 (dd, J ¼ 8.5, 2.1 Hz, 1H), 7.17 (d, J ¼ 8.4 Hz, 2H),
2
(6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0.072 mL) gave 1j (97 mg, 70%). Eluent: ethyl acetate–hexanes
1
3
) d 8.41 (s,
1
ourless gel; H NMR (500 MHz, CDCl
3
) d 8.41 (s, 1H), 7.80 (dd, 6.94 (dd, J ¼ 8.3, 2.1 Hz, 2H), 6.76 (t, J ¼ 7.8 Hz, 1H), 6.25
13
J ¼ 8.7, 1.3 Hz, 1H), 7.22 (dd, J ¼ 8.7, 2.1 Hz, 2H), 7.12 (d, J ¼ 8.0 (br, 1H), 3.86 (s, 3H), 3.84 (s, 1H); C NMR (125 MHz,
Hz, 2H), 6.98 (t, J ¼ 8.5 Hz, 1H), 6.28 (br s, 1H), 3.86 (s, 3H), 2.59 CDCl ) d 167.8, 162.2, 157.0, 140.8, 137.9, 129.5, 123.8, 120.4,
3
1
3
+
(
t, J ¼ 7.6 Hz, 2H), 1.65 (m, 2H), 0.95 (m, 3H); C NMR (125 114.5, 110.6, 96.1, 56.3, 51.8; MS (ESI): m/z ¼ 384 [M + H] ;
+
3 3
MHz, CDCl ) d 166.1, 147.7, 137.3, 137.0, 132.3, 130.5, 128.4, HRMS (ESI): m/z calcd for C15H14INO [M + H] : 384.0091;
1
3
3
20.1, 119.5, 113.0, 97.6, 50.7, 36.4, 23.6, 12.8; MS (ESI): m/z ¼ found: 384.0100.
+
+
96 [M + H] ; HRMS (ESI): calcd for C17
96.0455; found: 396.0446.
H
18INO
2
[M + H] :
Methyl
5-iodo-2-methoxy-4-(3-methoxyphenylamino)-
benzoate (1k). The reaction of methyl 4-amino-5-iodo-2-
Methyl 4-(3-chlorophenylamino)-3-iodobenzoate (1g). The methoxybenzoate (100 mg, 0.32 mmol), 3-methoxyphenylbor-
reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 onic acid (74 mg, 0.48 mmol), Cu(OAc) (5.8 mg, 0.032 mmol),
2
mmol), 3-chlorophenylboronic acid (84 mg, 0.54 mmol), n-decanoic acid (11 mg, 0.064 mmol) and 2,6-lutidine (68.5 mg,
Cu(OAc)2 (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 0.64 mmol) in toluene (5 mL) gave 1k (105 mg, 72%). Eluent:
1
0
.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene ethyl acetate–hexanes (3 : 7); colourless gel; H NMR (400 MHz,
(
(
5 mL) gave 1g (92 mg, 66%). Eluent: ethyl acetate–hexanes CDCl
3
) d 8.27 (s, 1H), 7.28 (dd, J ¼ 8.6, 2.3 Hz, 2H), 6.82 (d, J ¼
1
2 : 8); colourless gel; H NMR (500 MHz, CDCl
3
) d 8.44 (s, 7.9 Hz, 1H), 6.77 (t, J ¼ 2.1 Hz, 1H), 6.72 (d, J ¼ 2 Hz, 2H), 6.24
1
3
1
1
6
1
1
H), 7.86 (m, 1H), 7.28 (t, J ¼ 1.3 Hz, 1H), 7.20 (d, J ¼ 1.7 Hz, (br s, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.76 (s, 3H); C NMR (125
H), 7.11 (d, J ¼ 1.1 Hz, 1H), 7.08 (dd, J ¼ 6.9, 5.1 Hz, 2H), MHz, CDCl ) d 164.8, 161.4, 160.8, 148.6, 142.9, 141.3, 130.4,
.29 (br s, 1H), 3.88 (s, 3H). C NMR (125 MHz, CDCl ) d 114.3, 112.2, 110.1, 107.7, 97.2, 56.0, 55.3, 51.7; MS (ESI): m/z ¼
3
1
3
3
+
+
65.5, 147.2, 141.6, 141.3, 135.2, 131.0, 130.6, 124.2, 123.0, 414 [M + H] ; HRMS (ESI): m/z calcd for C H INO [M + H] :
1
6
16
4
+
21.6, 119.7, 113.0, 86.2, 52.0; MS (ESI): m/z ¼ 388 [M + H] ; 414.0197; found: 414.0222.
+
HRMS (ESI): m/z calcd for C14
H
11IClNO
2
[M + H] : 387.9596;
Methyl
5-iodo-2-methoxy-4-(4-methoxyphenylamino)-
found: 387.9587.
benzoate (1l). The reaction of methyl 4-amino-5-iodo-2-
Methyl 4-(4-uorophenylamino)-3-iodobenzoate (1h). The methoxybenzoate (500 mg, 1.62 mmol), 4-methoxyphenylbor-
reaction of methyl 4-amino-3-iodobenzoate (100 mg, 0.36 onic acid (371 mg, 2.44 mmol), Cu(OAc) (30 mg, 0.16 mmol),
2
mmol), 4-uorophenylboronic acid (76 mg, 0.54 mmol), n-decanoic acid (56 mg, 0.32 mmol) and 2,6-lutidine (348 mg,
Cu(OAc)2 (6.5 mg, 0.036 mmol), n-decanoic acid (12.4 mg, 3.24 mmol) in toluene (20 mL) gave 1l (450 mg, 70%). Eluent:
1
0
.072 mmol) and 2,6-lutidine (77.1 mg, 0.72 mmol) in toluene ethyl acetate–hexanes (1 : 9); colourless gel; H NMR (400 MHz,
(
(
5 mL) gave 1g (88 mg, 65%). Eluent: ethyl acetate–hexanes CDCl ) d 8.25 (s, 1H), 7.17 (d, J ¼ 8.8 Hz, 2H), 6.94 (d, J ¼ 8.7 Hz,
3
1
1
3
2 : 8); colourless gel; H NMR (400 MHz, CDCl
3
) d 8.42 (s, 1H), 2H), 6.35 (s, 1H), 6.14 (br s, 1H), 3.84 (s, 6H), 3.69 (s, 3H);
C
7
.80 (m, 1H), 7.19 (m, 2H), 7.08 (m, 2H), 6.84 (dd, J ¼ 8.7, 2.1 NMR (125 MHz, CDCl
3
) d 164.8, 161.7, 157.4, 150.4, 142.8, 132.6,
1
3
Hz, 1H), 6.24 (br s, 1H), 3.86 (s, 3H). C NMR (125 MHz, 130.9, 126.0, 116.0, 114.9, 95.8, 55.8, 55.5, 51.6; MS (ESI): m/z ¼
+
+
CDCl
1
3
) d 165.6, 148.7, 141.2, 135.9, 130.9, 128.8, 125.5, 121.9, 414 [M + H] ; HRMS (ESI): m/z calcd for C16
H
16INO
4
[M + H] :
+
16.5, 111.6, 84.7, 51.9; MS (ESI): m/z ¼ 372 [M + H] ; HRMS 414.0197; found: 414.0222.
4964 | RSC Adv., 2014, 4, 4960–4969
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General procedure for preparation of carbazoles (2a–l)
Methyl 6-phenoxy-9H-carbazole-3-carboxylate (2d). The
reaction of methyl 3-iodo-4-(4-phenoxyphenylamino)benzoate
Methyl 9H-carbazole-3-carboxylate (2a). An oven-dried
sealed tube was charged with, methyl 3-iodo-4-(phenylamino)
1
K
d (100 mg, 0.22 mmol), Pd(OAc)
2
(5 mg, 0.022 mmol) and
ꢁ
2
CO
3
(62.1 mg, 0.45 mmol) in DMSO (5 mL) at 130 C for 6 h
benzoate 1a (80 mg, 0.220 mmol), K
2 3
CO (62.6 mg, 0.453
afforded 2d as white solid (60 mg, 85%). Eluent: ethyl acetate–
mmol), Pd(OAc) (5 mg, 0.022 mmol), DMSO (5 mL) and
2
ꢁ
ꢀ1
hexanes (2 : 3); mp 182–183 C; IR (NaCl) n (cm ) 3340, 2919,
850, 1687, 1633, 1608, 1588, 1489, 1460, 1437, 1308, 1282,
magnetic stir bar under argon atmosphere. The tube was
2
sealed with Teon cap and the reaction mixture was stirred at
1
ꢁ
1257, 1219, 1168, 1119, 1095; H NMR (400 MHz, CDCl ): d 8.71
3
1
30 C for 3 h. The progress of the reaction was monitored by
(
s, 1H), 8.30 (br s, 1H), 8.13 (dd, J ¼ 8.6, 1.6 Hz, 1H), 7.76 (d, J ¼
TLC and aer completion the mixture was allowed to cool
down to room temperature. The reaction mixture was diluted
8
8
1
1
1
.1 Hz, 1H), 7.44 (d, J ¼ 8.6 Hz, 2H), 7.34 (m, 2H), 7.22 (dd, J ¼
.7, 2.3 Hz, 1H), 7.09 (dd, J ¼ 10.6, 4.2 Hz, 1H), 7.02 (dd, J ¼ 8.7,
with H
mL). The combined organic layer was dried over Na
was evaporated under vacuum. The crude product was puri-
ed by column chromatography (ethyl acetate–hexanes; 2 : 3)
to afford the corresponding carbazole 2a as white solid
2
O (3 mL) and was extracted with ethyl acetate (3 ꢂ 10
1
3
3
.0 Hz, 2H), 3.95 (s, 3H); C NMR (125 MHz, CD OD): d 168.2,
2
SO and
4
59.2, 150.28, 143.85, 137.3, 129.3, 126.9, 123.57, 122.42, 122.0,
20.1, 119.1, 117.2, 111.1, 110.7, 110.2, 50.9; MS (ESI): m/z ¼ 316

+
+
[
M ꢀ H] ; HRMS (ESI): m/z calcd for C H NO [M ꢀ H] :
2
0
14
3
ꢁ ꢁ
47 mg, 92%). mp. 174–176 C (ref. 6: 168–170 C); IR (NaCl)
316.0979; found: 316.0967.
(
ꢀ
1
Methyl 6-butoxy-9H-carbazole-3-carboxylate (2e). The reac-
tion of methyl 4-(4-butoxyphenylamino)-3-iodobenzoate 1e (100
n (cm ) 3344, 2947, 1692, 1591, 1522, 1497, 1448, 1434, 1327,
1
1
1
(
312, 1250, 1172, 1110; H NMR (400 MHz, acetone-d ) d
6
mg, 0.23 mmol), Pd(OAc)
2
(5.3 mg, 0.023 mmol), K
2
CO
3
(65 mg,
0.77 (br s, 1H), 8.82 (s, 1H), 8.26 (d, J ¼ 7.8 Hz, 1H), 8.09
ꢁ
0.470 mmol) in DMSO (5 mL) at 130 C for 5 h afforded 2e as
dd, J ¼ 8.6, 1.6 Hz, 1H), 7.58 (dd, J ¼ 8.3, 3.5 Hz, 2H), 7.46
13
white solid (56 mg, 80%); eluent: ethyl acetate–hexanes (2 : 3);
(
m, 1H), 7.28 (m, 1H), 3.92 (s, 3H); C NMR (125 MHz,
ꢁ
ꢀ1
mp 123–125 C; IR (NaCl) n (cm ) 3320, 2955, 2918, 2870, 1692,
630, 1604, 1497, 1467, 1433, 1384, 1290,1273, 1196, 1175, 1117,
CDCl
3
) d 167.9, 142.3, 139.9, 127.4, 126.5, 123.3, 123.1, 122.9,
1
1
+
2
21.4, 120.6, 120.3, 110.9, 110.1, 51.9; MS (ESI): m/z ¼ 226 [M
1
+
+
1097; H NMR (400 MHz, acetone-d ) d 10.58 (br s, 1H), 8.82 (s,
6
H] ; HRMS (ESI): m/z calcd for C H NO [M + H] :
1
4
11
2
1
8
1
2
1
1
H), 8.06 (d, J ¼ 8.6 Hz, 1H), 7.85 (d, J ¼ 2.1 Hz, 1H), 7.55 (d, J ¼
.6 Hz, 1H), 7.48 (d, J ¼ 8.8 Hz, 1H), 7.11 (dd, J ¼ 8.7, 2.3 Hz,
H), 4.16 (t, J ¼ 6.5 Hz, 2H), 3.92 (s, 3H), 1.83 (m, 2H), 1.57 (m,
26.0863; found: 226.0859.
The following carbazoles 2b–l were prepared by following
this procedure.
1
3
H), 1.02 (t, J ¼ 7.4 Hz, 3H). C NMR (125 MHz, CDCl
3
): d 167.9,
Clausine C (2b). The reaction of methyl 3-iodo-4-(3-methoxy-
53.9, 142.9, 134.6, 127.1, 123.7, 123.0, 122.8, 120.7, 116.5,
phenylamino)benzoate 1b (100 mg, 0.26 mmol), Pd(OAc)
2
(5.8
11.5, 110.2, 104.2, 68.6, 51.8, 31.4, 19.2, 13.8; MS (ESI): m/z ¼
mg, 0.025 mmol), and K
mL) at 130 C for 4 h afforded 2b as yellow solid (58 mg, 88%):
2
CO
3
(72.1 mg, 0.521 mmol) in DMSO (5
+
+
ꢁ
320 [M + Na] ; HRMS (ESI): m/z calcd for C18H19NO [M + H] :
3
ꢁ
298.1438; found: 298.1431.
Methyl 6-propyl-9H-carbazole-3-carboxylate (2f). The reac-
tion of methyl 3-iodo-4-(4-propylphenylamino)benzoate 1f (80
eluent: ethyl acetate–hexanes (2 : 3); mp 194–195 C (ref. 30b:
ꢁ
ꢀ1
1
1
95 C); IR (NaCl) n (cm ) 3271, 2921, 2850, 1698, 1605, 1440,
1
403, 1328, 1291, 1265, 1193, 1160, 1135, 1098; H NMR (500
mg, 0.20 mmol), Pd(OAc)
2
(4.5 mg, 0.020 mmol) and K
2
CO
3
MHz, CDCl
3
) d 8.70 (s, 1H), 8.18 (br s, 1H), 8.12 (d, J ¼ 8.6 Hz,
H), 8.06 (dd, J ¼ 8.1, 2.5 Hz, 1H), 7.56 (d, J ¼ 8.6 Hz, 1H), 7.11
d, J ¼ 2.5 Hz, 1H), 6.92 (dd, J ¼ 8.4, 2.1 Hz, 1H), 3.97 (s, 3H),
ꢁ
(55.9 mg, 0.404 mmol) in DMSO (5 mL) at 130 C for 5 h
1
(
3
1
5
afforded 2f as white solid (47 mg, 88%); eluent: ethyl acetate–
ꢁ
ꢀ1
1
3
hexanes (2 : 3); mp 144–146 C; IR (NaCl) n (cm ) 3298, 2959,
922, 2852, 1697, 1632, 1607, 1466, 1430, 1384, 1320, 1281,
3
.92 (s, 3H); C NMR (125 MHz, CDCl ) d 167.4, 160.6, 143.5,
2
42.7, 126.7, 124.2, 122.2, 122.0, 121.7, 117.4, 111.2, 109.8, 95.7,
ꢀ1 1
+
1261, 1193, 1161, 1131, 1093, 861, 803, 759, 632 cm ; H NMR
(400 MHz, CDCl
) d 8.80 (s, 1H), 8.29 (br s, 1H), 8.10 (dd, J ¼ 7.8,
.9 Hz, 1H), 7.92 (s, 1H), 7.37 (dd, J ¼ 8.9, 1.9 Hz, 2H), 7.26 (dd,
J ¼ 8.6, 2.9 Hz, 1H), 3.97 (s, 3H), 2.76 (t, J ¼ 7.9 Hz, 2H), 1.73 (dd,
5.2, 51.8; MS (ESI): m/z ¼ 256 [M + H] ; HRMS (ESI): m/z calcd
+
3
for C H NO [M + H] : 256.0968; found: 256.0973.
1
5
13
3
1
Methyl 6-methoxy-9H-carbazole-3-carboxylate (2c). The
reaction of methyl 3-iodo-4-(4-methoxyphenylamino)benzoate
1
3
J ¼ 15.0, 7.5 Hz, 2H), 0.98 (dd, J ¼ 7.7, 7.0 Hz, 3H); C NMR (125
MHz, CDCl ) d 168.0, 142.6, 138.3, 134.7, 127.3, 127.1, 123.3,
23.0, 122.7, 120.9, 119.9, 110.5, 110.0, 51.9, 38.0, 25.1, 13.7; MS
1
K
c (90 mg, 0.23 mmol), Pd(OAc)
2
(5.2 mg, 0.023 mmol) and
ꢁ
3
2
CO
3
(64.9 mg, 0.47 mmol), in DMSO (5 mL) at 130 C for 4 h
1
afforded 2c as white solid (50 mg, 86%). Eluent: ethyl acetate–
+
ꢁ
ꢁ
(ESI): m/z ¼ 290 [M + Na] ; HRMS (ESI): m/z calcd for C17
H17NO
2
hexanes (2 : 3); mp 148–150 C (ref. 6: 147–149 C); IR (NaCl) n
+
ꢀ1
[M + H] : 268.1332; found: 268.1333.
(
1
8
cm ) 3281, 2921, 2851, 1699, 1631, 1606, 1441, 1401, 1384,
329, 1292, 1191, 1161, 1099, 1033; H NMR (400 MHz, CDCl ) d
1
Methyl 7-chloro-9H-carbazole-3-carboxylate (2g). The reac-
tion of methyl 4-(3-chlorophenylamino)-3-iodobenzoate 1g (80
3
.70 (s, 1H), 8.18 (br s, 1H), 8.06 (dd, J ¼ 8.5, 1.9 Hz, 1H), 7.98 (d,
mg, 0.20 mmol), Pd(OAc)
2
(4.6 mg, 0.020 mmol) and K
2
CO
3
(57
J ¼ 8.5 Hz, 1H), 7.38 (d, J ¼ 8.5 Hz, 1H), 6.92 (d, J ¼ 7.9 Hz, 1H),
ꢁ
1
3
mg, 0.412 mmol) in DMSO (5 mL) at 130 C for 5 h afforded 2g
as white solid (40 mg, 75%). Eluent: ethyl acetate–hexanes
6
(
1
(
.89 (dd, J ¼ 8.6, 2.1 Hz, 1H), 3.97 (s, 3H), 3.91 (s, 3H); C NMR
125 MHz, CDCl ) d 167.9, 154.5, 143.0, 134.7, 127.2, 123.8,
23.1, 122.9, 120.9, 115.9, 111.6, 110.2, 103.2, 55.9, 51.9; MS
3
ꢁ
ꢀ1
(
2 : 3); mp 224–226 C; IR (NaCl) n (cm ) 3441, 2922, 2852,
1
+
1701, 1627, 1436, 1335, 1264, 1133, 1016, 912, 820; H NMR (400
ESI): m/z ¼ 256 [M + H] ; HRMS (ESI): m/z calcd for C15
H13NO
3
+
MHz, acetone-d ) d 10.89 (br s, 1H), 8.81 (s, 1H), 8.26 (d, J ¼ 8.4
6
[
M + H] : 256.0968; found: 256.0973.
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Hz, 1H), 8.10 (dd, J ¼ 8.6, 1.6 Hz, 1H), 7.62 (d, J ¼ 8.1 Hz, 1H), 8.48 (s, 1H), 8.21 (br s, 1H), 7.86 (d, J ¼ 8.5 Hz, 1H), 7.12 (s, 1H),
1
3
7
(
.60 (s, 1H), 7.27 (dd, J ¼ 8.4, 1.9 Hz, 1H), 3.92 (s, 3H); C NMR 6.90 (d, J ¼ 2.6 Hz, 1H), 6.86 (dd, J ¼ 8.5, 2.1 Hz, 1H), 3.96 (s,
13
125 MHz, CDCl ) d 167.4, 142.7, 141.4, 128.4, 123.4, 123.4, 3H), 3.94 (s, 3H), 3.89 (s, 3H). C NMR (125 MHz, CDCl ) d
3
3
1
23.1, 123.0, 123.0, 122.7, 122.4, 118.2, 118.2, 111.0, 110.6, 167.6, 160.0, 158.8, 143.4, 141.2, 123.8, 120.5, 118.0, 116.8,
+
110.5, 52.1; MS (ESI): m/z ¼ 260 [M + H] ; HRMS (ESI): m/z calcd 114.9, 108.5, 96.8, 95.6, 56.3, 55.6, 51.8; MS (ESI): m/z ¼ 286 [M +
+
+
+
for C14
H
10ClNO
2
[M + H] : 260.0473; found: 260.0474.
4
H] ; HRMS (ESI) calcd for C16H15NO [M + H] : 286.1072; found:
Methyl 6-uoro-9H-carbazole-3-carboxylate (2h). The reac- 286.1081.
tion of methyl 4-(4-uorophenylamino)-3-iodobenzoate 1h (80
Methyl 2,6-dimethoxy-9H-carbazole-3-carboxylate (2l). The
mg, 0.21 mmol), Pd(OAc)
2
(4.8 mg, 0.021 mmol) and K
2
CO
3
reaction of methyl 5-iodo-2-methoxy-4-(4-methoxyphenylamino)
ꢁ
(59.5 mg, 0.43 mmol) in DMSO (5 mL) at 130 C for 5 h afforded benzoate 1l (450 mg, 1.08 mmol), Pd(OAc)2 (24.4 mg, 0.109
2
h as white solid (39 mg, 75%). Eluent: ethyl acetate–hexanes mmol) and K CO (301.1 mg, 2.178 mmol) in DMSO (20 mL) at
2 3
ꢁ
ꢀ1
ꢁ
(2 : 3); mp 196–199 C; IR (NaCl) n (cm ) 3436, 2925, 2853, 130 C for 5 h afforded 2l as white crystals (240 mg, 78%).
1
ꢁ
634, 1466, 1431, 1315, 1286, 1261, 1159, 1016, 768; H NMR Eluent: ethyl acetate–hexanes (3 : 7); mp 165–167 C; IR (NaCl) n
1
ꢀ1
(400 MHz, CDCl
3
) d 8.76 (s, 1H), 8.32 (br s, 1H), 8.15 (dd, J ¼ 8.6, (cm ) 3327, 2999, 2948, 2834, 1704, 1635, 1618, 1492, 1470,
1
1
.4 Hz, 1H), 7.77 (d, J ¼ 8.6 Hz, 1H), 7.43 (d, J ¼ 8.5 Hz, 1H), 7.38 1346, 1296, 1246, 1199, 1157, 1081; H NMR (400 MHz, acetone-
13
(
dd, J ¼ 8.7, 4.1 Hz, 1H), 7.20 (m, 1H), 3.98 (s, 3H). C NMR (125
MHz, acetone-d
) d 167.9, 159.4, 157.6, 144.5, 137.8, 128.2, (d, J ¼ 8.4 Hz, 1H), 7.12 (s, 1H), 6.99 (dd, J ¼ 8.7, 2.5 Hz, 1H),
23.8, 121.8, 115.0, 114.7, 113.0, 111.7, 106.9, 52.0; MS (ESI): 3.87 (s, 3H), 3.83 (s, 3H), 3.75 (s, 3H); C NMR (125 MHz,
d
6
) d 10.33 (br s, 1H), 8.54 (s, 1H), 7.70 (d, J ¼ 7.9 Hz, 1H), 7.40
6
1
3
1
+
m/z ¼ 244 [M + H] ; HRMS (ESI): m/z calcd for C H FNO [M + acetone-d ) d 167.4, 159.7, 155.4, 145.1, 135.9, 125.2, 117.0,
1
4
10
2
6
+
H] : 244.0769; found: 244.0773.
114.9, 113.2, 112.4, 112.3, 103.5, 94.7, 56.3, 56.1, 51.7; MS (ESI):
+
+
Methyl 5H-[1,3]dioxolo[4,5-b]carbazole-8-carboxylate (2i). m/z ¼ 286 [M + H] ; HRMS (ESI): calcd for C16
The reaction of methyl 4-(benzo[d][1,3]dioxol-5-ylamino)-3- 286.1072; found: 286.1081.
4
H15NO [M + H] :
iodobenzoate 1i (80 mg, 0.21 mmol), Pd(OAc)
2
(4.8 mg, 0.021
(69.6 mg, 0.503 mmol) in DMSO (5 mL) at zole-3-carboxylate 2c (40 mg, 0.16 mmol) in THF (3 mL) was
(12.1 mg, 0. 32
Glycozoline (3). A solution of methyl 6-methoxy-9H-carba-
mmol) and K
2
CO
3
ꢁ
130 C for 6 h afforded 2i as light yellow solid (60 mg, 87%); added drop wise to a suspension of LiAlH
4
ꢁ
ꢁ
eluent: ethyl acetate–hexanes (2 : 3); mp 220–222 C; IR (NaCl) n mmol) in dry THF (4 mL) at 0 C. The suspension was then
ꢀ1
ꢁ
(
cm ) 3341, 2923, 2853, 1708, 1601, 1521, 1501, 1485, 1433, allowed to warm to 65 C and was stirred until the reaction was
1
1
1
(
3
1
5
280, 1233, 1173, 1107, 1037; H NMR (400 MHz, acetone-d ) d completed. The reaction mixture was quenched by methanol
6
0.62 (br s, 1H), 8.68 (s, 1H), 7.96 (dd, J ¼ 8.5, 1.6 Hz, 1H), 7.69 and ice cold water followed by the methanol was removed under
s, 1H), 7.50 (d, J ¼ 8.7 Hz, 1H), 7.06 (s, 1H), 6.05 (s, 2H), 3.90 (s, reduced pressure in a rotary evaporator. The reaction mixture
13
H). C NMR (125 MHz, acetone-d
6
) d 168.0, 148.8, 143.8, 137.0, was diluted with ethyl acetate and washed with water (3 ꢂ 10
and evaporated
1.9; MS (ESI): m/z ¼ 270 [M + H] ; HRMS (ESI): calcd for under reduced pressure. The residue was then puried by
29.0, 126.1, 124.0, 122.3, 121.5, 117.1, 111.2, 102.0, 100.3, 93.3, mL). The organic layer was dried over MgSO
4
+
+
C H NO [M + H] : 270.0761; found: 270.0755.
column chromatography on silica gel by using ethyl acetate–
1
5
11
4
Clausine L (2j). The reaction of methyl 5-iodo-2-methoxy-4- hexanes (3 : 7) to give glycozoline (3) in 75% yield (25 mg). Light
ꢁ ꢁ
phenylamino)benzoate 1j (80 mg, 0.21 mmol), Pd(OAc) (4.8 yellow solid; mp180–182 C (ref. 33b: 179–180 C); IR (NaCl) n
2
(
ꢀ1
mg, 0.021 mmol) and K
2
CO
3
(57.7 mg, 0.417 mmol) in DMSO (cm ) 3404, 2922, 2851, 1742, 1585, 1495, 1461, 1437, 1331,
ꢁ
1
(
5 mL) at 130 C for 4 h afforded 2j as colourless solid (45 1295, 1254, 1209, 1172, 1143, 1032; H NMR (400 MHz, CDCl
3
) d
mg, 87%). Eluent: ethyl acetate–hexanes (3 : 7); mp 171–172 8.21 (br s, 1H), 7.93 (s, 1H), 7.67 (s, 1H), 7.41 (d, J ¼ 8.5 Hz, 1H),
ꢁ
ꢁ
ꢀ1
C (ref. 30c: 172–173 C); IR (NaCl) n (cm ) 3325, 2923, 1704, 7.35 (d, J ¼ 8.1 Hz, 1H), 7 (d, J ¼ 7.8 Hz, 1H), 7.08 (dd, J ¼ 8.5, 1.2
1
3
1
1
8
3
635, 1618, 1588, 1492, 1469, 1433, 1384, 1346, 1296, 1246, Hz, 1H), 3.97 (s, 3H), 2.54 (s, 3H); C NMR (125 MHz, CDCl ) d
199, 1156, 1116, 1081, 1027; H NMR d (400 MHz, CDCl3) 150.6, 133.3, 128.4, 127.2, 124.21, 123.5, 120.1, 119.5, 113.4,
1
+
.60 (s, 1H), 8.27 (br s, 1H), 8.00 (d, J ¼ 7.8 Hz, 1H), 7.39 (dd, 112.6, 110.3, 99.7, 55.5, 23.6; LC-MS (ESI): m/z ¼ 212 [M + H] ;
+
J ¼ 8.7, 2.7 Hz, 2H), 7.26 (d, J ¼ 8.3 Hz, 1H), 6.93 (s, 1H), HRMS (ESI): calcd for C H NO [M + H] : 212.1070; found:
1
4
13
1
3
3
1
1
.98 (s, 3H), 3.95 (s, 3H). C NMR (125 MHz, CDCl
3
) d 167.9, 212.1083.
Glycozolidine (4). Following the same reaction procedure as
13.7, 111.6, 94.4, 55.9, 51.9; MS (ESI): m/z ¼ 256 [M + H] ; reported for glycozoline (3) reaction of carbazole 2l (50 mg, 0.17
60.23, 144.81, 143.0, 127.2, 125.3, 123.8, 120.9, 119.9, 117.3,
+
+
HRMS (ESI): calcd for C15
56.0973.
Clausine H (2k). The reaction of methyl 5-iodo-2-methoxy-4- (3 : 7); light yellow solid; mp164–166 C (ref. 35a: 158–161 C);
H
13NO
3
[M + H] : 256.0968; found: mmol) with LiAlH
4
(13.3 mg, 0.35 mmol) in THF (5 mL) afforded
2
glycozolidine 4 (21 mg, 65%). Eluent: ethyl acetate–hexanes
ꢁ
ꢁ
ꢀ1
(
3-methoxyphenylamino)benzoate 1k (80 mg, 0.20 mmol), IR (NaCl) n (cm ) 3404, 2922, 2851, 1742, 1585, 1461, 1437,
Pd(OAc)2 (4.4 mg, 0.019 mmol) and K CO (53.5 mg, 0.387 1384, 1331, 1295, 1254, 1209, 1172, 1032; H NMR (400 MHz,
mmol) in DMSO (5 mL) at 130 C for 5 h afforded 2k as white acetone-d
1
2
3
ꢁ
6
) d 9.94 (br, 1H), 7.78 (s, 1H), 7.53 (d, J ¼ 2.4 Hz, 1H),
crystals (44 mg, 80%). Eluent: ethyl acetate–hexanes (3 : 7); mp 7.32 (d, J ¼ 8.7 Hz, 1H), 6.98 (s, 1H), 6.90 (dd, J ¼ 8.7, 2.6 Hz,
ꢁ
ꢁ
ꢀ1
13
1
2
1
92–193 C (ref. 30a: 191–192 C); IR (NaCl) n (cm ) 3350, 2922, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 2.30 (s, 3H); C NMR (125 MHz,
850, 1692, 1591, 1522, 1492, 1458, 1434, 1337, 1311, 1277, CDCl ) d 157.5, 153.1, 141.3, 134.4, 123.4, 121.0, 118.6, 116.9,
192, 1174, 1156, 1109, 1045 cm ; H NMR (400 MHz, CDCl
3
ꢀ
1 1
3
) d 112.5, 110.1, 102.3, 92.3, 56.0, 55.3, 14.1; MS (ESI): m/z ¼ 242
4966 | RSC Adv., 2014, 4, 4960–4969
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+
+
+
[
M + H] ; HRMS (ESI): calcd for C15
H
15NO
2
[M + H] : 242.1176; 114.9, 112.3, 103.5, 94.7, 56.3, 56.1; MS (ESI): m/z ¼ 256 [M + H] ;
+
found: 242.1171.
HRMS (ESI): calcd for C H NO [M + H] : 256.0968; found:
1
5
13
3
Clausenalene (5). Following the same reaction procedure as 256.0972.
reported for glycozoline (3) reaction of carbazole 2i (50 mg, 0.18
mmol) with LiAlH
clausenalene 5 (31 mg, 72%). Eluent: ethyl acetate–hexanes
4
(14.1 mg, 0.37 mmol) in THF (4 mL) afforded
Acknowledgements
ꢁ
ꢁ
(
(
3 : 7); white solid; mp 224–227 C (ref. 36a: 224–225 C); IR Sk. R and K. R. thank CSIR for research fellowship. N. R. likes to
NaCl) n (cm ) 3386, 2918, 2850, 1687, 1585, 1484, 1458, 1378, thank UGC for research fellowship. CSIR, New Delhi (BSC 0108)
ꢀ
1
1
1318, 1297, 1269, 1217, 1189, 1151, 1036; H NMR (400 MHz, is acknowledged for the nancial support.
acetone-d ) d 10.04 (br s, 1H), 7.75 (s, 1H), 7.49 (s, 1H), 7.31 (d,
6
J ¼ 8.2 Hz, 1H), 7.09 (dd, J ¼ 8.3, 1.2 Hz, 1H), 6.97 (s, 1H), 5.99 (s,
References
1
3
2
1
9
H), 2.45 (s, 3H); C NMR (125 MHz, acetone-d ) d 148.0, 142.9,
6
39.2, 136.7, 128.3, 126.1, 124.5, 119.8, 116.8, 111.3, 101.7, 99.8,
1 (a) D. P. Chakraborty, The Alkaloids, ed. A. Bossi, Academic
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K. R. Reddy, in The Alkaloids, ed. G. A. Cordell, Academic
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H.-J. Kn ¨o lker, in Heterocycles in Natural Product Synthesis,
ed. K. C.Majumdar and S. K. Chattopadhyay, Wiley-VCH,
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H.-J. Kn ¨o lker, Top. Curr. Chem., 2012, 309, 203.
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P. A. P. M. van Doremalen, G. A. Somsen,
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+
2.9, 21.5; LC-MS (ESI): m/z ¼ 226 [M + H] ; HRMS (ESI): calcd
+
for C14H
11NO
2
[M + H] : 226.0863; found: 226.0859.
Sansoakamine (6). Boron tribromide (1 M solution in
ꢁ
CH
2
Cl
2
, 0.34 mL, 0.34 mmol) was added at ꢀ78 C to a solution
of 2l (50 mg, 0.17 mmol) in CH Cl (5 mL) under nitrogen
2
2
atmosphere and the mixture was stirred at that temperature for
ꢁ
2
h. The reaction mixture was warmed to ꢀ20 C and was stirred
for another 20 h. The progress of the reaction was monitored by
TLC and aer completion the reaction mixture was quenched
ꢁ
with saturated aqueous solution of NaHCO
3
at 0 C and diluted
with ethyl acetate. The aqueous layer was extracted with ethyl
acetate (2 ꢂ 10 mL). The combined organic layer was dried over
anhydrous Na SO and was evaporated under reduced pressure.
2
4
The crude product was puried by silica gel column chroma-
tography by using ethyl acetate–hexanes (2 : 8) to give san-
soakamine (6) in 76% (34 mg) yield. Light brown solid; mp 243–
ꢁ
ꢁ
ꢀ1
2
2
46 C (ref. 9: 243.8–245.6 C); IR (NaCl) n (cm ) 3338, 2923,
1
853, 1660, 1597, 1436, 1383, 1265, 1162, 1089, 1042; H NMR
(
400 MHz, acetone-d
6
) d 10.31 (br s, 1H), 8.53 (s, 1H), 7.51 (d, J ¼
2
1
1
1
.2 Hz, 1H), 7.29 (d, J ¼ 8.6 Hz, 1H), 6.93 (dd, J ¼ 8.6, 2.3 Hz,
1
3
H), 6.86 (s, 1H), 3.99 (s, 3H); C NMR (125 MHz, CDCl ) d
3
71.6, 160.6, 152.2, 147.9, 135.2, 125.5, 122.1, 114.3, 112.6,
09.8, 107.8, 104.4, 95.2, 51.8; MS (ESI): m/z ¼ 258 [M + H] ;
+
+
HRMS (ESI) calcd for C14
H
11NO
4
[M + H] : 258.0761; found:
258.0762.
Glycozolidal (7). To a solution of 2l (50 mg, 0.17 mmol) in dry
toluene (5 mL) was added a solution of DIBAL-H (1.0 M in THF,
ꢁ
0
.17 mL, 0.17 mmol) at ꢀ78 C under nitrogen atmosphere. The
ꢁ
mixture was stirred at ꢀ78 C for 1 h. The progress of the
reaction was monitored by TLC. The resulting mixture was
quenched with methanol (5 mL) followed by ice cold water
(
5 mL). The methanol was removed under reduced pressure and
the reaction mixture was diluted with ethyl acetate. The organic
layer was separated dried over Na SO and was concentrated
2
4
under vacuum. The crude reaction mixture was puried by
column chromatography on silica gel by using by using ethyl
acetate–hexanes (2 : 8) to afford glycozolidal (7) in 86% (37.8
6 W.-S. Li, J. D. McChesney and F. S. El-Feraly, Phytochemistry,
1991, 30, 343.
7 (a) T.-S. Wu, S.-C. Huang and P.-L. Wu, Phytochemistry, 1996,
43, 1427; (b) T.-S. Wu, S.-C. Huang, P.-L. Wu and C.-M. Teng,
Phytochemistry, 1996, 43, 133; (c) T.-S. Wu, S.-C. Huang,
P.-L. Wu and C.-S. Kuoh, Phytochemistry, 1999, 52, 523.
8 (a) T.-S. Wu, S.-C. Huang, J.-S. Lai, C.-M. Teng, F.-N. Ko and
C.-S. Kuoh, Phytochemistry, 1993, 32, 449; (b) C. Ito,
S. Katsuno, H. Ohata, M. Omura and I. Furukawa, Chem.
Pharm. Bull., 1997, 45, 48.
ꢁ
ꢁ
mg) yield. Yellow solid; mp190–193 C (ref. 35b: 188–193 C); IR
ꢀ
1
(
1
NaCl) n (cm ) 3400, 2923, 2852, 1606, 1487, 1469, 1433, 1384,
1
6
295, 1274, 1202, 1112; H NMR (400 MHz, acetone-d ) d 10.49
(
br s, 1H), 10.45 (s, 1H), 8.50 (s, 1H), 8.03 (d, J ¼ 2.2 Hz, 1H), 7.76
(d, J ¼ 8.4 Hz, 1H), 7.39 (dd, J ¼ 8.7, 2.1 Hz, 1H), 7.12 (s, 1H),
1
3
4
6
.02 (s, 3H), 3.91 (s, 3H); C NMR (125 MHz, acetone-d ) d
189.7, 159.7, 155.4, 145.1, 135.9, 125.2, 121.1, 118.7, 117.0,
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9
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1
1
1
0 W. Maneerat, T. Ritthiwigrom, S. Cheenpracha, T. Promgool,
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Chem., Int. Ed., 2003, 42, 5400; (c) D. S. Surry and 23 For rececnt carbazole synthesis, see: (a) S.-W. Youn,
S. L. Buchwald, Angew. Chem., Int. Ed., 2008, 47, 6338; (d)
F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2009,
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4
8, 6954; (e) C. Fisher and B. Koenig, Beilstein J. Org.
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2
1
3 Selected palladium catalyzed N-arylation reaction, see: (a)
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(
d) D. Maiti, B. P. Fors, J. L. Henderson, Y. Nakamura and 24 Carbazole synthesis from o-haloaniline, see: (a)
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4 Selected copper catalyzed N-arylation reaction, see: (a)
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3
056.
28 D. Alberico, M. E. Scotts and M. Lautens, Chem. Rev., 2007,
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1
1
1
5 D. M. T. Chan, K. L. Monaco, R. P. Wang and M. P. Winters,
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6 D. A. Evans, J. L. Katz and T. R. West, Tetrahedron Lett., 1998,
29 For synthesis of methyl carbazole-3-carboxylate, see: (a)
T. G. Back, A. Pandyra and J. E. Wulff, J. Org. Chem., 2003,
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39, 2937.
7 P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters,
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2941.
1
1
2
2
8 (a) J. P. Collman and M. Zhong, Org. Lett., 2000, 2, 1233; (b) 30 For synthesis of clausine alkaloids, see: (a) O. Kataeva,
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Chem., 2001, 66, 7892.
9 D. M. T. Chan and P. Y. S. Lam, in Boronic Acids: Preparation and
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Wiley-VCH, 2006, p. 205.
0 For Chan–Lam type coupling review, see: (a) J. X. Qiao and
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T. S. Wu, Tetrahedron, 2012, 68, 7735.
M. P. Krahl and H.-J. Kn ¨o lker, Org. Biomol. Chem., 2005, 5,
3099; (b) M. P. Krahl, A. Jager, T. Krause and H.-J. Kn ¨o lker,
Org. Biomol. Chem., 2006, 4, 3215; (c) R. Forke, A. Jager and
H.-J. Kn ¨o lker, Org. Biomol. Chem., 2008, 6, 2481; (d)
T. Watanabe, S. Oishi, N. Fuji and H. Ohno, J. Org. Chem.,
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A. W. Schmidt and H.-J. Kn ¨o lker, Eur. J. Org. Chem., 2013, 59.
1 For recent Chan–Lam type coupling of N-arylation, see: (a) 31 For synthesis of methyl 6-methoxycarbazole-3-carboxylate,
C. He, C. Chen, J. Cheng, C. Liu, W. Liu, Q. Li and A. Li,
see: R. Forke, M. P. Krahl, T. Krause, T. G. Schlechtingen
Angew. Chem., Int. Ed., 2008, 47, 6414; (b)
and H.-J. Kn ¨o lker, Synlett, 2007, 268.
K.
Sreeramamurthy,
E.
Ashok,
V.
Mahendar, 32 Crystal data of 2f: C17
H
17
N
1
O
2
, M ¼ 267.32, monoclinic, space
G. Santoshkumar and P. Das, Synlett, 2010, 721; (c)
N. Matsuda, K. Hirano, T. Satoh and M. Miura, Angew.
Chem., 2012, 51, 3702; (d) R. Adepu, K. Shivakumar,
S. Sandra, D. Ramababu, G. Ramakrishna, C. Mallareddy,
group: P21/n, a ¼ 12.8565(7), b ¼ 13.8210(7), c ¼ 8.0271(4)
ꢁ
˚
3
˚
A, b ¼ 98.229(5) , V ¼ 1411.63(13) A , Z ¼ 4, D
c
¼ 1.258 g
ꢀ3
ꢀ1
˚
cm , m ¼ 0.082 mm , T ¼ 293(2) K, l ¼ 0.71073 A,
ꢁ
q range: 3.9–27.0 , 1 1900 reections measured, 3031
4968 | RSC Adv., 2014, 4, 4960–4969
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independent (Rint
RSC Advances
¼
0.0305), 249 parameters. The 35 For synthesis of glycozolidine and glycozolidal, see: (a)
structure was solved by direct methods and rened by
full-matrix least-squares on F ; nal R indices for 1989
observed reections [I > 2s(I)]: R1 ¼ 0.0520, wR
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2
¼
2
0
0
.1298; maximal/minimum residual electron density: 36 For synthesis of clausenalene, see: (a) P. Bhattacharayya,
ꢀ3
˚
.158/ꢀ0.213 A . See ESI†
G. K. Biswas, A. K. Barua, C. Saha, I. B. Roy and
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37 M. Fuchsenberger, R. Forke and H.-J. Kn ¨o lker, Synlett, 2011,
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3
3 For synthesis of glycozoline, see: (a) M. Iwao, H. Takehara,
S. Furukawa and M. Watanabe, Heterocycles, 1993, 36,
1483; (b) D. Kajiyama, K. Inoue, Y. Ishikawa and
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3
4 C. Borger and H.-J. Kn ¨o lker, Tetrahedron, 2012, 68, 6727.
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