Palladium-catalyzed arylation of 2H-chromene: A new entry to pyrano[2,3-c]carbazoles

Article abstract of DOI:10.1039/c5ob01295c

Pyrano[2,3-c]carbazoles which are biologically valuable and synthetically challenging frameworks are synthesized in high yields over five steps from commercially available resorcinol. Palladium-catalyzed arylation remains a key step in this novel strategy. The versatility of this protocol has been demonstrated by the synthesis of naturally occurring alkaloid clauraila C and 7-methoxyglycomaurin. The anti-proliferative activity of these designed compounds (5a, 5f, and 5l) has been evaluated in a cancer cell line (MOLT-4). The molecular docking study revealed that this pyrano[2,3-c]carbazole class of molecules selectively occupies the colchicine binding site of the tubulin-polymer.

Full text of DOI:10.1039/c5ob01295c

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PAPER
Palladium-catalyzed arylation of 2H-chromene: a new
entry to pyrano[2,3-c]carbazoles
Cite this: DOI: 10.1039/x0xx00000x
K. Ranjith Reddy,a,b A. Siva Reddy,a,b Devendra K Dhaked,c Sk. Rasheed,a,b Anup Singh Pathania,d
Ravi Shankar,a,b Fayaz Malik,d and Parthasarathi Dasa,b,
*
Received 00th 2015
Accepted 00th 2015
Pyrano[2,3ꢀc]carbazoles which are biologically valuable and synthetically challenging frameworks are
synthesized in high yields over five steps from commercially available resorcinol. Palladiumꢀcatalyzed
arylation remain a key step in this novel strategy. Versatility of this protocol has been demonstrated by
the synthesis of naturally occurring alkaloid clauraila C and 7ꢀmethoxyglycomaurin. The antiꢀ
proliferative activity of these designed compounds (5a, 5f, 5l) has been evaluated in cancer cell line
(MOLTꢀ4). Molecular docking study reaveled that these pyrano[2,3ꢀc]carbazole class of molecules
selectively occupy the colchicine binding site of the tubulinꢀpolymer.
DOI: 10.1039/x0xx00000x
www.rsc.org/obc
In view of natural abundance and biological importance synthesis of
pyrano[2,3ꢀc]carbazoles are of great value. Kerr et al reported an
elegant procedure to access pyrano[2,3ꢀc]carbazole eustifoline A
Introduction
Heterocycles annulated carbazoles exhibit wide variety of
interesting medicinal properties (e.g. antiꢀcancer, antiꢀ
inflammatory, antiꢀmalarial etc.) which has led to the development
of various synthetic routes to those important class of
molecules.1,2Among these, pyranocarbazoles formed a prominent
group due to their occurance in various plants and for their
intriguing structural features (Fig.1). Furthermore, pyranocarbazole
derivatives have also used in the field of medicinal chemistry as a
pharmacophore for different therapeutic indications.3 Glycomaurin
the first pyrano[2,3ꢀc]carbazole alkaloid was isolated from the
dichloromethane extract of the stem bark of Glycosmis
mauritiana.4a 7ꢀmethoxyglycomaurin was isolated from the bark of
Glycosmis rupestris.4c Chakravarty et al. reported the isolation of
glycoborinine from the root of Glycosmis arborea.4b Eustifoline A
and eustifoline B are isolated from the root bark of Murraya
euchrestifolia.4d Recently, clauraila C, clauraila D were isolated
from Clausena harmandiana (Rutaceae).4e
along with other pyrano carbazoles, in a multiꢀstep sequence.5
Knölker et al. recently reported the synthesis of eustifoline A and
eustifoline B.2k Thus a general method to accessing these molecules
with diverse substitution pattern is highly desirable. The Suzukiꢀ
Miyaura crossꢀcoupling reaction is frequently used in the
construction of functional biaryl architectures, used in medicinal,
agriculture and material chemistry.6 Development of new
electrophiles particularly C−Oꢀbased electrophiles as crossꢀcoupling
partner in SuzukiꢀMiyaura coupling reaction has attracted interest
from various research groups.7 The use of the phenolꢀderived
sulfonated hydroxyl group as pseudoꢀhalide electrophiles is indeed
highly attractive.8 Further, 2, 2ꢀdimethylꢀ2Hꢀchromenes are found
in biologically active natural products9 and medicinally important
compounds.10 Therefore,
a modular straightforward approach
allowing for the synthesis of arylated 2, 2ꢀdimethylꢀ2Hꢀchromenes
may be of great interest in organic synthesis.
Thus to prepare pyrano[2,3ꢀc]carbazoles bearing diverse
substituent’s, we envisaged a twoꢀstep transformation involving an
initial Pdꢀcatalyzed SuzukiꢀMiyaura coupling of nitro substituted 2,
2ꢀdimethylꢀ2Hꢀchromenes, followed by Cadogan cyclization, as
depicted retro synthetically in Scheme 1.
O
O
O
O
H
MeOOC
HO
N
H
N
H
N
H
Glycomaurin
(Eustifoline A)
Clauraila D
Clauraila C
O
O
O
TfO
Suzuki-coupling
O2N
Cadogan-
cyclization
Me
MeO
O
N
O2N
O
Me
HO
O
H
Pyrano[2,3-c]carbazole
N
H
OH
N
H
N
H
OH
HO
O
HO
HO
Glycoborinine
7-Methoxyglycomaurin
Eustifoline B
O2N
O2N
Resorcinol
Fig. 1
Naturally occurring pyrano[2,3-c]carbazoles
This journal is © The Royal Society of Chemistry 2014
Scheme 1
Retro synthetic approach for pyrano[2,3-c]carbazole
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DOI: 10.1039/C5OB01295C
on the reaction of 3 with disubstituted boronic acid and found that
the arylated products (4p-q) were isolated in excellent yield (82ꢀ
85%). Two bicyclic boronic acids were also investigated, in the case
of 2ꢀnaphthylboronic acid the yield is 88% (4r) whereas
benzo[d][1,3]dioxolꢀ5ꢀylboronic acid (4s) resulted in 83% yield. To
enhance the generality of the reaction conditions different
heterocyclic boronic acids were subjected to crossꢀcoupling reaction
with 3. To our delight the optimized conditions worked well for the
theonyl, furyl and pyridylboronic acids and the resulted heteroaryl
coupling products (4t-4v) in excellent yields (77ꢀ83%). In this
context heterobicyclic boronic acids have also been investigated in
case of indoloboronic acid the yield is 80% (4w), whereas
benzothiopheneboronic acid resulted the desired arylated product
(4x) in 82% yield.
Results and discussion
Our experimental process commenced with nitration of
commercially available resorcinol. Resorcinol was subjected to
nitration to synthesize 4ꢀnitroresorcinol (1
) in 56% yield.10a
Next, we planned to make propargyl ether of nitroresorcinol
with 3ꢀchloroꢀ3ꢀmethylbutꢀ1ꢀyne (1.5 equiv.), KI (1.7 equiv.),
K2CO3 (2 equiv.), CuI (10 mol%) in DMF at 65 C, but to our
o
astonishment, we got pyran annulated product (2). This
reaction protocol was performed under milder coditions
compare to previous reports11aꢀb and the pyran annulated
product was isolated in excellent yield (93%). Interestingly,
formation of other regioisomer of nitrochromene
observed. In this stepeconomical process the nitrochromene
derivative ( ) could be obtained by the initial formation of
propargyl ether of 4ꢀnitroresorcinol ( ) followed by Claisen
rearrangement mediated pyran annulation.2
2 was not
2
Table 1 Suzuki-Miyaura cross coupling of arylboronic acids with 2H-chromenea
1
d,g,h
Ar
(HO)2
B
Ar
Although the
O
TfO
O
Pd(PPh3
1,4-dioxane, 80 o
3 h
)4/K3PO4
origin of regioselectivity is not clear but we assumed that the
presence of nitro group could influence the selectivity.12
O2
N
O2N
C
4a-x
3
R
R
Subsequently, 2,2ꢀdimethylꢀ6ꢀnitroꢀ2
treated with triflic anhydride/pyridine to afford the OꢀTf 2
chromene (
) in almost quantitative yield (96%) (Scheme 2).13
Thus structurally designed OꢀTf nitrochromene ( ) became
Hꢀchromenꢀ5ꢀol (2) was
R
R
O
O
H
ꢀ
O
O
3
O2
N
O2
N
O2
N
O2N
4l, R= Cl, 84%
4m,R= CF3, 80%
4n
, R= CHO, 86%,
4a
, R= H, 80%
4b, R= Me, 84%
4c, R= OMe, 82%,
4d, R= propyl, 86%
4e, R= isopropyl, 87%
4f, R= n-butyl, 88%
4i, R= 4-F, 77%
3
4g
, R= Me, 90%
R= OMe, 88%
4j
, R= 4-CN, 83%
4h,
4k
, R=4-Ac,79%
true coupling partner for SuzukiꢀMiyaura reaction, where the
nitro group present ortho to OTf group, thus making a perfect
substrate for the synthesis of pyrano[2,3ꢀc]carbazoles.
4o, R= COOMe,85%
O
R1
O
R2
O
O
O2
O
O
O
Cl
N
O2
N
O2
N
O2
N
4t, 77%
OH
O
(1.5 equiv.)
4p, R1=R2=OMe. 85%
HO
4s,
83%
O
HO
OH
HO
4r
, 88%
HNO3
4q,
R1=Me,R2=OMe,82%
KI(1.7 equiv.)
K2CO3 (2 equiv.)
CuI (10 mol%)
DMF, 3h, 65 o
93%
CHCl3 / AcOH
1h, rt, 56%
O2N
O2N
N
1
Resorcinol
2,2-dimethyl-6-nitro-2H-
chromen-5-ol (2)
O
O
O
N
S
S
H
C
(only product)
O2N
O2
N
O2
N
O2
N
4x,
82%
4v
, 79%
4w, 80%
4u, 83%
O
a Reaction conditions: 3 (1.0 equiv.), boronic acid (1.2 equiv.), Pd(PPh3)4 (10 mol%), K3PO4 (1.6 equiv.),
1,4ꢀdioxane (0.2M), 80 oC, 3h.
TfO
Tf2
O
Py/DCM,
6h, 0 oC-rt
96%
O2N
3
With this nitro chromeneꢀ2H derivatives (4a-x) in hand we
performed Cadogan reaction on these substrates to synthesize the
pyrano[2,3ꢀc]carbazoles.14 We choose PPh3 as a suitable reagent
due to its low cost and ease of handling. As Cadogan reaction
usually requires high boiling point solvents thus we carried out the
cyclization of 4a by using different solvents e. g. DMF, DMAc, Oꢀ
DCB in presence of PPh3 (3.0 equiv.) at 150 oC. And it was
observed that in DMAc gave the best yield (79%), as DMF was
quite inferior (65%) where as OꢀDCB also afforded good yield
(73%). With optimized conditions in hand we focused on the
synthesis various pyrano[2,3ꢀc]carbazoles (Table 2). Phenyl ring
substituted with various electronꢀdonating such as Me, OMe,
isopropyl, nꢀbutyl, propyl (4b-c, 4h, 4d-f) works well under this
Cadoganꢀcyclization conditions and afforded the corresponding
pyranoꢀcarbazoles (5b-g) in good yields (60ꢀ82%). In this context
disubstituted phenyl derivatives (4p-4q) were also tested the
dimethoxy pyrano deriavtive resulted the pyranoꢀcarbazole (5h),
where as methyl and methoxy derivatives gave a seperable mixture
of compounds (5ia : 5ib; 42: 30 ratio). Carbazole 5ia was identified
Scheme 2 Synthesis of 2,2-dimethyl-6-nitro-2H-chromen-5-ol
In order to find an optimized conditions for crossꢀcoupling of
arylboronic acid with nitro 2Hꢀchromene 3 different Pdꢀsource and
various bases were tested in different solvent system. In view of
efficiency and simplicity we have identified Pd(PPh3)4/ K3PO4/
o
dioxane/ 80 C as our optimized conditions for the crossꢀcoupling
reaction (for details see supporting information).
With optimized conditions in hand we focused on the scope of this
method with various arylboronic acids (Table 1). The
arylated/heteroaylated 2Hꢀchromene derivatives (4a-x) were
isolated in excellent yields (77ꢀ90%). Phenylboronic acids
substituted at paraꢀ and metaꢀposition both electronꢀdonating (e. g.
4b-f and 4g-h) and electronꢀwithdrawing groups (e.g. 4i-k and 4l-o)
gave the desired arylated product in excellent yields. These results
clearly demonstrate that this method tolerates both the electronꢀ
donating and electronꢀwithdrawing groups. It is noteworthy that
functional group like formyl (4n) and carboxylate (4o) both are well
tolerated under these crossꢀcoupling conditions. Then we focused
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as naturally occurring 7ꢀmethoxyglycomaurin.4c In further
investigation, we observed electronꢀwithdrawing groups like Ac,
CN, COOMe also undergoes smooth Cadoganꢀcyclization in giving
pyranoꢀcarbazoles (5j-5l) in good yields (69ꢀ80%). Compound 5l is
known as naturally occurring carbazole clauraila C4e and to the best
of our knowledge this is the first total synthesis of clauraila C. Two
novel pentacyclic carbazoles ( 5m and 5n) were also synthesized
under these conditions in good yields (65ꢀ78%).
hydrogen bonding interactions between Serα178 –OH and
ꢀ
COOMe group (Fig. 2B). Other residues which were present within
4Å distance from the ligand included Glnα11, Thrα179, Alaα180,
Valα181, Cysβ241, Glnβ247, Asnβ249, Alaβ250, Lysβ254,
Leuβ255, Asnβ258, Metβ259, Alaβ316, Lysβ352, Thrβ353 and
Alaβ354.
Table 2 Cadogan reaction and synthesis of pyrano[2,3-c] carbazolesa
O
O
Ar
PPh3 (3.0 equiv.)
Ar
DMAc, 150 o
24 h
C
N
H
O2N
5a-n
4
O
O
O
O
Me
MeO
N
H
N
H
N
H
N
H
MeO
5c, 77%
5b, 82%
5d, 60%
5a, 79%
O
O
O
Me
Fig. 2. Molecular recognition interaction of A) Superimposition of
podophyllotoxin (yellow carbons) with 5l (magenta carbons) and B)
Compound 5l in the colchicine binding site of α,βꢀtubulin dimer. The αꢀ
subunit of tubulin is in green color and βꢀsubunit of tubulin is in cyan color.
Black dashed lines indicate the hydrogen bonding interactions.
Me
Me
Me
N
H
N
H
N
H
5g, 74%
5f, 80%
5e, 80%
O
O
Me
MeO
O
Me
MeO
MeO
O
C
MeO
N
H
Conclusion
O
N
H
Me
N
H
N
H
5j, 69%
5ia,42%
5ib, 30%
5h, 83%
(7-Methoxy glycomaurin)
Synthetically challenging pyrano[2,3ꢀc]carbazole are accessed
from commercially available resorcinol via SuzukiꢀMiyaura
crossꢀcoupling as one of the key step in this synthetic
sequence.Various structurally diverse pyrano[2,3ꢀc]carbazoles
are synthesized along with naturally occurring clauraila C and
7ꢀmethoxyglycomaurin. Preliminary biological data and
molecular docking suggested that these designed pyranoꢀfused
carbazoles exhibit moderate antiꢀcancer activities. The
molecular modeling study revealed that these heterocyclic
molecules bind selectively in the colchicine binding site of
tubulin polymer. These initial studies will definitely help in
identifying the lead molecules with antiꢀcancer properties and
these studies are currently underway in our laboratory.
O
O
O
O
MeO2C
O
N
H
O
C
N
N
N
H
H
N
H
5n, 78%
5l, 80%
5m, 65%
(Clauraila-C)
5k,75%
aReaction conditions: 4 (1.0 equiv.), PPh3 (3.0 equiv.), DMAc (0.2 M), 150 o
C
Pyranoꢀcarbazoles are known to exhibit antiꢀcancer activities via
inhibition of tubulin polymerization.3 Thus the antiꢀproliferative
activity of these designed pyrano[2,3ꢀc]carbazoles on lymphoid
leukemia cell line (MOLTꢀ4), was investigated by employing the
MTT assay. Designed compounds like 5a, 5f and 5l exhibited 40%,
46% and 34
% growth inhibition at 30µM concentration
respectively. To understand the nature of interaction of these
carbazoles in the tubulin binding site, molecular docking study was
performed (Fig. 2). The naturally occurring carbazole clauraila C
(5l) was docked into a cavity at the interface of α,βꢀtubulin dimer.15
Molecular docking studies demonstrated that both the pyrano[2, 3ꢀ
c]carbazole (5l) selectively occupy the colchicine binding site of the
tubulin polymer. Clauraila C (5l) was found to fit comfortably in the
colchicineꢀbinding domain with comparable molecular docking
pose and scores to the reference ligand podophyllotoxin (Glide
gscore podophylotoxin ꢀ6.913; clauraila C ꢀ6.359).16 The interaction
domain for 5l is highly overlapping with the reference ligand
podophyllotoxin (Fig. 2A). The docked molecule (5l) showed
strong hydrogen bonding interactions with the O of Asnβ258
Experimental
General information
All the purchased chemicals were used without further purification.
Thin layer chromatography (TLC) was performed using preꢀcoated
silica gel 60 F254 MERCK. TLC plates were visualized by
exposing UV light or by iodine vapors. Organic solutions were
concentrated by rotary evaporation on BUCHIꢀSwitzerland; Rꢀ120
rotary evaporator and vacuum pump Vꢀ710. Flash column
chromatography was performed on Merck flash silica gel 230ꢀ400
mesh size. Melting points of solid compounds were determined on
BUCHIꢀBꢀ545ꢀSwitzerland melting point apparatus. 1H and 13C
through (NH....O, distance ~2.5ꢀ3.0Å). Compound 5l also exhibited
NMR spectra were recorded with Bruker 500 and 400 MHz NMR
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