Total synthesis of carbazole alkaloids

Article abstract of DOI:10.1016/j.tet.2019.01.003

A Suzuki-Miyaura cross coupling, followed by triphenylphosphine mediated Cadogan reductive cyclization sequence provided efficient access to a series of carbazole alkaloids. In the present work, this approach was applied to the total synthesis of mukonine, clauszoline K, koenoline, murrayanine, murrayafoline A, mukoeic acid, glycoborine, glycozolicine, mukolidine, mukoline, glycozoline, 3-methoxy-9H-carbazole-1-carboxylic acid methyl ester, (3-methoxy-9H-carbazol-1-yl)-methanol, 3-methoxy-9H-carbazole-1-carbaldehyde, 3-methoxy-9H-carbazole-1-carboxylic acid, 2-methyl-9H-carbazole and nonsteroidal anti-inflammatory drug (NSAID) carprofen and its derivatives.

Full text of DOI:10.1016/j.tet.2019.01.003

Accepted Manuscript
Total synthesis of carbazole alkaloids
Bharath kumar goud Bhatthula, Janardhan reddy Kanchani, Veera reddy Arava,
M.C.S.Subha
PII:
S0040-4020(19)30003-1
https://doi.org/10.1016/j.tet.2019.01.003
TET 30055
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 October 2018
Revised Date: 2 January 2019
Accepted Date: 3 January 2019
Please cite this article as: Bhatthula Bkg, Kanchani Jr, Arava Vr, M.C.S.Subha , Total synthesis of
carbazole alkaloids, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.01.003.
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Total synthesis of carbazole alkaloids
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Bharath kumar goud Bhatthula*, Janardhan reddy Kanchani, Veera reddy Arava and M.C.S.Subha
'
R
X
'
R
R
O
R
B
O
NO2
N
H
X=F,Cl or Br

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Total synthesis of carbazole alkaloids
Bharath kumar goud Bhatthulaa , Janardhan reddy Kanchania,b, Veera reddy Aravaa and M.C.S.Subhab
aResearch and Development Center, Suven Life Sciences Limited., Hyderabad, India
bDepartment of Chemistry, Sri Krishnadevaraya University, Anantapur, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A Suzuki-Miyaura cross coupling, followed by triphenylphosphine
mediated Cadogan reductive cyclization sequence provided efficient
access to a series of carbazole alkaloids.
Available online
In the present work, this approach was applied to the total synthesis of
mukonine, clauszoline K, koenoline, murrayanine, murrayafoline A,
mukoeic acid, glycoborine, glycozolicine, mukolidine, mukoline,
glycozoline, 3-methoxy-9H-carbazole-1-carboxylic acid methyl ester, (3-
Keywords:
Carbazole alkaloids
Bis(pinacolato)diborane
Suzuki-Miyaura cross coupling
Reductive cyclization
methoxy-9H-carbazol-1-yl)-methanol,
3-methoxy-9H-carbazole-1-
carbaldehyde, 3-methoxy-9H-carbazole-1-carboxylic acid, 2-methyl-9H-
carbazole and nonsteroidal anti-inflammatory drug (NSAID) carprofen
and its derivatives.
2009 Elsevier Ltd. All rights reserved
.
biologically active carbazole alkaloids have been isolated
from natural sources.3-11
1. Introduction
Carbazole derivatives are well known for their
pharmacological activities. Due to their biological and
pharmacological activities,1 carbazoles are important
targets for natural product synthesis. Carbazole (Fig. 1)
was isolated first from coal tar in 1872 by Graebe and
Glazer.2
Carbazole alkaloids and its derivatives are having
extensive potential applications in the field of medicinal
chemistry as anti-tumor,4,12 antiplatelet aggregative,13
antibiotic,4,14,15 anti-viral,16-18 anti-plasmodial,19 anti-
convulsant,20 and sigma receptor antagonist21,22 properties.
Because of their importance, a large number of
methodologies have been developed to construct the
skeleton of substituted carbazole analogues. These include
Fischer–Borsche synthesis,23 Graebe–Ullmann synthesis,24
and conversion of indole derivatives to carbazoles.25
Although numerous synthetic approaches to substituted
3
4
5
4a
B
4b
2
A
6
C
1
9a
7
N
8a
H
9
8
Fig. 1. Structure of Carbazole
Carbazole ring is present in a variety of naturally
occurring medicinally active substances. A large number of
———
Corresponding author. Tel.: +0091-40-23191690; fax: +0091-40-23193541; e-mail: goudbk@yahoo.com

2
carbazoles have been reported, improvement is still needed
K,32 glycoborine,33,34 glycozolicine,35 glycozoline,34,36
ACCEPTED MANUSCRIPT
to provide a step economic and regioselective method. In
the synthesis of carbazoles, regioselective installation of
appropriate substituents on the eight different available
sites in the aromatic ring systems is a challenging task.
One of the most common methods for carbazole
synthesis involves the reductive cyclization of 2-
nitrobiphenyl derivatives in the presence of suitable
organophosphorus reagents.26 This method is commonly
referred to as the Cadogan cyclization and has a number of
advantages, which include increased substrate scope and
functional group tolerance, and more precise regiocontrol
of functional group placement within the product. Many
substituents are tolerated in this reductive cyclization,
which represents the best procedure for the cyclization of
the 2-nitrobiphenyls to the carbazole derivatives. The
starting materials 2-nitrobiphenyl derivatives are easily
prepared by the Suzuki-Miyaura cross-coupling of
haloarenes with arylboronic acids.
mukolidine,
mukoline,
3-methoxy-9H-carbazole-1-
carboxylic acid methyl ester, (3-methoxy-9H-carbazol-1-
yl)-methanol, 3-methoxy-9H-carbazole-1-carbaldehyde, 3-
methoxy-9H-carbazole-1-carboxylic acid, 2-methyl-9H-
carbazole and anti-inflammatory drug carprofen and its
derivatives from commercially available simple starting
materials utilizing a Suzuki-Miyaura cross coupling
reaction, followed by Cadogan reductive cyclization in
good to excellent yields (see Fig. 2). This methodology
provides an efficient route to carprofen with no deschloro
impurity and its derivatives.
The first carbazole alkaloid to be isolated from plant
source was murrayanine (5) extracted from the stem bark
of the small tree Murraya Koenigii (Fam. Rutaceae)37 an
Indian medicinal plant commonly known as “curry-leaf
tree”. It exhibits antimicrobial properties against human
pathogenic fungi.38 Since then, the field has expanded
enormously large due to the promising biological activities
of many of the carbazole alkaloids.
Suzuki-Miyaura reaction is a palladium catalyzed cross-
coupling reaction between organic boron compounds and
organic halides.27-30 This is relatively simple and versatile
C-C bond formation reaction can be extended to various
substrates and therefore finds wide application for the
synthesis of pharmaceuticals and total synthesis of
complex natural products.
Mukoeic acid (6), isolated from the bark of the Murraya
koenigii. It represents the first carbazole carboxylic acid
isolated from a plant source.39 The corresponding methyl
ester of mukoeic acid, mukonine (2) was isolated in 1978
by Chakraborty et al. from Murraya koenigii40 and later
also by Wu et al. from Clausena excavata.13,41 The shrub
clausena excavata is traditionally used in China for the
treatment of snakebites, abdominal pain and as a
detoxification agent.
Herein, we report a concise and efficient total synthesis
of
carbazole
alkaloids
mukonine,31
koenoline,
murrayafoline A, murrayanine, mukoeic acid, clauszoline

3
ACCEPTED MANUSCRIPT
CH2OH
OMe
OMe
CO2Me
OMe
OMe
N
CH2OH
N
H
CO2Me
N
H
N
H
H
2
3
3a
2a
Koenoline
Mukonine
(3-Methoxy-9H-carbazol-1-yl)-
3-Methoxy-9H-carbazole-1-
methanol
carboxylic acid methyl ester
CO2H
CHO
OMe
OMe
N
OMe
N
CHO
OMe
N
H
N
H
H
H
6
5
5a
4
Mukoeic acid
Murrayanine
3-Methoxy-9H-carbazole-
Murrayafoline A
1-carbaldehyde
OMe
MeO
OMe
OHC
OMe
N
H
N
H
CO2H
N
H
N
H
9
8
6a
7
Glycozolicine
Clauszoline K
3-Methoxy-9H-carbazole-1-
Glycoborine
carboxylic acid
OMe
HOH2C
OHC
N
H
OMe
N
H
OMe
N
H
N
H
13
12
11
10
2-methyl-9H-carbazole
Mukoline
Mukolidine
Glycozoline
CO2H
R
N
H
14a-d
Carprofen & its derivatives
R=H or Cl
Fig. 2. Structures of carbazole alkaloids
Koenoline (3), a carbazole alkaloid, has been isolated
from the root bark of Murraya koenigii for the first time as
a natural product by M.Fiebig et al.42 Its structure was
established as 1-methoxy-3-hydroxymethylcarbazole by
analysis of spectroscopic data and was confirmed by partial
synthesis from murrayanine isolated from M. siamensis
roots. It shows the biological activities such as cytotoxic,
antiproliferative activities against MCF-7 breast
adenocarcinoma cell line.43
Murrayafoline A (4) exhibited strong fungicidal activity
against Cladosporium cucumerinum which was isolated
from the root of several species of the Murraya.44,45

4
Chakravarty and co-workers isolated glycoborine (7),
from the root of Glycosmis arborea.33 This was the first 5-
oxygenated tricyclic natural carbazole ever isolated.33
In 1992, Bhattacharyya et al. isolated glycozolicine (9)
from the roots of Glycosmis pentaphylla46 and its structure
assigned as the isomeric 5-methoxy-3-methyl-9H-
carbazole, but in 2001, Chakravarty et al. reassigned its
structure as 8-methoxy-3-methylcarbazole (9) on the basis
of the total syntheses of both isomeric compounds and the
comparison of spectroscopic data with those of the natural
product.33 This structural assignment was confirmed by
The spectroscopic data confirmed that glycozoline is 6-
ACCEPTED MANUSCRIPT
methoxy-3-methylcarbazole.52,54 Chemical support for this
structural assignment was derived through transformation
into known carbazole derivatives54 and total synthesis.55
In 1997, Ito et al. described the isolation and structural
elucidation of clauszoline K (8)56 from the stem bark of the
Chinese medicinal plant Clausena excavata.
Carprofen is
a
non-narcotic, non-steroidal anti
inflammatory drug (NSAID) with characteristic analgesic
and antipyretic activity.57-59 NSAIDs are classified as
arylpropionic acid derivates, with the characteristic of an
iso-propionic acid group bound on an aromatic compound.
NSAIDs are commonly used to treat acute and chronic
pain. NSAIDs produce their beneficial action by inhibiting
the two isoforms of the cyclooxygenase (COX) enzyme,
COX-1 and COX-2.60,61 These enzymes convert
arachidonic acid into prostaglandins and thromboxane,
which are important physiological and pathological
effectors.
synthesis
via
Fischer
indolization
of
2-
methoxyphenylhydrazine and 4-methylcyclohexanone.33 It
exhibits moderate antimicrobial activity.47
Carbazoles Mukolidine (11) and mukoline (12) were
isolated from the root, leaves, and fruit of Murraya
koenigii Spreng,48 whose extracts exhibit antibacterial
activity.49 Chakraborty et al. confirmed the structures for
11 and 12 by their total syntheses, which included a
Fischer–Borsche cyclization as the key step. Tamariz et al.
described the total syntheses of 11 and 12 by using a
The anti-inflammatory effect of Carprofen is caused by
an inhibition of the COX-2 activity. COX-2 is the second
enzyme of the conversion of arachidonic acid to
prostaglandin H2 (PGH2), which is the first step in the
prostanoid synthesis that causes pain and inflammation.62
Carprofen binds as a competitive inhibitor in the active site
of COX-2.63
Diels–Alder cycloaddition of
a
4,5-dimethylene
oxazolidin-2-one and acrolein as the key step.50
A wide range of 6-oxygenated carbazole alkaloids has
been isolated from natural sources. Glycozoline (10) was
the first member of this class of alkaloids and originally
isolated from the stem bark of Glycosmis pentaphylla51 and
later also by Chakravarty et al. from the roots of
G.arborea.52 It exhibits antibacterial, antifungal,
antifeedant and antiinflammatory properties.53
2. Results and discussion
Carbazole natural product mukonine (2)31,64-68 is an
alkaloid from the Indian curry-leaf tree (Murraya

5
Koenigii).7,8 We synthesize mukonine (2) starting from 3-
ACCEPTED MANUSCRIPT
bis(pinacolato)
diboron (17)
PdCl2(PPh3)2
CH3COOK
1,4-dioxane
90oC, 6h
66%
bromo-5-hydroxybenzoic acid, which is converted into 3-
Br
CO2H
Br
CO2Me
MeI
Cs2CO3
DMF,
bromo-5-methoxybenzoic acid methyl ester (16) in 99%
12h RT, 99%
OH
OMe
16
15
yield.
This
ester
16
was
treated
with
CO2Me
Br
NO2
Bis(pinacolato)diboron (17) in 1,4-dioxane under nitrogen
atmosphere to get 3-methoxy-5-(4,4,5,5-tetramethyl-
[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (18) in
66% yield. We carried out Suzuki-Miyaura cross-coupling
reaction of compound 18 with commercially available o-
bromonitrobenzene (19), followed by reductive cyclization
of compound 20, synthetic route is shown in Scheme 1.
Two possibilities exist in 20, which gives a mixture of 2
and its regioisomer 3-methoxy-9H-carbazole-1-carboxylic
acid methyl ester 2a (combined yields of 93%, 2/2a, 2.5:1);
Mukonine (2) is the major product as a white, crystalline
solid in 66% yield. The regioisomer 2a is obtained in 27%
yield as an off-white solid. The spectroscopic data of
synthetic 2 are in full agreement with those reported for the
natural product.65 The structure of 2a was assigned on the
basis of HRMS, 1H and 13C NMR spectroscopic data.
Starting from mukonine (2), the alkaloids 3-6 were
synthesized in a few steps (Scheme 2). Reduction of 2 with
diisobutylaluminum hydride66c,69 provided Koenoline (3) in
84% yield. Reduction of ester 2 with lithium aluminum
hydride in diethyl ether gave 4 in 79% yield. Murrayanine
(5)70 was obtained by oxidation of 3 with manganese
dioxide. Saponification of 2 with potassium hydroxide in
water and ethanol gave Mukoeic acid (6).39,71 The
spectroscopic data of synthetic 3-6 were identical with
those reported in the literature.42,36b,66c,72
O
B
CO2Me
O
OMe
19
K2CO3, Toluene
Pd(PPh3)4
15h, reflux
88%
NO2
OMe
18
20
OMe
CO2Me
PPh ,
o-DCB
3
CO2Me
OMe
N
10h, reflux
93%
N
H
H
2
2 a
Scheme 1. Synthesis of mukonine and its regioisomer 3-
methoxy-9H-carbazole-1-carboxylic acid methyl ester
CO2H
OMe
N
H
mukoeic acid 6
Aq.KOH
4h reflux
EtOH
96%
CO2Me
LiAlH4
EtO2/CH2Cl2
4h rt
OMe
murrayafoline A 4
OMe
N
N
H
H
79%
mukonine 2
1M DIBAL-H
Et2O
84%
-78o C, 2h
CH2OH
CHO
MnO2, CCl4
12h rt
81%
OMe
N
OMe
N
H
H
murrayanine 5
Koenoline 3
Scheme 2. Synthesis of koenoline, murrayanine, mukoeic
acid and murrayafoline A.

6
OMe
OMe
acetate in 1,4-dioxane to afford 2-(2-methoxyphenyl)-
ACCEPTED MANUSCRIPT
Aq.KOH
EtOH
4h reflux
85%
4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (23) in 80%
yield. We carried out a Suzuki–Miyaura cross coupling of
23 and 2-chloro-4-methyl-1-nitrobenzene (25) by treatment
CO2Me
N
H
CO2H
N
H
6a
2a
1M DIBAL-H
Et2O
75%
-78o C, 2h
with catalytic
amounts of
tetrakis(triphenyl
OMe
CHO
OMe
phosphine)palladium in the presence of potassium
carbonate in toluene afforded 2′-methoxy-5-methyl-2-
nitrobiphenyl (26) in 56% yield. The reductive cyclization
of 26 provided glycoborine (7) in 93% yield. The spectral
data of 7 agree with those described for the natural33,34 and
synthetic46,73 products.
MnO2, CCl4
5h rt
80%
CH2OH
N
H
N
H
3a
5a
Scheme 3. Synthesis of 3a, 5a and 6a.
Starting from regioisomer 2a, the alkaloids 3a, 5a and
6a were synthesized in a few steps (Scheme 3). Reduction
of 2a with the milder reducing agent diisobutylaluminum
hydride gave (3-methoxy-9H-carbazol-1-yl)-methanol (3a)
in 75% yield. Oxidation of 3a with manganese dioxide
provided 3-methoxy-9H-carbazole-1-carbaldehyde (5a) in
80% yield. Mukoeic acid (6) regioisomer 6a was obtained
by saponification of 2a with potassium hydroxide in water
and ethanol. The structures of 3a, 5a and 6a were
determined by Mass, 1H and 13C NMR spectroscopic data.
The glycoborine (7) was prepared by treating 2-
bromoanisole (21) with bis(pinacolato)diboron (17) and
bis(triphenylphospine)palladium(II)dichloride, potassium
For the synthesis of clauszoline K (8), we carried out a
borlyation reaction of p-bromoanisole (22) with
Bis(pinacolato)diboron (17), this reaction afforded 2-(4-
methoxy-phenyl)-4,4,5,5-tetra methyl-[1,3,2]dioxaborolane
(24) in 80% yield. The subsequent Suzuki–Miyaura
reaction of 24 with 2-chloro-4-methyl-1-nitrobenzene (25)
afforded 4′-methoxy-5-methyl-2-nitrobiphenyl (27) in 51%
yield. The reductive cyclization of compound 27, followed
by oxidation of methyl group of 2-methoxy-6-methyl-9H-
carbazole (28) at C-6 by treatment with DDQ in methanol-
water mixture provided clauszoline K (8) in 75% yield.
Cl
R2
R1
R1
R1
R1
O
B
bis(pinacolato)diboron (17)
NO2
R2
Br
PdCl2(PPh3)2
25
PPh3
o-DCB
reflux
O
Pd(PPh3)4
K2CO3, Toluene
Reflux
CH3COOK
R2
NO2
R2
90oC
N
H
7 R1 = OMe, R2 = H, 93%, 10h
28 R1 = H, R2 = OMe, 77%, 10h
21 R1 = OMe, R2 = H
22 R1 = H, R2 = OMe
23 R1 = OMe, R2 = H, 80%, 5h
24 R1 = H, R2 = OMe, 80%, 7h
26 R1 = OMe, R2 = H, 56%, 80h
27 R1 = H, R2 = OMe, 51%, 25h
OMe
DDQ
OMe
OHC
MeOH:H2O 10:1
7h rt, 75%
N
H
N
H
28
8
Scheme 4. Synthesis of glycoborine (7) and clauszoline K (8).

7
Synthetic route is shown in Scheme 4. The
spectroscopic data of synthetic 8 are in full agreement with
those reported for the natural product.56,73
reductive cyclization of 32 provided two products
ACCEPTED MANUSCRIPT
glycozolicine (9) and glycozoline (10) in 76% yield
(combined yield of 76%, 9/10, 1:1).
Our approach to the carbazole alkaloids glycozolicine
(9), glycozoline (10), mukolidine (11), and mukoline (12)
started with methylation of 3-bromophenol (29) (see
Scheme 5). Methylation, followed by boronic acid pinacol
ester synthesis provided 31 in 74% yield. The subsequent
Suzuki–Miyaura cross coupling of 31 and 2-chloro-4-
methyl-1-nitrobenzene (25) by treatment with catalytic
amount of tetrakis(triphenylphosphine)palladium in the
presence of potassium carbonate in toluene afforded 3′-
methoxy-5-methyl-2-nitrobiphenyl (32) in 53% yield. The
We found that the reaction of 3′-methoxy-5-methyl-2-
nitro-biphenyl (32) provided two products 9 and 10 in
equal amounts.
Starting from glycozolicine (9), the alkaloids mukolidine
(11) and mukoline (12) were synthesized in a few steps48,50
(Scheme 5). The oxidation of the methyl group at C-3 of
glycozolicine (9) by treatment with 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) provided mukolidine
(11) in 85% yield. The reduction of 11 with sodium
borohydride gave mukoline (12) in 91% yield.
Cl
bis(pinacolato)
diboron (17)
O
Br
Br
NO2
MeI
K2CO3
2h rt
B
25
PdCl2(PPh3)2
O
Pd(PPh3)4
K2CO3, Toluene
1,4-dioxane
CH3COOK
6h 90o C
74%
92%
OH
OCH3
31
35 h reflux
29
OMe
53%
30
OMe
PPh
3 o-DCB
OMe
OMe
10h, reflux
76%
N
N
9
H
NO2
10
H
32
5h r.t
85%
MeOH/H2O
DDQ
NaBH4
MeOH
HOH2C
OHC
0oC, 2h
91%
OMe
OMe
N
N
H
H
11
12
Scheme 5. Synthesis of glycozolicine (9), glycozoline (10), mukolidine (11) and mukoline (12).
NO2
bis(pinacolato)diboron (17)
PdCl2(PPh3)2
CH3COOK
Br
19
PPh
3 o-DCB
Pd(PPh3)4
K2CO3, Toluene
60h, reflux
86%
6h, reflux
94%
1,4-dioxane
5h at 90oC
91%
B
N
H
13
NO2
O
O
33
34
35
Br
Scheme 6. Synthesis of 2-methyl-9H-carbazole (13)

8
ACCEPTED MANUSCRIPT
methanol
SOCl2
2h reflux
CO2Me
LDA, THF
MeI
CO2Me
CO2H
a)
-78oC 1h, 12 hrt
66%
Br
Br
Br
94%
36
37
38
O
OH
Br
TMSCN
K2CO3
methanol
PBr3
b)
NaBH4
2h rt
99%
CHCl3
22h rt
84%
30 h reflux
ACN
63%
Br
Br
Br
40
39
41
CN
CO2H
Methanol
SOCl2
Aq.NaOH
EtOH
CO2Me
16 h reflux
55%
2 h reflux
75%
Br
Br
Br
42
43
38
X
X= F,Cl or Br
R= H or Cl
CO2Me
CO2Me
R
Bis(pinacolato)diborane (17)
c)
NO2
Pd(dppf)Cl2
O
Pd(PPh3)4
K2CO3
Toluene
1,4-dioxane
CH3COOK
6 h reflux
92%
Br
B
O
38
44
CO2Me
CO2H
R
CO2Me
Aq.NaOH
6N HCl, MTBE
R
o-DCB, PPh3
reflux
N
R
N
H
H
NO2
R=H or Cl
45a-d
14a-d R=H or Cl
R=H or Cl
46a-d
Scheme 7. a) Synthesis of Methyl 2-(4-bromophenyl) propionate (38).
b) Synthesis of Methyl 2-(4-bromo phenyl) propionate (38) by an alternate route.
c) Synthesis of Carprofen and its analogues.
The spectroscopic data of the synthetic carbazoles 9, 10,
11 and 12 were in full agreement with those reported for
the corresponding natural products.33,48
nitrobiphenyl (35) in 86% yield. The reductive cyclization
of 35 provided 2-methyl-9H-carbazole (13) in 94% yield.
Carprofen was synthesized starting with readily
available 4-bromophenyl acetic acid (36); the acid was
converted to its methyl ester 37 with methanol and
catalytic amount of thionyl chloride. Treatment of ester 37
with LDA and methyl iodide gave the methyl derivative
38.74
Synthesis of alkaloid 2-methyl-9H-carbazole (13) started
with borylation of 4-bromotoluene (33). The palladium
catalyzed boronic acid pinacol ester synthesis of 4-
bromotoluene with bis(pinacolato)diboron (17) provided
4,4,5,5-tetramethyl-2-p-tolyl-[1,3,2]dioxa borolane (34) in
91% yield. The subsequent Suzuki–Miyaura reaction of 34
with 1-bromo-2-nitrobenzene (19) afforded 4′-methyl-2-
Methyl derivative 38 was also prepared by an alternative
route, starting from commercially available 4′-

9
bromoacetophenone (39). Reduction of the acetophenone
gave 1-(4-bromophenyl)ethanol (40), which was converted
The cyanation of compound 41 with TMS cyanide,76
ACCEPTED MANUSCRIPT
and hydrolysis of the resulting nitrile (42) provided 2-(4-
bromo phenyl)propanoic acid (43). Esterification of 43
afforded Methyl 2-(4-bromophenyl)propionate (38).
75
into 1-bromo-4-(1-bromoethyl)benzene (41) using PBr3.
Table 1
Table 2
2-Nitrobiphenyls prepared by Suzuki-Miyaura cross
coupling
Reductive cyclization of nitrobiphenyls to carbazoles
CO2Me
CO2Me
CO2Me
X
Pd(PPh3)4
O
R
CO2Me
PPh3
B
O
Toluene
K2CO3
R
R
R
NO2
N
H
o-DCB
reflux
NO2
45a-d
NO2
44
X=F, Br or Cl
R= H or Cl
46a-d
45a-d
R= H or Cl
Nitrobiphenyla
Time (h) Yield (%)b
Entry
Carbazole
Yield (%)b
Entry
Time (h)
Nitrobiphenyl
Halonitro
benznea
CO2Me
Cl
Cl
9
89
77
1
CO2Me
45a
46a
N
H
NO2
CO2Me
Cl
Cl
Cl
1
28
54
NO2
45a
Cl
CO2Me
Cl
NO2
2
6
CO2Me
CO2Me
45b
NO2
NO2
N
H
Cl
46b
46c
Cl
CO2Me
CO2Me
CO2Me
Cl
2
20
56
58
71
CO2Me
NO2
45b
45c
NO2
NO2
NO2
3
4
10
88
81
45c
Cl
N
Cl
H
Cl
3
20
CO2Me
Cl
NO2
Cl
9
CO2Me
45d
NO2
N
H
46d
Cl
4
100
NO2
45d
aGeneral conditions: Substrate (45a-d, 1.0 eq),
triphenylphosphine (2.5 eq), o-dichlorobenzene (15 mL),
180–185 °C, 6–10 h, b Isolated yields.
CO2Me
Br
5
40
81
NO2
45d
NO2
Ester 38 was treated with bis(pinacolato)diboron and
[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium,
potassium acetate in 1,4-dioxane to give phenyl
dioxaborolane ester 44.77
CO2Me
F
6
120
10
NO2
45d
NO2
aGeneral conditions: Halonitrobenzene (1.0 eq), Methyl
2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboralan-2-yl)phenyl]
propionate (1.11 eq), Pd(PPh3)4 (0.011eq), potassium
carbonate (2.24 eq), toluene (20 mL), water ( 2 mL), 100
°C, bIsolated yields.
Nitrobiphenyls 45a-d (Scheme 7 and Table 1) were
synthesized via Suzuki-Miyaura cross coupling of phenyl
dioxaborolane 44 and halonitrobenzenes.78

10
Reductive cyclization of the 2-nitro biphenyls 45a-d
using triphenylphosphine in o-dichlorobenzene gives
carbazole esters 46a-d (Scheme 7 and Table 2), which was
hydrolyzed to carbazole acids 14a-d in excellent yields by
aqueous NaOH (Scheme 7 and Table 3). These conditions
provided carprofen (14a) in high yield, with no deschloro
impurity.
drug carprofen (14a) and its analogues via Suzuki-
ACCEPTED MANUSCRIPT
Miayura cross coupling, followed by Cadogan reaction.
Our route also provided alkaloids, 2-methyl-9H-carbazole
(13), 3-methoxy-9H-carbazole-1-carboxylic acid methyl
ester (2a), (3-methoxy-9H-carbazol-1-yl)-methanol (3a), 3-
methoxy-9H-carbazole-1-carbaldehyde (5a) and 3-
methoxy-9H-carbazole-1-carboxylic acid (6a). These
carbazole alkaloids (2a, 3a, 5a and 6a) are regioisomers of
mukonine (2), koenoline (3), murrayanine (5) and mukoeic
acid (6).
Table 3
Hydrolysis of carbazole ester to acid
Aq.NaOH(2eq)
CO2Me
CO2H
R
R
N
H
N
H
4. Experimental section
R=H,Cl
46 a-d
14 a-d
Estera
Yield (%)b
Time (h)
Acid
Entry
4.1 General Description
Cl
1
Cl
Solvents and chemicals were purchased from
commercial sources and used without further purification.
Reverse-phase HPLC analysis was carried out using YMC
CO2Me
CO2Me
CO2H
4
88
N
H
N
H
14a
46a
Cl
Cl
CO2H
4
2
86
95
86
N
H
N
H
46b
46c
46d
14b
14c
14d
1
pack C18 (5µm), 250x4.6 mm. H and 13C NMR spectra
were recorded on Bruker AV 300 & 400-MHz instrument.
Chemical shifts (δ) are reported in parts per million (ppm),
and coupling constants (J) are reported in Hertz (Hz).
Splitting pattern are described as follows; br, broad; s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet.
Column chromatography was performed on silica gel (100-
200 mesh). IR spectra were recorded on a PerkinElmer
Spectrum 100 FTIR spectrophotometer as KBr pellets or
with the neat product. Mass spectra (MS) were recorded on
an API 2000 LCMS/MS AB Sciex spectrometer. HRMS
(ESI) were taken on an AB Sciex tripleTOF 5600+ and
Bruker Daltonics MicrOTOF mass analyzers. Analytical
thin-layer chromatography was carried out using E-Merck
60F254 aluminum-packed plates of silica gel (0.2mm).
CO2Me
CO2Me
CO2H
4
3
N
H
N
Cl
Cl
H
CO2H
4
4
N
H
N
H
aGeneral conditions: Substrate (46 a-d, 1.0 eq), aq.sodium
hydroxide solution (2.0 eq), reflux, 4h
b Isolated yields.
3. Conclusion
In conclusion, we have reported a convenient method for
the total synthesis of eleven natural carbazole alkaloids
mukonine (2), koenoline (3), murrayafoline A (4),
murrayanine (5), mukoeic acid (6), glycoborine (7),
clauszoline K (8), glycozolicine (9), glycozoline (10),
mukolidine (11), mukoline (12) and anti-inflammatory

11
Developed plates were visualized by using UV light or
potassium permanganate solution.
reaction mixture was cooled to room temperature and
ACCEPTED MANUSCRIPT
diluted with ethyl acetate (50 mL). After the dilution, the
mixture was filtered through a short pad of celite, and the
filtrate was concentrated. The residue was purified by
chromatography on a silica gel column (only hexane)
provided compound 1879 as a white solid (2.0 g, 66%), mp
94.8–100.5 °C: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H),
7.64 (s, 1H), 7.51 (d, J = 2.40 Hz, 1H), 3.90 (s, 3H), 3.86
(s, 3H), 1.35 (s, 12H); 13C NMR (100 MHz, CDCl3) δ
167.03, 159.16, 131.01, 128.13, 124.55, 117.56, 84.13,
55.53, 52.09, 24.86; IR (KBr) νmax 2996.88, 2975.45,
1716.95, 1597.34, 950.98, 702.29 cm-1; MS: m/z 293.1 (M
+ H)+.
4.2. 3-Bromo-5-methoxybenzoic acid methyl ester (16).
To a mixture of 3-Bromo-5-hydroxybenzoic acid (2.5 g,
11.52 mmol) and cesium carbonate (7.5 g, 23.04 mmol) in
DMF (20 mL) was added methyl iodide (4.08 g, 28.8
mmol) at 0 °C. After 10 min. the ice bath was removed and
the reaction allowed to warm to room temperature. The
reaction mixture was stirred at room temperature for 12 h.
The reaction was quenched with water (50 mL) and
extracted with methyl t-butyl ether (30 mL x 3), combined
organic layer was dried over sodium sulfate. Concentration
of the organic layer in vacuo followed by silica gel column
chromatographic purification of the resulting residue using
hexane as an eluent gave the product 16 as a brown syrup
4.4. 5-Methoxy-2′-nitrobiphenyl-3-carboxylic acid methyl
ester (20).
1
(2.8 g, 99%): H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H),
To a stirred solution of 1-bromo-2-nitrobenzene (19) (1.2
g, 5.94 mmol) in toluene (20 mL) was added Pd(PPh3)4
(343 mg, 0.297 mmol), 18 (1.73 g, 5.94 mmol) and
potassium carbonate (1.64 g, 11.88 mmol), and the
resulting mixture was refluxed for 15 h. under nitrogen
atmosphere. After cooling to room temperature, the solvent
was evaporated. Purification of the residue by column
chromatography (silica gel, 2–3% ethyl acetate in hexane)
provided 20 as a light green solid (1.5 g, 88%), mp 108.2–
7.48 (s, 1H), 7.23 (s, 1H), 3.91 (s, 3H), 3.83 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 165.69, 160.23, 132.69,
124.91, 122.70, 122.18, 113.47, 55.76, 52.48; IR (Neat)
νmax 2952.04, 1727.14, 1678.80, 1286.68, 1049.20, 766.94
1
cm− ; MS: m/z 245.2 (M + H)+.
4.3. 3-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan
-2-yl)benzoic acid methyl ester (18).
To a stirred solution of 16 (2.5 g, 10.2 mmol) in 1,4-
dioxane (30 mL) under nitrogen atmosphere was added
bis(pinacolato)diboron (2.58 g, 10.2 mmol), PdCl2(PPh3)2
(0.36 g, 0.51 mmol) and potassium acetate (2.0 g, 20.4
mmol) at room temperature, and the reaction mixture was
stirred at 90 °C for 6 h under nitrogen atmosphere. The
1
111.4 °C: H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.0
Hz, 1H), 7.63–7.52 (m, 4H), 7.44 (dd, J = 7.6, 1.2 Hz, 1H),
7.03 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 166.47, 159.67, 148.98, 139.07, 135.43,
132.53, 131.91, 131.87, 128.72, 124.29, 121.59, 118.93,

12
1H), 7.58 (d, J = 2.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H),
113.85, 55.64, 52.34; IR (KBr) νmax 29
A
24
C
.6
C
8,
E
1
P
7
TED
6, MANUSCRIPT
08
.4
7.18 (t, J = 7.4 Hz, 1H), 4.00 (s, 3H), 3.90 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 166.67, 152.62, 141.41,
134.36, 126.85, 125.71, 122.00, 120.94, 119.37, 114.38,
112.47, 112.26, 111.06, 56.46, 52.53; IR (KBr) νmax
1521.88, 1343.61 cm-1; MS: m/z 287.9 (M + H)+.
4.5. Mukonine (2) and its regioisomer 3-methoxy-9H-
carbazole-1-carboxylic acid methyl ester (2a).
To a stirred solution of 20 (1.5 g, 5.22 mmol) in 1,2-
dichlorobenzene (10 mL) was charged triphenylphosphine
(2.74 g, 10.44 mmol) at room temperature, and the reaction
mixture was refluxed for 10 h. The reaction mixture was
concentrated in vacuo, and the obtained residue was
purified by column chromatography to provide products 2a
(2% ethyl acetate in hexane) and 240,66,80 (7–8% ethyl
acetate in hexane).
1
3415.11, 2925.43, 1681.89, 1485.93 cm− ; MS: m/z 256.2
(M + H)+; HRMS (M)+ calcd for C15H13NO3 255.0893,
found 255.0895.
4.6. Koenoline (3).
To a stirred solution of 2 (100 mg, 0.392 mmol) in
diethylether (15 mL) under nitrogen was added DIBAL-H
(25% in toluene) (335 mg, 0.587 mmol) at -78 °C, and the
resulting solution was stirred for 2 h. at the same
temperature. The reaction was quenched with water (30
mL), and extracted with dichloromethane (25 mL x 3).
The combined organic layers dried over sodium sulfate,
and the solvent was evaporated. The residue was purified
by column chromatography (silica gel, hexane–ethyl
acetate, 80:20) to give 371,66a,c as a white solid (75 mg,
84%), mp 127.8–129.4 °C (ref.71 127 °C), (ref.66c 142 °C):
1H NMR (400 MHz, CDCl3) δ 8.27 (br s, 1H, exchangeble
with D2O, NH), 8.04 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H),
7.46–7.39 (m, 2H), 7.24-7.20 (m, 1H), 6.95 (s, 1H), 4.84
(d, J = 4.0 Hz, 2H), 4.02 (s, 3H), 1.69 (br s, 1H,
exchangeble with D2O, -OH); 13C NMR (100 MHz,
CDCl3) δ 145.78, 139.46, 132.88, 129.46, 125.80, 124.08,
123.56, 120.51, 119.49, 111.70, 111.05, 105.69, 66.49,
55.57; IR (KBr) νmax 3447.73, 3238.13, 2918.02, 1586.88,
4.5.1. Mukonine (2).
(887 mg, 66%), as a white solid, mp 192.4–196.8 °C
1
(lit.40 mp.198–200 °C), (lit.80 169–170 °C); H NMR (400
MHz, DMSO-d6) δ 11.80 (s, 1H), 8.45 (s, 1H), 8.22 (d, J =
7.6 Hz, 1H), 7.54-7.52 (m, 2H), 7.43 (t, J = 7.6 Hz, 1H),
7.21 (t, J = 7.4 Hz, 1H), 4.05 (s, 3H), 3.89 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 167.46, 145.62, 140.64,
133.27, 126.61, 123.43, 123.21, 121.09, 121.04, 120.04,
116.24, 112.26, 106.54, 56.00, 52.28; IR (KBr) νmax
3319.28, 1697.73, 1351.49 cm-1; MS: m/z 256.3 (M + H)+.
4.5.2. 3-Methoxy-9H-carbazole-1-carboxylic acid methyl
ester (2a).
1
(350 mg, 27%), off-white solid, mp 163.8–164.1 °C: H
NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.18 (d, J =
7.6 Hz, 1H), 8.08 (d, J = 2.8 Hz, 1H), 7.69 (d, J = 8.0 Hz,
1
1226.14, 735.13 cm− .

13
4.7. Murrayafoline A (4).
Hz, 1H), 7.51–7.47 (m, 2H), 7.32 (t, J = 7.4 Hz, 1H),
ACCEPTED MANUSCRIPT
4.11 (s, 3H); 13C NMR (100 MHz, Acetone-d6) δ 190.93,
146.41, 140.40, 134.15, 130.29, 126.35, 123.65, 123.49,
120.48, 120.14, 119.54, 111.93, 103.34, 55.25; IR (KBr)
A mixture of 2 (40 mg, 0.156 mmol) and LiAlH4 (18
mg, 0.47 mmol) in a mixture of CH2Cl2–diethylether (20
mL, 1:1) was stirred at 25 °C under nitrogen for 4 h. The
reaction was quenched with 2N HCl (10 mL). The reaction
mixture was extracted with dichloromethane (20 mL x 3),
and combined organic layer was dried over sodium sulfate.
The solvent was removed under vacuum and the residue
was purified by column chromatography (silica gel, 2%
ethyl acetate in hexane) to give 481 (26 mg, 79%) as a pale
1
νmax 3149.46, 1659.05, 1342.26, 1136.97, 847.24 cm− ;
MS: m/z 226.0 (M + H)+.
4.9. Mukoeic acid (6).
To a solution of 2 (100 mg, 0.391 mmol) in water (10
mL) and ethanol (2 mL) mixture was added potassium
hydroxide (44 mg, 0.783 mmol) at 25 °C, and the reaction
mixture was refluxed for 4 h. The reaction mixture was
filtered through celite and concentrated in vacuo. Silica gel
column chromatographic purification of the obtained
residue using ethyl acetate-hexane (1:1) as an eluent
provided product 666a,c,80 as a light brown solid (90 mg,
96%), mp 226.5–228.8 °C (ref.80 215 °C), (ref.4 242 °C):
1H NMR (400 MHz, Acetone-d6) δ 10.77 (br s, 1H), 8.52
(s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.65-7.63 (m, 2H), 7.48
(t, J = 7.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 4.09 (s, 3H);
13C NMR (100 MHz, Acetone-d6) δ 167.58, 145.45,
140.43, 133.14, 126.12, 123.47, 121.87, 120.42, 119.76,
116.03, 111.69, 106.58, 55.17; IR (KBr) νmax 3418.95,
1
yellow syrup, H NMR (400 MHz, CDCl3) δ 8.06 (br s,
1H), 7.93 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.33–7.27 (m,
2H), 7.14–7.08 (m, 1H), 6.64 (s, 1H), 3.89 (s, 3H), 2.44 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 144.29, 138.42,
128.40, 126.95, 124.45, 123.28, 122.49, 119.40, 118.10,
111.48, 109.86, 106.64, 54.42, 20.88; IR (Neat) νmax
1
3037.36, 2978.16, 1605.85, 1030.91, 831.93 cm− ; MS: m/z
212.0 (M + H)+.
4.8. Murrayanine (5).
To a solution of 3 (50 mg, 0.22 mmol) in dry CCl4 (20
mL) was added MnO2 (382 mg, 4.4 mmol) at r.t., and the
reaction mixture was stirred at room temperature for 12 h.
The reaction mixture was filtered through celite, and the
solvent was removed under vacuum. Purification of the
residue by chromatography on a silica gel column (20%
ethyl acetate in hexane) provided 566,80 (40 mg, 81%), as a
1
2928.28, 1685.61, 1585.88, 1384.81 cm− ; MS: m/z 242.0
(M + H)+.
4.10. (3-Methoxy-9H-carbazol-1-yl)-methanol (3a).
1
white solid, mp 169.7–171.3 °C (ref.80 154–156 °C): H
To a stirred solution of 2a (107 mg, 0.419 mmol) in
diethylether (20 mL) was added DIBAL-H (25% in
toluene) (357 mg, 0.628 mmol) under nitrogen at -78 °C
NMR (400 MHz, Acetone-d6) δ 10.94 (br s, 1H), 10.08 (s,
1H), 8.37 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0

14
and the resulting solution was stirred at same temperature
7.32 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 3.84 (s,
ACCEPTED MANUSCRIPT
3H); 13C NMR (100 MHz, Acetone-d6) δ 192.56, 153.41,
141.47, 132.73, 126.52, 125.51, 121.70, 120.36, 120.01,
119.56, 117.94, 112.04, 111.64, 55.75; IR (KBr) νmax
for 2 h. The reaction was quenched with water (30 mL) and
extracted with dichloromethane (25 mL x 3). The
combined organic layers were dried over sodium sulfate
and the solvent was removed under vacuum. The residue
was purified by column chromatography (silica gel,
hexane-ethyl acetate, 9:1) to give 3a (72 mg, 75%) as a
1
3343.00, 1671.18, 1490.26, 1117.40 cm− ; HRMS (M +
H)+ calcd for C14H12NO2 226.0868, found 226.0861.
1
off-white solid, mp 139.2–140.4 °C: H NMR (400 MHz,
4.12. 3-Methoxy-9H-carbazole-1-carboxylic acid (6a).
To a stirred solution of 2a (30 mg, 0.117 mmol) in water
(10 mL) and ethanol (2 mL) mixture was added potassium
hydroxide (13 mg, 0.235 mmol) at 25 °C, and the resulting
mixture was refluxed for 4 h. The reaction mixture was
allowed to room temperature and concentrated in vacuo.
The residue was purified by column chromatography
(silica gel, ethyl acetate–hexane, 1:1) to give 6a (24 mg,
85%) as a pale yellow solid, mp 201.2–202.8 °C: 1H NMR
(400 MHz, Acetone-d6) δ 10.58 (br s, 1H), 8.17 (d, J = 7.6
Hz, 1H), 8.03 (s, 1H), 7.73-7.71 (m, 2H), 7.45 (t, J = 7.4
Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 3.96 (s, 3H); 13C NMR
(100 MHz, Acetone-d6) δ 152.96, 141.06, 135.15, 126.30,
125.38, 122.20, 120.25, 119.03, 114.74, 111.71, 111.66,
110.02, 55.62; IR (KBr) νmax 3411.82, 2930.74, 1672.41,
CDCl3) δ 8.63 (br s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.48 (d,
J = 2.0 Hz, 1H), 7.42–7.36 (m, 2H), 7.21–7.17 (m, 1H),
6.87 (d, J = 2.0 Hz, 1H), 5.00 (s, 2H), 3.90 (s, 3H), 1.97 (br
s, 1H); 13C NMR (100 MHz, CDCl3) δ 153.52, 140.25,
133.28, 125.88, 124.17, 123.51, 123.05, 120.24, 118.99,
113.21, 110.98, 102.56, 64.37, 56.15; IR (KBr) νmax
3446.98, 3237.06, 2915.96, 1587.29, 1226.78, 1033.87,
1
735.99 cm− ; MS: m/z 226.1 (M - H)- ; HRMS (M + Na)+
calcd for C14H13NNaO2 250.0843, found 250.0841.
4.11. 3-Methoxy-9H-carbazole-1-carbaldehyde (5a).
To a stirred solution of 3a (38 mg, 0.167 mmol) in dry
CCl4 (10 mL) was added MnO2 (291 mg, 3.38 mmol) at 25
°C, and the reaction mixture was stirred for 5 h. at the same
temperature. The reaction mixture was filtered through a
short pad of celite and the filtrate was concentrated under
vacuum. The residue was purified by chromatography on a
silica gel column (3% ethyl acetate in hexane) to provide
5a as a light green solid (30 mg, 80%), mp 178.3–180.9
1
1582.66, 1107.73 cm− ; MS: m/z 240.2 (M - H)- ; HRMS
(M + H)+ calcd for C14H12NO3 242.0817, found 242.0812.
4.13. 2-(2-Methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]
dioxaborolane (23).
1
To a stirred solution of 1-Bromo-2-methoxybenzene (3.0
g, 16.04 mmol) in 1,4-dioxane (30 mL) was added
bis(pinacolato)diboron (4.06 g, 16.04 mmol), PdCl2(PPh3)2
°C: H NMR (400 MHz, Acetone-d6) δ 10.75 (br s, 1H),
10.06 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 2.0 Hz,
1H), 7.62 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H),

15
(0.56 g, 0.802 mmol) and potassium acetate (3.14 g, 32.08
4.15. Glycoborine (7).
ACCEPTED MANUSCRIPT
mmol) at room temperature, and the resulting mixture was
stirred at 90 °C under nitrogen for 5 h. The reaction
mixture was diluted with ethyl acetate (50 mL) and filtered
through celite. The filtrate was concentrated under vacuum
and the residue was purified by column chromatography on
silica gel (hexane) to give 2382 (3.0 g, 80.0%) as a off-
To a stirred solution of 26 (0.5 g, 2.05 mmol) in 1,2-
dichlorobenzene (10 mL) was added triphenylphosphine
(1.35 g, 5.13 mmol) at room temperature, and the resulting
mixture was refluxed for 10 h. The reaction mass was
concentrated under vacuum and the residue purified by
column chromatography (silica gel, 1% ethyl acetate in
hexane) to give 746 as a off-white solid (0.4 g, 93%), mp
1
white solid, mp 76.5–77.8 °C (ref.82 80–81 °C): H NMR
1
133.4–137.9 °C (ref.46 135 °C): H NMR (400 MHz,
(400 MHz, CDCl3) δ 7.68 (dd, J = 7.2, 1.2 Hz, 1H), 7.39 (t,
J = 7.2 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.86 (d, J = 8.4
Hz, 1H), 3.83 (s, 3H), 1.35 (s, 12H); IR (Neat) νmax
2979.20, 1576.49, 1356.44, 1145.35 cm-1.
CDCl3) δ 8.11 (s, 1H), 7.94 (br s, 1H), 7.33–7.28 (m, 2H),
7.20 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.66 (d,
J = 8.0 Hz, 1H), 4.08 (s, 3H), 2.52 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 156.27, 141.24, 136.92, 128.92, 126.49,
126.23, 122.97, 122.85, 112.48, 109.61, 103.57, 100.19,
55.43, 21.50; IR (KBr) νmax 3400.95, 2913.91, 1586.90,
1102.69 cm-1; MS: m/z 212.0 (M + H)+.
4.14. 2′-Methoxy-5-methyl-2-nitrobiphenyl (26).
To a stirred solution of 3-chloro-4-nitrotoluene (1 g, 5.83
mmol) in toluene (20 mL) was added Pd(PPh3)4 (336 mg,
0.29 mmol), 23 (1.36 g, 5.83 mmol) and potassium
carbonate (1.61 g, 11.65 mmol), and the reaction mixture
was refluxed under nitrogen for 80 h. The reaction mixture
was cooled to room temperature and filtered through celite.
The filtrate was concentrated under vacuum followed by
silica gel column purification of the obtained residue using
ethyl acetate (0–1%) in hexane as an eluent provided
product 26 as a yellow solid (0.8 g, 56%), mp 88.2–92.8
4.16. 2-(4-Methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]
dioxaborolane (24).
To a stirred solution of 1-Bromo-4-methoxybenzene (5.0
g, 26.73 mmol) in 1,4-dioxane (50 mL) was added
bis(pinacolato)diboron (6.77 g, 26.73 mmol), PdCl2(PPh3)2
(0.94 g, 1.33 mmol) and potassium acetate (5.2 g, 53.46
mmol) at room temperature, and the reaction mixture was
stirred at 90 °C under nitrogen atmosphere for 7 h. The
reaction mixture was diluted with ethyl acetate (75 mL)
and filtered through celite. The filtrate was concentrated
under vacuum and the residue was purified by column
chromatography (silica gel, only hexane) to give 24 (5.0
1
°C: H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.4 Hz,
1H), 7.35 (t, J = 8.0 Hz, 1H), 7.30 (dd, J = 7.6, 1.6 Hz,
1H), 7.25 (d, J = 7.6 Hz, 1H), 7.19 (s, 1H), 7.07 (t, J = 7.6
Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 3.69 (s, 3H), 2.45 (s,
3H); IR (KBr) νmax 2930.22, 1609.77, 1522.7, 1354.94 cm-
1; MS: m/z 244.1 (M + H)+.
1
gm, 80%) as a pale yellow syrup: H NMR (400 MHz,

16
125.82, 123.29, 121.21, 119.59, 116.51, 110.76, 107.92,
CDCl3) δ 7.76 (d, J = 8.4 Hz, 2H), 6.88
A
(d
C
,
C
J
E
=
P
8
TED
z, MANUSCRIPT
.4
H
2H), 3.77 (s, 3H), 1.31 (s, 12H); 13C NMR (100 MHz,
CDCl3) δ 162.22, 136.56, 113.34, 83.52, 55.03, 24.89; IR
(Neat) νmax 2978.67, 1605.71, 1361.37, 1248.39, 1144.45
cm-1; MS: m/z 235.2 (M + H)+.
94.86, 55.68, 21.58; IR (KBr) νmax 3399.99, 2937.25,
1
1471.78, 1211.25, 808.56 cm− ; MS: m/z 212.0 (M + H)+.
4.19. Clauszoline K (8).
To a stirred solution of 28 (100 mg, 0.473 mmol) in
methanol (10 mL), and water (1 mL) mixture was added
DDQ (451 mg, 1.987 mmol) at 25 °C, and the reaction
mixture was stirred for 7 h. at the same temperature. The
solvent was removed under vacuum and the residue was
purified by column chromatography (silica gel, 2% ethyl
acetate in hexane) to give 883 (80 mg, 75%) as a off-white
solid, mp 169.3–174.3 °C (ref.83 170–171 °C), (ref.73 184–
4.17. 4′-Methoxy-5-methyl-2-nitrobiphenyl (27).
To a stirred solution of 3-chloro-4-nitrotoluene (2 g,
11.65 mmol) in toluene (30 mL) were added Pd(PPh3)4
(0.67 g, 0.583 mmol), 24 (2.73 g, 11.65 mmol) and
potassium carbonate (3.22 g, 23.3 mmol) at 25 °C under
nitrogen, and the reaction mixture was refluxed for 25 h.
The reaction mixture was allowed to reach room
temperature and concentrated under vacuum to give 27
(crude) as light green syrup (1.45 g, 51%).
1
185 °C): H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H),
10.02 (s, 1H), 8.60 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.86
(dd, J = 7.6, 1.2 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.05 (d,
J = 2.0 Hz, 1H), 6.89 (dd, J = 8.4, 2.0 Hz, 1H), 3.86 (s,
3H); 13C NMR (100 MHz, DMSO-d6) δ 192.43, 159.67,
144.09, 142.39, 128.75, 125.90, 123.40, 123.33, 122.02,
116.57, 111.50, 109.53, 95.56, 55.84; IR (KBr) νmax
4.18. 2-Methoxy-6-methyl-9H-carbazole (28).
To a stirred solution of 27 (0.3 g, 1.23 mmol) in 1,2-
dichlorobenzene (10 mL) was charged triphenylphosphine
(0.81 g, 3.08 mmol) at room temperature, and the resulting
mixture was refluxed for 10 h. The solvent was removed
under vacuum and the residue was purified by column
chromatography (silica gel, 1–2% ethyl acetate in hexane)
to provide 2873,81,83 as a white solid (0.2 g, 77%), mp
226.8–228.0 °C (lit.81 228–229 °C), (lit.83 229–231 °C): 1H
NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.91 (d, J =
8.4 Hz, 1H), 7.77 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.11 (d,
J = 8.0 Hz, 1H), 6.92 (d, J = 1.6 Hz, 1H), 6.74 (dd, J = 8.4,
2.0 Hz, 1H), 3.82 (s, 3H), 2.43 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ 158.84, 141.81, 138.41, 127.57,
1
3288.53, 2925.00, 1673.56, 1161.66, 808.55 cm− ; MS: m/z
226.0 (M + H)+.
4.20. 2-(3-Methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]
dioxaborolane (31).
To a stirred solution of 1-Bromo-3-methoxybenzene
(30) (3.0 g, 16.04 mmol) in 1,4-dioxane (30 mL) were
added bis(pinacolato)diboron (4.06 g, 16.04 mmol),
PdCl2(PPh3)2 (0.563 g, 0.802 mmol) and potassium acetate
(3.14 g, 32.08 mmol) at 25 °C, and the reaction mixture

17
was stirred at 90 °C under nitrogen atmosphere for 6 h. The
138.08, 135.28, 131.41, 128.56, 127.66, 123.20, 119.20,
ACCEPTED MANUSCRIPT
reaction mixture was diluted with ethyl acetate (50 mL)
and filtered through a short pad of celite. The filtrate was
concentrated under reduced pressure and the residue was
purified by column chromatography (silica gel, hexane) to
112.56, 112.50, 54.21, 20.29; IR (Neat) νmax 2958.89,
1599.49, 1519.98 cm-1; MS: m/z 244.1 (M + H)+.
4.22. Glycozolicine (8-methoxy-3-methylcarbazole) (9) and
Glycozoline (10).
1
give 3184 (2.8 g, 74%) as a pale yellow oil: H NMR (400
To a stirred solution of 32 (1.2 g, 4.933 mmol) in 1,2-
dichlorobenzene (10 mL) was added triphenylphosphine
(3.2 g, 12.33 mmol) at room temperature, and the reaction
mass was refluxed for 10 h. The reaction mass was
concentrated under vacuum and the residue was purified by
column chromatography (silica gel, 0–0.5% ethyl acetate
in hexane) to provide compound 923d,50 and (1–2% ethyl
acetate in hexane) 1023d,85 with 50:50 ratio.
MHz, CDCl3) δ 7.41 (d, J = 7.2 Hz, 1H), 7.32–7.25 (m,
2H), 7.01 (dd, J = 8.4, 2.6 Hz, 1H), 3.83 (s, 3H), 1.34 (s,
12H); 13C NMR (100 MHz, CDCl3) δ 159.09, 134.76,
128.95, 127.71, 127.21, 118.81, 117.88, 83.82, 55.22,
24.88; IR (Neat) νmax 2979.17, 1356.52, 1145.52, 706.51
cm-1.
4.21. 3′-Methoxy-5-methyl-2-nitrobiphenyl (32).
To a stirred solution of 3-chloro-4-nitrotoluene (2 g,
11.65 mmol) in toluene (30 mL) were added Pd(PPh3)4
(673 mg, 0.582 mmol), 31 (2.73 g, 11.65 mmol) and
potassium carbonate (3.22 g, 23.31 mmol), and the reaction
mixture was refluxed for 35 h. under nitrogen atmosphere.
The reaction mixture was allowed to reach room
temperature and diluted with water (30 mL), stirred for 15
min. The reaction mixture was filtered through celite, the
filtrate extracted with toluene (30 mL x 3), and the solvent
removed under vacuum. The residue was purified by
column chromatography on silica gel (0–0.5% ethyl acetate
in hexane) to give 32 (1.5 g, 53%) as pale yellow syrup: 1H
NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 1H), 7.31
(t, J = 7.8 Hz, 1H), 7.26–7.22 (m, 2H), 6.93 (dd, J = 8.4,
2.4 Hz, 1H), 6.87-6.83 (m, 2H), 3.82 (s, 3H), 2.45 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 158.58, 145.91, 142.29,
4.22.1. Glycozolicine (9).
(400 mg, 38%), as a white solid, mp 130.8–132.7 °C
(lit.86 mp 145–146 °C), (lit.33 mp 137–138 °C), (lit.87 129–
1
130 °C): H NMR (400 MHz, CDCl3) δ 8.15 (br s, 1H),
7.84 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.35 (d, 8.4 Hz, 1H),
7.23 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.89 (d, J
= 8.0 Hz, 1H), 4.00 (s, 3H), 2.52 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 145.69, 137.46, 130.14, 128.67, 127.08,
124.22, 123.86, 120.44, 119.50, 112.82, 110.59, 105.77,
55.51, 21.44; IR (KBr) νmax 3414.12, 2931.15, 1577.33 cm-
1; MS: m/z 212.0 (M + H)+; HRMS (M)+ calcd for
C14H13NO 211.0992, found 211.0997.
4.22.2. Glycozoline (10).
(400 mg, 38%), as a off-white solid, mp 174.2–178.4 °C
(lit.85 176–179 °C) (lit.51 181–182 °C): H NMR (400
1

18
4.24. Mukoline (3-hydroxymethyl-8-methoxy carbazole)
MANUSCRIPT
MHz, CDCl3) δ 7.82 (s, 1H), 7.79 (br s, 1
A
H
C
),
C
7.
E
52
P
(
T
d,
E
J
D
=
(12).
2.4 Hz, 1H), 7.31-7.28 (m, 2H), 7.22 (d, J = 8.0 Hz, 1H),
7.05 (dd, J = 8.4, 2.4 Hz, 1H), 3.92 (s, 3H), 2.51 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 153.77, 138.58, 134.78,
128.35, 127.20, 123.67, 123.55, 120.14, 114.89, 111.28,
110.43, 103.14, 56.09, 21.42; IR (KBr) νmax 3399.91,
2937.99, 1458.93, 1211.08 cm-1; MS: m/z 212.0 (M + H)+.
To a stirred solution of 11 (60 mg, 0.266 mmol) in
methanol (15 mL) was added sodium borohydride (30.2
mg, 0.799 mmol) at 0 °C and stirred for 2 h. at the same
temperature. The solvent was removed under vacuum and
the residue was purified by column chromatography (silica
gel, hexane–ethyl acetate, 7:3) to give 1250,87 as a off-white
solid (55 mg, 91%), mp 146.2–148.1 °C (ref.87 155–157
4.23. Mukolidine (8-methoxycarbazole-3-carbaldehyde)
(11).
°C), (ref.50 125–126 °C): H NMR (400 MHz, CDCl3) δ
1
8.30 (br s, 1H), 8.03 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.41
(s, 2H), 7.15 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H),
4.82 (s, 2H), 4.00 (s, 3H), 1.74 (br s, 1H); 13C NMR (100
MHz, CDCl3) δ 145.73, 138.86, 132.10, 130.22, 125.52,
124.24, 123.80, 119.88, 119.59, 112.88, 111.02, 106.08,
66.13, 55.54; IR (KBr) νmax 3509.04, 3293.24, 2924.21,
To a stirred solution of 9 (100 mg, 0.473 mmol) in
methanol (10 mL) and water (1 mL) mixture was added
DDQ (451 mg, 1.987 mmol) and stirred for 5 h. at r.t. The
reaction mass was diluted with ethyl acetate (50 mL) and
the organic layer was washed with sat. sodium bicarbonate
solution (30 mL x 2) and water (30 mL x 2) and dried over
sodium sulfate. The solvent was removed under vacuum.
Purification of the residue by column chromatography
(silica gel, hexane-ethyl acetate, 92:8) provided 1150,87 (90
mg, 85%) as a off-white solid, mp 167.6–168.7 °C (ref.87
1
1574.77, 1097.80, 821.55 cm− .
4.25. 4,4,5,5-Tetramethyl-2-p-tolyl-[1,3,2]dioxaborolane
(34).
To a stirred solution of 4-bromotoluene (5 g, 29.23
mmol) in 1,4-dioxane (50 mL) were added
bis(pinacolato)diboron (7.41 g, 29.23 mmol), PdCl2(PPh3)2
(1.02 g, 1.56 mmol, 5 mol%) and potassium acetate (5.7 g,
58.46 mmol) at 25 °C, and the reaction mixture was stirred
at 90 °C under nitrogen atmosphere for 5 h. The reaction
mixture was diluted with ethyl acetate (50 mL) and filtered
through celite. The filtrate was concentrated under reduced
pressure and the residue was purified by column
chromatography (silica gel, hexane) to give product 34 (5.8
1
175–176 °C), (ref.50 148–150 °C): H NMR (400 MHz,
CDCl3) δ 10.09 (s, 1H), 8.60 (br s, 1H), 8.58 (s, 1H), 7.98
(dd, J = 8.8, 1.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.54 (d,
J = 8.4 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 8.0
Hz, 1H), 4.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
191.86, 145.86, 142.82, 130.31, 129.14, 127.05, 124.54,
124.27, 123.87, 121.22, 113.02, 111.26, 106.97, 55.63; IR
(KBr) νmax 3322.59, 2925.18, 1674.26, 1572.70, 1242.00,
1091.95, 817.15 cm− ; MS: m/z 226.0 (M + H)+.
1

19
1
g, 91%) as a light brown oil: H NMR (400 MHz, CDCl )
obtained residue using 0–1% ethyl acetate-hexane as an
ACCEPTED MANUSCRIPT
3
eluent provided product 13 (120 mg, 94%) as a white solid,
mp 256.7–259.7 °C (lit.88 mp. 258–260 °C): 1H NMR (400
MHz, DMSO-d6) δ 11.08 (br s, 1H), 8.04 (d, J = 8.0 Hz,
1H), 7.97 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H),
7.32 (t, J = 7.6 Hz, 1H), 7.26 (s, 1H), 7.11 (t, J = 7.4 Hz,
1H), 6.98 (d, J = 8.0 Hz, 1H), 2.46 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ 140.66, 140.17, 135.43, 125.39,
122.95, 120.63, 120.48, 120.30, 120.23, 118.81, 111.34,
111.25, 22.16; IR (KBr) νmax 3399.96, 2914.05, 1439.51,
1327.31 cm-1; MS: m/z 182.0 (M + H)+.
δ 7.62 (d, J = 7.6 Hz, 2H), 7.09 (d, J = 7.6 Hz, 2H), 2.26 (s,
3H), 1.23 (s, 12H); 13C NMR (100 MHz, CDCl3) δ 141.38,
134.88, 128.55, 83.62, 24.90, 21.75; IR (Neat) νmax
2979.33, 1613.77, 1361.25, 1145.86, 859.94 cm-1.
4.26. 4′-Methyl-2-nitrobiphenyl (35).
To a solution of 1-bromo-2-nitrobenzene (0.2 g, 0.99
mmol) in toluene (10 mL) were added Pd(PPh3)4 (57 mg,
0.495 mmol), 34 (0.21 g, 0.99 mmol) and potassium
carbonate (0.27 g, 1.98 mmol) at 25° C, and the resulting
solution was refluxed for 60 h. under nitrogen atmosphere.
The reaction mixture was allowed to reach r.t. and
concentrated in vacuo. The obtained residue was purified
by column chromatography on silica gel using 1% ethyl
acetate in hexane to give 35 (0.18 g, 86%) as a pale yellow
4.28. Methyl 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan
-2-yl)phenyl]propionate (44).
A mixture of Methyl 2-(4-bromophenyl)propionate (38)
(5 g, 20.56 mmol), potassium acetate (4.04 g, 41.11 mmol),
Bis(pinacolato)diboron (10.45 g, 41.13 mmol) and [1,1′-
bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(0.84 g, 1.03 mmol) in 1,4-dioxane (100 mL) was refluxed
for 6 h. under nitrogen atmosphere. The reaction mixture
was cooled to 60 °C and concentrated under reduced
pressure. Water (50 mL) and ethyl acetate (50 mL) were
charged, stirred for 30 minutes and filtered through celite.
Organic layer was separated, dried over sodium sulphate
and concentrated. The residue was purified using column
chromatography (silica gel, 3-5% ethyl acetate in hexane)
1
oil: H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz,
1H), 7.61–7.57 (m, 1H), 7.47–7.42 (m, 2H), 7.25–7.20 (m,
13
4H), 2.39 (s, 3H); C NMR (100 MHz, CDCl3) δ 149.42,
138.18, 136.29, 134.41, 132.20, 131.95, 129.47, 127.92,
127.77, 124.03, 21.25; IR (Neat) νmax 2924.80, 1527.84,
1
1358.87, 818.93 cm− .
4.27. 2-Methyl-9H-carbazole (13).
To a stirred solution of 4'-methyl-2-nitrobiphenyl (35)
(150 mg, 0.703 mmol) in o-dichlorobenzene (10 mL) was
added triphenylphosphine (461 mg, 1.76 mmol) at 25 °C,
and the reaction mixture was refluxed for 6 h. The reaction
mixture was allowed to reach r.t. and concentrated under
vacuum, followed by silica gel column purification of the
to
afford
Methyl
2-[4-(4,4,5,5-tetramethyl-
[1,3,2]dioxaboralan-2-yl)phenyl]propionate (44) (5.5 g,
92%) as a colourless syrup: 1H NMR (400 MHz, CDCl3) δ
7.78 (d, J = 7.6 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 3.73 (q,

20
J = 6.8 Hz, 1H), 3.63 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H), 1.32
(s, 12H); 13C NMR (100 MHz, CDCl3) δ 174.72, 143.73,
135.18, 134.97, 126.89, 124.98, 83.76, 52.02, 45.61, 24.85,
4.29.2. Methyl 2-{2'-chloro-6'-nitro-[1,1'-biphenyl]-4yl}
ACCEPTED MANUSCRIPT
propionate (45b).
1
Yield: 1.12 g (56%), pale yellow syrup: H NMR (300
MHz, CDCl3) δ 7.73-7.68 (m, 2H), 7.46-7.36 (m, 3H), 7.22
(d, J = 8.1 Hz, 2H), 3.77 (q, J = 7.1 Hz, 1H), 3.70 (s, 3H),
1.55 (d, J = 7.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
174.72, 151.26, 140.95, 135.82, 134.39, 133.28, 132.63,
129.04, 128.91, 128.80, 127.69, 127.54, 121.93, 52.14,
45.21, 18.55; IR (Neat) νmax 3022.43, 1733.07, 1534.11,
758.14 cm-1; MS: m/z 320.0 (M + H)+.
1
18.50; IR (KBr) νmax 2980.90, 1740.69 cm− ; MS: m/z
291.1 (M + H)+.
4.29. General procedure for the preparation of nitro
biphenyls 45a-d
To a stirred solution of Methyl 2-[4-(4,4,5,5-tetramethyl-
[1,3,2]dioxaboralan-2-yl)phenyl]propionate (44) (2 g, 6.89
mmol) in toluene (20 mL) under nitrogen atmosphere were
added halonitrobenzene ( 6.2 mmol), potassium carbonate
(1.92 g, 13.89 mmol), Pd(PPh3)4 (80 mg, 0.069 mmol) and
water (2 mL). The reaction mixture was stirred for 20-100
h at 100 °C, until TLC had indicated complete
consumption of the aryl halide. The reaction mixture was
evaporated, and the residue was purified by column
chromatography.
4.29.3. Methyl 2-{4'-chloro-2'-nitro-[1,1'-biphenyl]-4yl}
propionate (45c).
1
Yield: 1.16 g (58%) light green color liquid: H NMR
(300 MHz, CDCl3) δ 7.84 (d, J = 1.8 Hz, 1H), 7.60 (dd, J =
8.1, 1.8 Hz, 1H), 7.39-7.35 (m, 3H), 7.26-7.23 (m, 2H),
3.78 (q, J = 7.0 Hz, 1H), 3.69 (s, 3H), 1.54 (d, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 174.68, 149.43,
140.95, 135.05, 134.38, 133.98, 133.02, 132.38, 128.14,
128.00, 124.22, 52.16, 45.13, 18.51; IR (Neat) νmax
2981.99, 1735.69, 1534.67, 738.15 cm-1; MS: m/z 320.0
(M + H)+.
4.29.1. Methyl 2-{5'-chloro-2'-nitro-[1,1'-biphenyl]-4-yl}
propionate (45a).
1
Yield: 1.08 g (54%) pale yellow syrup: H NMR (300
MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 10.2
Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.27-7.24 (m, 2H), 3.79
(q, J = 7.1 Hz, 1H), 3.69 (s, 3H), 1.54 (d, J = 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 174.68, 149.43, 140.95,
135.05, 134.38, 133.98, 133.02, 132.38, 128.14, 128.00,
124.22, 52.16, 45.13, 18.51; IR (Neat) νmax 2982.71,
1738.60, 1732.74 cm-1; MS: m/z 320 (M + H)+.
4.29.4. Methyl 2-{2'-nitro-[1,1'-biphenyl]-4yl}propionate
(45d).
Yield: 1.25 g (71%), pale yellow solid, mp 86.8–89.3
1
°C: H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 8.1 Hz,
1H), 7.60 (t, J = 7.5 Hz, 1H), 7.50-7.41 (m, 2H), 7.37 (d, J
= 7.8 Hz, 2H ), 7.29 (d, J = 8.4 Hz, 2H ), 3.78 (q, J = 7.0
13
Hz, 1H), 3.69 (s, 3H), 1.54 (d, J = 6.9 Hz, 3H); C NMR

21
(75 MHz, CDCl3) δ 174.90, 140.66,
A
13
C
6.
C
29
E
,
P
1
T
36
E
.0
D
5, MA
M
N
H
U
z,
S
C
C
D
R
ClI3P
) δ 8.51 (d, J = 8.1 Hz, 1H), 8.16 (br s,
T
132.39, 132.09, 128.31, 127.98, 126.19, 124.19, 52.27,
45.26, 18.66; IR (Neat) νmax 2981.59, 1735.85, 1527.98
cm-1; MS: m/z 286.1 (M + H)+.
1H), 7.39 (s, 1H), 7.32-7.30 (m, 2H), 7.23-7.18 (m, 2H),
3.91 (q, J = 7.0 Hz, 1H), 3.67 (s, 3H), 1.60 (d, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 175.38, 140.82,
139.83, 139.02, 128.59, 126.08, 123.18, 121.47, 120.50,
120.23, 119.66, 109.08, 108.95, 52.17, 45.80, 18.94; IR
(KBr) νmax 3354.09, 1719.23 cm-1; MS: m/z 288 (M + H)+.
4.30. General procedure for the preparation of carbazole
esters 46a-d
To a stirred solution of compound 45 (2-nitrobiphenyl
derivative) (0.01 mol) in o-dichlorobenzene (50 mL) was
added triphenylphosphine (0.025 mol) under nitrogen
atmosphere at room temperature, and the reaction mixture
was refluxed for 6–10 h. The solvent was evaporated under
reduced pressure at 75 °C, and the residue was purified by
column chromatography (silica gel, hexane-ethyl acetate,
8.5:1.5).
4.30.3. Methyl 2-(7-chloro-9H-carbazol-2-yl)propionate
(46c).
Yield: 2.52 g (88%), off-white solid, mp 123.1–127.7
°C; HPLC (239 nm), tR 21.88 min, 97.09%: 1H NMR (300
MHz, CDCl3) δ 8.05 (br s, 1H), 7.97-7.91 (m, 2H), 7.40 (d,
J = 8.7 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 3.89 (q, J = 7.05
13
Hz, 1H), 3.67 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H); C NMR
4.30.1. Methyl 2-(6-chloro-9H-carbazol-2-yl)propionate
(46a).
(100 MHz, CDCl3) δ 175.28, 140.24, 140.01, 138.86,
131.38, 121.95, 121.76, 121.06, 120.41, 120.11, 119.78,
110.68, 109.51, 52.17, 45.79, 19.01; IR (KBr) νmax
3402.56, 1735.87 cm-1; MS: m/z 287.9 (M + H)+.
Yield: 2.55 g (89%), pale yellow solid, mp 97.5–99.2
1
°C; HPLC (239 nm) tR 21.74 min, 96.20%: H NMR (300
MHz, CDCl3) δ 8.11 (br s, 1H), 7.97 (s, 1H), 7.95 (d, J =
8.1 Hz, 1H), 7.35-7.28 (m, 3H), 7.18 (d, J = 8.1 Hz 1H),
3.89 (q, J = 7.1 Hz, 1H), 3.68 (s, 3H), 1.59 (d, J = 6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 174.36, 139.32,
138.13, 137.03, 124.76, 123.86, 123.22, 120.60, 119.57,
118.89, 118.56, 110.53, 108.50, 51.13, 44.78, 17.91; IR
(KBr) νmax 3410.62, 1732.94 cm-1.
4.30.4. Methyl 2-(9H-carbazol-2-yl)propionate (46d).
Yield: 2.3 g (81%), white solid, mp 61.7–64.5 °C;
1
HPLC (235 nm), tR 13.99 min, 96.72%: H NMR (300
MHz, CDCl3) δ 8.05-7.99 (m, 3H), 7.41-7.38 (m, 3H),
7.22-7.16 (m, 2H), 3.90 (q, J = 6.8 Hz, 1H), 3.67 (s, 3H),
1.60 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
175.51, 139.85, 138.46, 125.77, 123.11, 122.51, 120.44,
120.26, 119.47, 119.22, 110.65, 109.38, 52.14, 46.89,
19.04; IR (KBr) νmax 3404.28, 1735.26 cm-1; MS: m/z
254.1 (M + H)+.
4.30.2. Methyl 2-(5-chloro-9H-carbazol-2-yl)propionate
(46b).
Yield: 2.2 g (77%), off-white solid, mp 112.4–113.7 °C;
1
HPLC (239 nm), tR 21.88 min, 97.03%: H NMR (300

22
4.31. General procedure for the preparation of carbazole
acids 14a-d
ACCEPTED MA
M
N
H
U
z,
S
D
C
M
R
SOIP-d
T
6) δ 12.30 (br s, 1H), 11.56 (s, 1H), 8.34
(d, J = 8.4 Hz, 1H), 7.47-7.38 (m, 2H), 7.36 (t, J = 8.0 Hz,
1H), 7.19–7.15 (m, 2H), 3.86 (q, J = 7.0 Hz, 1H), 1.46 (d, J
To the sodium hydroxide solution (50 mL, 0.02 mol
sodium hydroxide) was added carbazole ester 46 (0.01
mol), and the reaction mixture was refluxed for 4 h. Upon
complete consumption of the ester starting material, the
reaction was cooled to room temperature, and acidified by
6 N HCl (4 mL). The reaction mixture was extracted with
methyl t-butyl ether (2 x 20 mL), and the combined
organic layer was dried over sodium sulfate, and
concentrated under vacuum. The product was purified by
column chromatography (silica gel, hexane-ethyl acetate,
7:3).
13
= 7.2 Hz, 3H); C NMR (100 MHz, DMSO-d6) δ 175.97,
141.60, 140.56, 140.18, 127.34, 126.56, 122.41, 120.30,
119.62, 119.47, 119.35, 110.33, 110.19, 45.55, 19.40; IR
(KBr) νmax 3408.70, 1703.19 cm-1; MS: m/z 272.1 (M - H)-
; HRMS (M + H)+ calcd for C15H13ClNO2 274.0635, found
274.0658.
4.31.3. 2-(7-Chloro-9H-carbazol-2-yl)propanoic acid
(14c).
Yield: 2.53 g (95%), white solid, mp 252.7–256.2 °C;
1
HPLC (239 nm), tR 11.79 min, 98.31%: H NMR (300
4.31.1. 2-(6-Chloro-9H-carbazol-2-yl)propanoic acid
(carprofen) (14a).
MHz, DMSO-d6) δ 12.31 (s, 1H), 11.36 (s, 1H), 8.10-8.03
(m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.17-7.10 (m, 2H), 3.83
(q, J = 6.6 Hz, 1H), 1.44 (d, J = 6.9 Hz, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 176.00, 140.99, 140.80, 139.88,
130.16, 121.87, 121.66, 121.12, 120.71, 119.37, 119.18,
111.05, 110.31, 45.57, 19.43; IR (KBr) νmax 3411.21,
1698.11 cm-1; MS: m/z 272.1 (M - H)- ; HRMS (M+H)+
calcd for C15H13ClNO2 274.0629, found 274.0641.
Yield: 2.34 g (88%), off-white solid, mp 186.3–189.5 °C;
1
HPLC (239 nm), tR 11.21 min, 99.29%: H NMR (300
MHz, DMSO-d6) δ 12.34 (br s, 1H), 11.39 (s, 1H), 8.17 (s,
1H), 8.10 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H),
7.40-7.34 (m, 2H), 7.11 (d, J = 7.8 Hz, 1H), 3.84 (q, J =
6.9 Hz, 1H), 1.44 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 174.62, 139.65, 138.85, 137.43, 124.17,
122.69, 121.95, 119.70, 119.51, 118.73, 117.83, 111.43,
108.89, 44.21, 18.05; IR (KBr) νmax 3425.24, 1696.92 cm-
1; MS: m/z 272.1 (M - H)-.
4.31.4. 2-(9H-carbazol-2-yl)propanoic acid (14d).
Yield: 2.27 g (86%), white solid, mp 238.4–242.7 °C;
HPLC (239 nm), tR 7.34 min, 99.53%: 1H NMR (400 MHz,
DMSO-d6) δ 12.24 (br s, 1H), 11.16 (s, 1H), 8.07 (d, J =
7.6 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz,
1H), 7.38-7.33 (m, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.09 (d, J
= 8.4 Hz, 1H), 3.82 (q, J = 7.2 Hz, 1H), 1.44 (d, J = 7.2
4.31.2. 2-(5-Chloro-9H-carbazol-2-yl)propanoic acid
(14b).
Yield: 2.28 g (86%), off-white solid, mp 179.5–182.5 °C;
1
HPLC (239 nm), tR 11.93 min, 98.38%: H NMR (400

23
Hz, 3H); 13C NMR (100 MHz, DMSO
A
-d6
C
)
C
δ
EP
1
TED
2, MANUSCRIPT
76
.1
Kirby, G.W., Ed.; Springer-Verlag, Wien
1977;34:299–371.
140.39, 139.32, 125.79, 122.70, 121.70, 120.52, 120.49,
118.98, 118.75, 111.34, 109.99, 45.58, 19.49; IR (KBr)
νmax 3413.46, 1697.91 cm-1; MS: m/z 238.1 (M - H)- ;
HRMS (M + Na)+ calcd for C15H13NNaO2 262.0844, found
262.0860.
5. Husson, H.-P. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York 1985;26:1–51.
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7. Chakraborty, D.P.; Roy, S. In Progress in the
Chemistry of Organic Natural Products; Herz, W.
Kirby, G.W.; Steglich, W.; Tamm, C., Ed.; Springer-
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Supporting Information
Full experimental details, 1H and 13C NMR spectra, HRMS
and HPLC traces can be found via the “Supplementary
Content” section of this article’s Webpage.
Acknowledgments
8. Chakraborty, D.P. In The Alkaloids; Cordell, G.A.,
Ed.; Academic Press, New York 1993;44:257–364.
9. Knolker H-J, Reddy KR. Chem. Rev. 2002;102:4303–
4427.
The authors are grateful to Suven Life Sciences
management for allowing us to publish these results.
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