Synthesis of furan-fused 1,4-dihydrocarbazoles via an unusual Garratt-Braverman Cyclization of indolyl propargyl ethers and their antifungal activity

Article abstract of DOI:10.1016/j.tet.2018.05.001

The reactivity of indole based bis-propargyl ethers 4a-4g under Garratt-Braverman condition (KOBu^t in refluxing toluene) has been studied. Interestingly, these propargyl systems with one arm attached with substituted 3-indolyl derivatives leavi

Full text of DOI:10.1016/j.tet.2018.05.001

Accepted Manuscript
Synthesis of furan-fused 1,4-dihydrocarbazoles via an unusual Garratt-Braverman
Cyclization of indolyl propargyl ethers and their antifungal activity
Arundhoti Mandal, Santi M. Mandal, Saibal Jana, Subhendu Sekhar Bag, Amit K.
Das, Amit Basak
PII:
S0040-4020(18)30509-X
10.1016/j.tet.2018.05.001
TET 29508
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 March 2018
Revised Date: 25 April 2018
Accepted Date: 1 May 2018
Please cite this article as: Mandal A, Mandal SM, Jana S, Bag SS, Das AK, Basak A, Synthesis of furan-
fused 1,4-dihydrocarbazoles via an unusual Garratt-Braverman Cyclization of indolyl propargyl ethers
and their antifungal activity, Tetrahedron (2018), doi: 10.1016/j.tet.2018.05.001.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
O
O
N
O
N
O
N
N
R
N
R
R
O
O
O
5a, 5d
10
12
4a-g
i
i
i
i
O
O
O
O
O
O
+
+
N
N
R
R
N
N
N
R
R
N
O
R
N
N
O
O
O
R
O
O
6
a-g
7a-g
9-15%
8
a, 8d
Not obtained
9a, 9d
81-84%
11
13
7
0-82%
t
i) KO Bu, Toluene, reflux

ACCEPTED MANUSCRIPT
Synthesis of Furan-fused 1,4-Dihydrocarbazoles via an
Unusual Garratt-Braverman Cyclization of Indolyl
Propargyl Ethers and Their Antifungal Activity
a+
b
a
c
d
a+
Arundhoti Mandal,* Santi M. Mandal, Saibal Jana, Subhendu Sekhar Bag, Amit K. Das and Amit Basak*
a
b
Department of Chemistry, Indian Institute of Technology Kharagpur, 721 302, India, Central Research Facility,
c
Indian Institute of Technology Kharagpur, 721 302, India, Department of Chemistry, Indian Institute of Technology
Guwahati, 781039, India, Department of Biotechnology, Indian Institute of Technology Kharagpur, 721 302, India
d
*
Corresponding authors
+
arundhoti@chem.iitkgp.ernet.in; absk@chem.iitkgp.ernet.in
Abstract
t
The reactivity of indole based bis-propargyl ethers 4a-4g under Garratt-Braverman condition (KOBu in
refluxing toluene) has been studied. Interestingly, these propargyl systems with one arm attached with
substituted 3-indolyl derivatives leaving the other arm unsubstituted produced the 3,4-furan fused
dihydrocarbazole derivatives 6a-6g (and not the expected carbazole derivatives) as the predominant product
(
70-82%) making this methodology to access such derivatives an attractive route. The results are supported
by computational studies and some of the carbazole derivatives showed good antifungal activities.
Keywords: Bispropargyl ethers, Garratt-Braverman Cyclization, Dihydrocarbazole, Benzophthalan,
Antifungal
Introduction
1
Garratt-Braverman Cyclization of bis-propargyl ethers has recently drawn interest primarily due to two
2
reasons. First of all, it involves formation of 2 C-C bonds in a single reaction and secondly, its interesting
3
reaction mechanism which involves a cascade of reactions. There has been a lingering controversy
1

ACCEPTED MANUSCRIPT
4
,5
regarding the intramolecular [4+2] Diels Alder (DA) cycloaddition vis-à-vis a diradical mechanism. The
DA pathway involves a monoallene while the diradical pathway requires the involvement of a bis-allene.
6
7
Recent computational and experimental studies seem to indicate that for the rearrangement of ethers in
presence of strong bases like NaH/DMSO (dimsal anion is the actual base), the monoallenide anion is
formed which readily undergoes an anionic [4+2] cycloaddition ultimately leading to the product, a
dihydrofuran-benzenoid system. The anionic nature reduces the gap between the HOMO-LUMO which
makes the cycloaddition very facile as compared to further isomerization to the bis-allene (Scheme 1). The
5
driving force for the reaction is the creation of a new benzene ring. An alternate diradical mechanism, which
is operative in case of the corresponding sulfones (with highly acidic propargylic hydrogens), is usually not
followed by the ethereal system. Apart from the mechanism (cycloaddition vs diradical), other major
difference between the two pathways is the involvement of an aromatic furanoid system in the diradical
pathway which then isomerizes to the more stable benzenoid derivative (vide infra). We intended to stop the
reaction at the furan stage in order to have an access to the furan fused 1,4-dihydrobenzenoid system. To
force the ether to follow a bis-allene route and hence a diradical pathway, one needs to adopt a two prong
a
strategy: i) to reduce the pK differences between the propargylic hydrogens and ii) to suppress the mono-
allenide anion formation by employing a weaker base, which in turn, should lead to the bis-allene.
C
O
O
C
R
slow
O
III
R
O
I
C
R
V
Dihydrofuran fused benzenoid system
R
II
fast
O
R IV
Scheme 1: Mechanism of NaH/DMSO mediated GB cyclization of bis-propargyl ether
2

ACCEPTED MANUSCRIPT
With this aim, we have prepared a series of bis-propargyl ethers as represented by A where one arm of the
terminal alkyne was substituted with an 3-indolyl moiety while the other arm was left unsubstituted as a
terminal alkyne. Our expectation was that unlike the benzenoid counterparts, the electron donating indole
moiety will make the propargylic hydrogens attached to it less acidic and may bridge the gap in acidity
between such hydrogens in the two arms. Thus the reaction is expected to follow a diradical pathway via the
bis-allene.
In the diradical mechanism, after intramolecular quenching of the diradical, one ends up with intermediate E
(
Scheme 2). The latter can lead to normal GB product, the dihydrofuran fused carbazole P (may also be
referred as indole fused phthalan), involving the following possible routes: Route 1, a 1,3-H shift followed
a
by another 1,3-shift of H along with a 1,3-H shift; Route 2, a 1,5-H shift followed by a 1,3-H shift; Route
a
b
a
b
3
, a 1,3-H shift followed by a 1,5-H shift, and finally in Route 4, a 1,3-H shift followed by two successive
b
a
b
1
,3-H shifts.
a
O
O
O
O
C
C
C
N
X
N
N
N
R
R
R
R
R
R
R
R
D
C
A
B
Ha
O
Route 2
1,5] H Shift
[
a
b
[1,3] H Shift
N
H
b
R
G
Ha
O
Ha
O
O
H
b
Route 1
[1,3] H Shift
[1,3] H
[1,3] H
Shift
Shift
a
N
Ha
H
b
N
a
N
Hb
b
R
R
E
R
P
F
[
1,3] H
b
Shift
Ha
O
O
Route 4
1,3] H Shift
H
b
H
b
[
a
N
a
[1,3] H Shift
R
N
Ha
I
Route 3
1,5] H Shift
R
H
[
b
Scheme 2: Possible routes to product formation by H-shifts
3

ACCEPTED MANUSCRIPT
Amongst all these probable routes, the one which the reaction will follow possibly depends on the relative
pk ’s of H and H at different locations. The migration terminus is expected to depend upon the stability of
a
a
b
the resulting intermediate/product. One interesting aspect of these possible pathways is the generation of
8
several intermediates like E to I which are interesting frameworks both from synthetic as well as biological
9
point of view. It would be nice if the reaction can be stopped at any one of the intermediate steps to get
access to these intermediates. Gratifyingly,using these indole propargyl systems, we have been able to isolate
intermediate F, namely the furan-fused dihydrocarbazole derivatives (may also be referred as indole fused
1
0
4
,7-dihydroisobenzofuran) as stable products and in high yields along with minor amounts of normal GB
products, the carbazole derivatives. This was quite an unexpected result considering the aromatic stability of
1
1
a carbazole system which is more than the combined aromaticity of indole and furan. We have done a
thorough study employing various substituted indoles 4a-4g and in the process isolated the corresponding
dihydrocarbazole derivatives as major product along with minor amount of normal GB product in varying
a
ratios. The dependence of the ratio of products nicely fits to our model of differential pK ’s based on the
stability differences of conjugate bases as assessed through computations. Some of the dihydrocarbazole
derivatives were shown to have antifungal activities with minimum inhibitory concentration (MIC) values in
-1
low µg.mL ranges. In this paper we provide a full account of the experimental results along with
computation based explanation of the observed reactivity and bio-activity of the synthesized
dihydrocarbazoles.
1
2
The starting monoindolyl derivatives 4a-4g were prepared from indole or its derivatives 1a-1g. Iodination
followed by N-protection with MOM-Cl afforded the MOM protected 3-iodoindoles 2a-2g. Sonogashira
1
3
coupling with propargyl alcohol produced the indolyl propargyl alcohols 3a-3g which upon O-alkylation
with propargyl bromide furnished the target bis-propargyl ethers 4a=4g. The synthetic strategy is shown in
Scheme 3.
4

ACCEPTED MANUSCRIPT
OH
O
O
i
I
iii
iv
v
7
0-97%
N
H
ii
N
N
N
N
R
70-80%
R
45%
N
7
4-82%
R
O60-70%
R
R
O
O
R
O
O
1a-g
2a-g
3a-g
4a-g
5a-g
o
1
1
1
1
1
1
1
a,R = H
b, R =5-OMe
c,R = 5-Br
d, R =5-Cl
e,R = 5-F
f,R= 7-methyl
g, R =7-ethyl
Reagents and conditions: i) I , KOH, DMF; ii) MOMCl, NaH, 0 C to rt, DMF; iii) propargyl alcohol,
2
o
PdCl (PPh ) CuI, Et N, r.t; iv) NaH, propargyl bromide, THF,0 C tor. t; v)2a/2d, PdCl (PPh )
2
3 2
3
2
3 2
CuI, Et N, r.t.
3
Scheme 3: Synthesis of target indolyl propargyl ethers
t
The ethers 4a-4g were subjected to the GB cyclization condition (treatment with KOBu in refluxing
1
4
toluene). The major product from all these substrates was the dihydrocarbazole derivatives 6a-6g along
with the normal GB products 7a-7g in minor amounts (Scheme 4). The products could be easily separated by
column chromatography over Si-gel. The isolated yields of the dihydrocarbazoles ranged from 70-80% thus
making this methodology an attractive one to access these compounds.
Scheme 4: Reactivity of monoindolyl and bisindolyl bis propargyl ethers
1
5
Very few methods have been reported in literature for the synthesis of such derivatives. In recent years,
1
6
some elegant methods on the synthesis of substituted furan derivatives have been reported based on tandem
Michael addition–annulation to allenes or intermolecular metal catalysed cascade reaction between propargyl
5

ACCEPTED MANUSCRIPT
alcohol and alkyne. These methods are intermolecular and do not lead to any heterofused furan derivatives.
Indoles attached with other protecting groups like methyl (4h) or benzyl (4i) also gave the corresponding 1,4-
dihydrocarbazoles (6h and 6i respectively) as major products. We could not study the reactivity of Boc or
Cbz protected indole derivatives as they proved to be unstable under the reaction conditions. The results of
cyclization are shown in Table 1. As a control experiment, we have also carried out the cyclization of two of
the bis-idolyl propargyl systems 5a and 5d which afforded only the normal GB products; no
dihydrocarbazole derivatives could be isolated in these cases.
Furano [4,7]
dihydrocarbazole
[2,5] Dihydrofurano
carbazole (% yield)
a
Product ratio
Substrates
b
(
dihydrocarbazole:carbazole)
(
% yield)
6a (80)
6b (82)
6c (72)
6d (74)
6e (70)
6f (79.1)
6g (77.8)
6h (82)
6i (83)
8a (0)
R= H, P = MOM (4a)
R= 5-methoxy, P = MOM (4b)
R= 5-Br, P = MOM (4c)
R= 5-Cl P = MOM (4d)
R= 5-F, P = MOM (4e)
R= 7-Methyl, P = MOM (4f)
R= 7-Ethyl, P = MOM (4g)
R= H, P = Me (4h)
7a (10)
7b (7.8)
7c (14.4)
7d (15.2)
7e (13.7)
7f (9.5)
7g (9.3)
7h (9)
8:1
10.3:1
5:1
4.9:1
5.1:1
8.3:1
8.4:1
9.2:1
7:1
R= H, P = CH Ph (4i)
7i (12)
9a (81)
9d (84 )
2
R = H, P = MOM (5a)
R = Cl, P = MOM (5d)
Only 9a
Only 9d
8d (0 )
t
a
t
b
Table 1: Results of GB cyclization with KOBu in refluxing toluene; 2.5 eq. of KO Bu was used; product
1
ratio obtained from H NMR of crude reaction mixture.
1
a-1b
It is pertinent to mention that Garratt et al.
had previously reported the formation of dihydronaphthalene
system from phenyl propargyl ether where one propargyl hand was unsubstituted and also from bis-phenyl
t
propargyl ether by treating with KOBu in THF at a low temperature in much lower yield. Upon raising the
temperature, these compounds rearranged to the naphthalene system. For our indole systems, no reaction
t
happens at low or even at room temperature upon similar treatment with KOBu possibly due to lower acidity
of the propargylic hydrogens as a result of electron donation from indole moiety.. The rearrangement only
6

ACCEPTED MANUSCRIPT
takes place in refluxing toluene giving the dihydrocarbazole derivatives in high yields. We have also studied
the reactivity of a mixed propargyl system with one arm substituted with indole and the other a phenyl or a
THP protected hydroxymethyl or a methyl. In case of the phenyl substituted one, normal GB product was
obtained via exclusive participation of the phenyl ring. The THP protected hydroxymethyl system reacted
1
7
following the 1,5-H shift mode. The methyl substituted one gave the normal GB product. The structures of
all the products were characterized by NMR and mass spectral studies. In the NMR spectra there were some
key differences which could successfully distinguish between the dihydro carbazole 6 and the carbazole
1
derivatives 7. One difference is the chemical shifts of the benzylic methylene protons in the H NMR spectra.
For example, for 6a, these appeared upfield as two separate singlets at
δ 3.95 and 3.92 while for 7a both the
methylenes, being adjacent to ethereal oxygen, appeared much downfield at δ 5.27 as a 4H singlet. Another
1
3
difference is in their C spectra where the benzylic carbons resonated at
a, these appeared downfield at 73.8 and 73.5 (Figure 1). Additionally, one of the dihydro carbazole
derivative 6a could be obtained as a single crystal for which the X-ray structure (ORTEP shown as inset in
δ 18.2 and δ 17.0 for 6a while for
7
δ
δ
1
8
Figure 1) was obtained which also confirmed the assigned structure.
Figure 1: Key differences in NMR spectral features and ORTEP structure of 6a
As mentioned earlier, the pK ’s of the migrating hydrogens are possibly playing a key role in controlling the
a
ratio of the products. To support this assertion, computations were carried out to evaluate the pK ’s of H and
a
a
H in the intermediates E and E’ (Scheme 5) which are the starting points of the prototropic shifts. This was
b
done by comparing the stabilities of the corresponding conjugate bases. In the intermediate E’ which arises
from the bis-indolyl propargyl system, H
b
is expected to be more acidic as it is α to both aromatic indole and
7

ACCEPTED MANUSCRIPT
-1
the furan ring [computations indicated the anion J’ generated after H abstraction is 3.3 kcal mol more
b
stable than the anion K’ formed after H abstraction]. Thus, the H proton will undergo 1,3 shift first which
a
b
will destroy the aromaticity of furan (intermediate H’). To compensate for this loss, the H will undergo a
a
1
,5-shift, which brings back aromaticity to the indole moiety as well as creation of a newly formed benzene
ring thus leading to a carbazole system (F’).
O
[1,3] Hb shift
H
b
N
R
Ha
R
N R
O
O
H'
R
N
R
Ha
[1,5] H
a
shift
N
R
H
b
R
R
N
R
J
Ha
J'
O
R
O
O
Ha
Hb
H
b
abstraction
H
b
N H
R
a
abstraction
H
R
N
Ha
b
N
N
R
R
R
N R
R
R
Hb
H
a
R
E
F'
abstraction
abstraction
R
E'
O
O
H
b
a
[1,3] H shift
N
R
N
R
Ha
R
R
N R
K'
K
R
H
a
O
indicates aromatic character
N
R
Hb
R
F
Scheme 5: Plausible pathways for the formation of furano dihydrocarbazole tetrahydrofurano carbazole from
monoindolyl and bis-indolyl propargyl respectively
On the other hand, for the monoindolyl propargyl system, H is expected to be more acidic and hence it
a
undergoes initial migration. Computations have shown that the stability of the anion J formed after H
a
abstraction is more than the anion K formed after the H abstraction. It prefers to undergo a 1, 3-shift as that
b
will bring back the aromaticity of indole moiety without perturbing the aromaticity of furan. Hence, we
observe F as the major product (Scheme 5). The computational results on the stability of anions formed due
1
9
to abstraction of the H and H in both E and E’ are calculated using Orca 4.0. software package at BP86-
a
b
2
0
D3BJ/def2-SVP level of theory and are shown in Table 2.
8

ACCEPTED MANUSCRIPT
It is also interesting to note that amongst the various intermediates F to I (Scheme 2), the intermediate F has
the highest stability having aromatic indole and furan moieties. This possibly explains why the reaction stops
t
at this stage even after refluxing F with KOBu in toluene for 72 h. Thus the minor GB products have not
originated via F (Route 1). These are generated through other possible routes as shown in Scheme 5.
To support the proposed mechanism, we have also prepared quinoline and isoquinoline propargyl ethers. In
these cases, because of the electron withdrawing nature of the quinoline and isoquinoline system, the
propargylic hydrogens attached to these moieties will be more acidic (mentioned in the computational part)
and hence the reaction will give rise to products via the monoallene. A [4+2]-addition followed by a 1,5
shift of H from intermediates R and T which is expected to be facile as it regains the aromaticity of
a
quinoline or isoquinoline moieties along with creation of a new benzene ring thus leading to a stable
phenathridine moiety (Scheme 6).
more acidic
Diradical
pathway
O
N
O
O
N
O
O
C
4+2
1,5 H shift
Not followed
b
H
H
a
N
H
a
N
N
11
Q'
10
Q
R
Regain of aromaticity of
isoquinoline;
Creation of a new bwnzene ring
O
more acidic
H
b
O
Diradical
pathway
O
O
H
a
O
1,5 H shift
C
H
a
N
N
Not followed
N
N
S'
N
1
2
S
T
13
Regain of aromaticity of oquinoline;
Creation of a new benzene ring
Scheme 6: Possible routes to product formation by H-shifts in quinoline/isoquinoline series
9

ACCEPTED MANUSCRIPT
H
1
H
O
H
2
O
H2
1
H
1
O
H2
H
1
O
H
2
N
N
N
R
N
R
R
N
R
O
R
O
4a-4g
10
11
O
5a, 5d
O
O
O
O
H
b
H
b
H
a
N
Ha
H
b
R
N
Ha
H
b
R
O
H
a
N
N
R
R
N
O
O
E'
S'
Q'
E
c
Substrates
∆E
∆E
Predicted major
Product ratio
miLogP
(
EH2 – E ) (EHb – E )
product based on
computational
calculations
(dihydrocarbazole:
carbazole)
H1
Ha
Bis-indolyl R= H (5a)
propargyl
-3.3
-3.7
Dihydrofurano
carbazole
Only 9a
Only 9d
Only 11
R= 5-Cl (5d)
Dihydrofurano
carbazole
Monoquin R=H (12)
oline
propargyl
12.51
13.43
35.58
Furano
dihydrophenathridine
Monoisoqu R=H (10)
inoline
propargyl
38.96
Furano
dihydrophenanthridi
ne
Only 13
Monoindol R= H (4a)
yl
propargyl R= 5-methoxy
2.97
4.05
5.63
5.42
3.99
2.96
2.92
16.9
20.0
11.2
11.2
11.1
17.2
17.0
Furano
dihydrocarbazole
Furano
dihydrocarbazole
Furano
dihydrocarbazole
Furano
dihydrocarbazole
Furano
dihydrocarbazole
Furano
dihydrocarbazole
Furano
dihydrocarbazole
8.0:1
10.3:1
5.0:1
4.9:1
5.1:1
8.3:1
8.4:1
3.40
3.43
4.18
4.05
2.57
3.80
4.27
(
4b)
R= 5-Br (4c)
R= 5-Cl (4d)
R= 5-F (4e)
R= 7-Methyl
(
4f)
R=
4g)
7-Ethyl
(
c
*
miLogP of terbinafine 5.72; calaculated using available software from molinspiration
Table 2: The energy difference between two isomeric anions (ꢀE = E(anion due to abstraction of Hb) - E(anion due to
abstraction of Ha), positive values of ꢀE indicate H is more acidic as the conjugate base is more stable whereas,
a
1
0

ACCEPTED MANUSCRIPT
negative value indicates H is more acidic) and the major product prediction based on the computational
b
calculations for bis-indolyl and monoindolyl propargyl systems
9
a
Encouraged by the report of antifungal activity of dihydrocarbazole derivatives, we went ahead to check if
these dihydrocarbazoles possess such activity. The antifungal activity of the synthesized compounds was
tested against four fungal strains, Candida albicans, Candida tropicalis, Aspergillus fumigatus, Fusarium
2
1
solani. Medium used and culture condition for fungal growth was described earlier by Sengupta et al. The
minimum inhibitory concentration (MIC) (Table 3) of all the compounds against the fungal pathogens were
2
2
assessed using micro dilution plate method in a 96-well micro test plate following CLSI, 2012. As shown
in Table 3, the compounds 6e and 6f with methyl and fluoro substituents respectively, possess good
antifungal activities against the pathogens, in particular, the Candida species, quite comparable to the
commonly used fluconazole.
Compound (s)
Candida
albicans
Candida
tropicalis
Aspergillus
fumigatus
Fusarium
solani
6
6
6
6
6
6
6
a
b
c
d
e
f
250
250
250
500
250
7.81
7.81
125
7.81
500
1000
500
250
500
500
250
250
250
250
125
15.62
7.81
250
15.62
15.62
31.25
125
125
125
g
62.5
15.62
Fluconazole
7.81
Table 3: In vitro antifungal activities of the furano dihydrohydrocarbazole derivatives. MIC values are
-1
represented as µg.mL .
It may be mentioned that compound 6f which has a miLogP value of 2.48 (terbinafine has a miLogP value of
5
.48) is intended for topical application to control the Candida like fungal infections. Hence, the
1
1

ACCEPTED MANUSCRIPT
biocompatibility of 6f against fibroblast cells (mouse embryonic fibroblast non-carcinoma cells)
wasconsidered. MTT reagent was used to determine the viable cells under the treated conditions. The cell
toxicity was low (<15%) up to a compound concentration 20 µg/mL (Figure 2). Although the toxicity
increased with increasing concentration of compound, the IC value of ~75 µg/mL was ~10 times above the
5
0
antifungal MIC value of 7.8 µg/mL. Therefore, the cytotoxicity data obtained from the MTT assay represents
its potentiality for topical use. However, in order to proceed further, extensive SAR studies are needed which
will be our future goal.
100
8
6
4
2
0
0
0
0
0
0
10 20 30 40 50 60 70 80
Sample concentration g/ mL
(
µ
)
Figure 2: Cell viability assay was monitored with MTT reagent against non-carcinoma, 3T3 cell line where
no significant cytotoxicity was observed up to 20 µg/mL concentration of compound 6f
To know the possible site of action for antifungal activity, the extracellular DNA and protein contents were
measured in the supernatants of compound 6f-treated Candida cells as against triton-100X treated ones. The
results indicated that compound 6f undoubtedly caused leakage of intracellular material from treated cells
(
Figure 3) as indicated by the leakage index. The SEM analysis taken after 4 h also suggested leakage of
intracellular material (Figure 4) which confirmed that the primary target of compound 6f is directed against
the cell wall and membrane integrity.
1
2

ACCEPTED MANUSCRIPT
1
0
0
0
0
0
.0
.8
.6
.4
.2
.0
DNA
Protein
2
4
6
8
Incubation time (h)
Figure 3: Determination of intracellular material leakage. Cellular leafage of both DNA and protein were
monitored after the treatment with compound, 6f with different time time intervals. The amount of
cytoplasmic material release was determined by subtracting the OD values from cells without treatment
treated as actual effect of compound. The cytoplasmic leakage index was calculated as actual OD value
obtained from the compound effect/ OD value obtained from the effect of Triton X-100 (1%) at same time.
Data are the mean of triplicates + S.E.
Figure 4: Effect of compound 6f against C. albicans. Scanning electron micrograph of C. albicans cells
without compound treatment, a: control, treated with 2% DMSO and b: treated with compound at 3.9 µg/
mL.
In conclusion, we have successfully developed a method for the synthesis of 3,4-furan fused
dihydrocarbazole derivatives starting from mono indolyl propargyl ethers using GB cyclization as the key
step. The probable cause of shifting the normal reaction pathway of GB cyclization has been explained
based on relative acidity of the migrating hydrogens. The dihydrocarbazole derivatives 6e and 6f with F and
1
3

ACCEPTED MANUSCRIPT
CH substituents respectively, have shown significant antifungal activity, especially against Candida
3
pathogens. Presently we were trying to come out with a better antifungal agent through SAR studies of more
derivatives and also studying the reactivity of other heteroaromatic propargyl systems.
Experimental
Synthesis and spectral data of compounds
1
13
All H and C NMR spectra for all the compounds were recorded at 400/500/600 and 100/125/150 MHz
TM
TM
TM
(
Bruker Ultrashield 400, Ascend 500, Ascend 600), respectively. The spectra were recorded in
deuterochloroform (CDCl ) as solvent at room temperature unless mentioned otherwise. The following
3
abbreviations are used to describe the peak patterns where appropriate: s = singlet, d = doublet, t = triplet, q
=
quartet, m = multiplet, ABq = AB quartet, dd = doublet of doublet, app. = apparent, and b = broad signal.
All coupling constants (J) are given in Hz. High resolution mass spectra were recorded in ESI+ mode (ion
trap) while LCMS were erecorded under low resolution. IR spectra were recorded as thin films, and bands
-1
are expressed in cm . All the dry solvents used for reactions were purified according to the standard
protocols. N, N-dimethylformamide (DMF), and triethylamine (Et N) were distilled from calcium hydride.
3
Solvents used for column chromatography were distilled prior to use. In most of the column
chromatographic purifications, ethyl acetate (EtOAc) and hexane of boiling range 60−80 °C were used as
eluents. Columns were prepared with silica gel (Si-gel, 60−120 and 230−400 flash, SRL).
General procedure for iodination of indole: To a solution of indole or its derivatives (1.25 mmol) in DMF
(
2
6 mL) was added KOH (2 equiv) and allowed to stir at room temperature for 20 min. I (1 equiv) dissolved
in DMF (1 mL) was added and the solution was stirred for an additional 45 min. The reaction mixture was
poured into ice water (40 mL) and the precipitate was collected by filtration, washed with water and dried by
azeotropic distillation with toluene to yield the 3-iodoindole derivatives. Because of their instability, these
derivatives were carried forward to the next step.
1
4

ACCEPTED MANUSCRIPT
General procedure for preparation of N-MOM protected 3-iodo indole: Synthesis of compounds (2a-
2
g).
To an ice-cold solution of 3-iodoindole (1.25 mmol) in dry DMF (6 mL) was added NaH (2 equiv, 60%
suspension in mineral oil), and the solution was stirred for 30 min at room temperature under N2
atmosphere. The reaction mixture was cooled again to 0 °C and MOM-Chloride (1.1 equiv) was added drop-
wise and was stirred for 2 h at room temperature. It was then partitioned between ethyl acetate and water.
2 4
The organic layer was washed with brine, and the organic layer was dried with anhydrous Na SO . The
solvent was removed, and the crude residue was purified by column chromatography (Si-gel, hexane−ethyl
acetate mixture as eluent) to furnish the title compounds.
3
-iodo-1-(methoxymethyl)-1H-indole (2a). Following the general procedure, pure product 2a was isolated by
column chromatography on silica gel (hexane:EtOAc 10:1). State: transparent liquid; yield: 286 mg, 80%;
1
13
H NMR (400 MHz, CDCl ) δ 7.50-7.46 (m, 2H), 7.35 – 7.25 (m, 3H), 5.41 (s, 2H), 3.25 (s, 3H). C NMR
3
(
100 MHz, CDCl
3
) δ 136.3, 132.1, 130.9, 123.4, 121.4, 121.3, 110.1, 77.4, 57.8, 56.1. LCMS: Calcd
10INO 287.1, found 287.2.
-iodo-5-methoxy-1-(methoxymethyl)-1H-indole (2b). Following the general procedure, pure product 2b was
Molecular weight for C10
H
3
isolated by column chromatography on silica gel (hexane:EtOAc 9:1). State: transparent liquid; yield: 317
1
mg, 80%; H NMR (400 MHz, CDCl ) δ 7.37 (d, J = 8.8 Hz, 1H), 7.28 (s, 1H), 6.95 (dd, J = 8.9, 2.4 Hz,
3
1
3
1
1
H), 6.89 (d, J = 2.3 Hz, 1H), 5.40 (s, 2H), 3.91 (s, 3H), 3.25 (s, 3H); C NMR (100 MHz, CDCl ) δ 155.5,
3
32.5, 131.6, 131.3, 113.9, 111.2, 102.7, 77.7, 57.2, 56.1, 55.9. LCMS: Calcd Molecular weight for
C H INO 317.1, found 317.2.
11
12
2
5
-bromo-3-iodo-1-(methoxymethyl)-1H-indole (2c). Following the general procedure, pure product 2c was
isolated by column chromatography on silica gel (hexane:EtOAc 10:1). State: transparent liquid; yield: 375
1
mg, 82%; H NMR (400 MHz, CDCl ) δ 7.59 (s, 1H), 7.40 – 7.31 (m, 2H), 7.26 (s, 1H), 5.39 (s, 2H), 3.23
3
1
5

ACCEPTED MANUSCRIPT
1
3
(
s, 3H); C NMR (100 MHz, CDCl ) δ 135.1, 133.2, 132.8, 126.4, 124.1, 114.7, 111.9, 77.8, 56.7, 56.3.
3
LCMS: Calcd molecular weight for C H BrINO 365.9, found 365.0.
1
0
9
5
-chloro-3-iodo-1-(methoxymethyl)-1H-indole (2d). Following the general procedure, pure product 2d was
isolated by column chromatography on silica gel (hexane:EtOAc 10:1). State: transparent liquid; yield: 321
1
mg, 80%; H NMR (400 MHz, CDCl ) δ 7.44 (d, J = 1.9 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.27 (s, 1H), 7.23
3
1
3
(
dd, J = 8.7, 1.9 Hz, 1H), 5.38 (s, 2H), 3.23 (s, 3H). C NMR (100 MHz, CDCl
27.3, 123.8, 120.9, 111.4, 77.8, 56.8, 56.2. LCMS: Calcd. For molecular weight for C10
found 321.2.
-fluoro-3-iodo-1-(methoxymethyl)-1H-indole (2e). Following the general procedure, pure product 2e was
3
) δ 134.8, 133.4, 132.2,
1
H
9
NClIO 321.5,
5
isolated by column chromatography on silica gel (hexane:EtOAc 10:1). State: transparent liquid; yield: 308
1
mg, 81%; H NMR (400 MHz, CDCl ) δ 7.41-7.38 (m, 1H), 7.30 (s, 1H), 7.12 (dd, J = 9.1, 2.4 Hz, 1H), 7.03
3
1
3
(
td, J = 9.0, 2.4 Hz, 1H), 5.40 (s, 2H), 3.25 (s, 3H); C NMR (100 MHz, CDCl ) δ 158.97 (d, J = 237.3 Hz),
3
1
7
3
31.87 (d, J = 9.4 Hz),133.7, 132.8, 111.99 (d, J = 26.8 Hz), 111.29 (d, J = 9.6 Hz), 106.63 (d, J = 25.6 Hz),
7.9, 56.97 (d, J = 4.3 Hz), 56.2. LCMS: Calcd. For molecular weight for C10 NFIO 305.1, found 305.2.
-iodo-1-(methoxymethyl)-7-methyl-1H-indole (2f). Following the general procedure, pure product 2f was
H
9
isolated by Chromatography on silica gel (hexane:EtOAc 10:1). State: transparent liquid; yield: 282 mg,
1
7
5%; H NMR (400 MHz, CDCl ) δ 7.30 (d, J = 7.9 Hz, 1H), 7.21 (s, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.05 (d, J
3
13
=
7.0 Hz, 1H), 5.50 (s, 2H), 3.25 (s, 3H), 2.73 (s, 3H); C NMR (101 MHz, CDCl ) δ 134.5, 133.9, 132.0,
3
1
26.1, 122.1, 121.4, 119.3, 79.2, 57.9, 55.4, 18.9. LCMS: Calcd for molecular weight for C H NIO 301.1,
11 12
found 301.2.
7
-ethyl-3-iodo-1-(methoxymethyl)-1H-indole (2g). Following the general procedure, pure product 2g was
isolated by column chromatography on silica gel (hexane:EtOAc 10:1).State: transparent liquid; yield: 284
1
mg, 72%; H NMR (400 MHz, CDCl ) δ 7.32 (d, J = 7.7 Hz, 1H), 7.21-7.17 (m, 2H), 7.12 (d, J = 7.1 Hz,
3
13
1
H), 5.48 (s, 2H), 3.24 (s, 3H), 3.10 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.5 Hz, 3H); C NMR (100 MHz,
1
6

ACCEPTED MANUSCRIPT
CDCl ) δ 134.3, 133.9, 132.5, 128.7, 124.20, 121.7, 119.5, 79.7, 58.3, 55.6, 24.8, 15.8. LCMS: Calcd for
3
molecular weight for C H NIO 315.1, found 315.2.
1
2
14
General procedure for Sonogashira Coupling: Synthesis of compounds (3a-3i). To a solution of N-
protected 3-iodo indole derivative (1 mmol) in dry degassed Et N (7 mL), PdCl (PPh ) (3 mol %), CuI (20
3
2
3 2
mol %) and propargyl alcohol (1.2 equiv) in were added under an inert atmosphere, and the mixture was
allowed to stir at room temperature for 6 h. The mixture was then poured into ethyl acetate, and the organic
layer was washed with brine. The organic layer was then dried over anhydrous Na
the purified product was obtained via flash chromatography by using hexane−ethyl acetate as eluent.
-(1-(methoxymethyl)-1H-indol-3-yl)prop-2-yn-1-ol (3a). Following the general procedure, pure product 3a
2 4
SO and evaporated, and
3
was isolated by flash chromatography on silica gel (hexane:EtOAc 1:1). State: viscous liquid; yield: 150 mg,
1
7
7
1
2
3
0%; H NMR (400 MHz, CDCl ) δ 7.75 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.33 (s, 1H), 7.29-
3
1
3
.20 (m, 2H), 5.33 (s, 2H), 4.59 (s, 2H), 3.18 (s, 3H); C NMR (100 MHz, CDCl ) δ 135.7, 131.9, 129.6,
3
+
+
23.3, 121.3, 120.1, 110.3, 97.9, 89.6, 78.7, 77.4, 55.9, 51.7. HRMS: Calcd for C13
38.0844, found 238.0847.
2
H13NO Na (M+Na)
-(5-methoxy-1-(methoxymethyl)-1H-indol-3-yl)prop-2-yn-1-ol (3b). Following the general procedure, pure
product 3b was isolated by flash chromatography on silica gel (hexane:EtOAc 1:1). State: viscous liquid;
1
yield: 147 mg, 60%; H NMR (400 MHz, Acetone) δ 7.37 – 7.31 (m, 2H), 7.15 (d, J = 2.3 Hz, 1H), 6.92 (dd,
1
3
J = 8.9, 2.3 Hz, 1H), 5.35 (s, 2H), 4.58 (s, 2H), 3.87 (s, 3H), 3.20 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
1
55.5, 132.3, 130.8, 130.3, 113.9, 111.3, 101.6, 97.6, 89.6, 79.1, 77.8, 56.0, 55.9, 52.1. HRMS: Calcd for
+
+
C H NO Na (M+Na) 268.0950, found 268.0951.
14
15
3
3
-(5-bromo-1-(methoxymethyl)-1H-indol-3-yl)prop-2-yn-1-ol (3c). Following the general procedure, pure
product 3c was isolated by flash chromatography on silica gel (hexane:EtOAc 1:1). State: viscous liquid;
1
yield: 199 mg, 68%; H NMR (400 MHz, CDCl ) δ 7.82 (s, 1H), 7.31 – 7.23 (m, 3H), 5.27 (s, 2H), 4.58 (s,
3
1
7

ACCEPTED MANUSCRIPT
1
3
2
7
3
H), 3.14 (s, 3H); C NMR (100 MHz, CDCl ) δ 134.1, 132.7, 131.1, 126.0, 122.5, 114.6, 111.8, 97.4, 89.9,
3
+
+
7.8, 77.5, 55.96, 51.51. HRMS: Calcd for C H BrNO Na (M+Na) 317.9929, found 317.9932.
1
3
12
2
-(5-chloro-1-(methoxymethyl)-1H-indol-3-yl)prop-2-yn-1-ol (3d). Following the general procedure, pure
product 3d was isolated by flash chromatography on silica gel (hexane:EtOAc 1:1). State: viscous liquid;
1
yield: 175 mg, 70%; H NMR (400 MHz, CDCl ) δ 7.69 (d, J = 1.8 Hz, 1H), 7.38-7.36 (m, J = 9.4 Hz, 2H),
3
1
3
7
.21 (dd, J = 8.8, 1.9 Hz, 1H), 5.36 (s, 2H), 4.56 (s, 2H), 3.20 (s, 3H), 2.25 (bs, 1H); C NMR (100 MHz,
CDCl ) δ 134.1, 132.9, 130.7, 127.3, 123.8, 119.8, 111.6, 97.7, 89.9, 78.2, 77.8, 56.2, 51.9. HRMS: Calcd
for C H ClNO (M+H) 250.0635, found 250.0632.
3
+
+
1
3
13
2
3
-(5-fluoro-1-(methoxymethyl)-1H-indol-3-yl)prop-2-yn-1-ol (3e). Following the general procedure, pure
product 3e was isolated by flash chromatography on silica gel (hexane:EtOAc 1:1). State: viscous liquid;
1
yield: 163 mg, 70%; H NMR (400 MHz, CDCl ) δ 7.38 – 7.33 (m, 3H), 6.99 (td, J = 9.0, 2.1 Hz, 1H), 5.34
3
1
3
(
s, 2H), 4.55 (s, 2H), 3.19 (s, 3H), 2.74 (bs, 1H). C NMR (100 MHz, CDCl ) δ 158.89 (d, J = 237.5 Hz),
3
1
33.2, 131.1, 130.28 (d, J = 10.2 Hz), 111.81 (d, J = 26.3 Hz), 111.34 (d, J = 9.6 Hz), 105.31 (d, J = 24.1
+
2
Hz), 97.97 (d, J = 4.5 Hz), 89.9, 78.2, 77.8, 56.1, 51.8. HRMS: Calcd for C13H12FNO Na (M+Na)
2
56.0750, found 256.0752.
-(1-(methoxymethyl)-7-methyl-1H-indol-3-yl)prop-2-yn-1-ol (3f). Following the general procedure, pure
3
product 3f was isolated by flash chromatography on silica gel (hexane:EtOAc 1:1). State: viscous liquid;
1
yield: 158 mg, 69%; H NMR (400 MHz, CDCl ) δ 7.58 (d, J = 7.8 Hz, 1H), 7.28 (s, 1H), 7.12 (t, J = 7.5 Hz,
3
1
3
1
H), 7.03 (d, J = 7.1 Hz, 1H), 5.44 (s, 2H), 4.57 (s, 2H), 3.20 (s, 3H), 2.70 (s, 3H), 2.70 (bs, 1H); C NMR
(
100 MHz, CDCl ) δ 134.1, 133.8, 130.9, 126.1, 122.4, 121.5, 118.0, 97.5, 89.5, 79.4, 79.0, 55.5, 51.9, 19.0.
3
+
HRMS: Calcd for C14
H15NO
2
Na (M+Na) 252.1000,found 252.1005.
3
-(7-ethyl-1-(methoxymethyl)-1H-indol-3-yl)prop-2-yn-1-ol (3g). Following the general procedure, pure
product 3g was isolated by flash chromatography on silica gel (hexane:EtOAc 1:1). State: viscous liquid;
1
yield: 158 mg, 65%; H NMR (400 MHz, CDCl ) δ 7.60 (d, J = 7.7 Hz, 1H), 7.30 (s, 1H), 7.18 (t, J = 7.5 Hz,
3
1
8

ACCEPTED MANUSCRIPT
1
1
9
2
H), 7.12 (d, J = 7.2 Hz, 1H), 5.43 (s, 2H), 4.58 (s, 2H), 3.20 (s, 3H), 3.09 (q, J = 7.5 Hz, 2H), 2.36 (bs, 1H),
13
.33 (t, J = 7.5 Hz, 3H); C NMR (100 MHz, CDCl ) δ 133.9, 133.3, 131.2, 128.8, 124.0, 121.6, 117.9,
3
+
7.7, 89.6, 79.7, 78.9, 55.5, 51.9, 24.6, 15.7. HRMS: Calcd for C H NO Na (M+Na) 266.1157, found
1
5
17
2
66.1155.
-(1-methyl-1H-indol-3-yl)prop-2-yn-1-ol (3h). Following the general procedure, pure product 3h was
3
isolated by flash chromatography on silica gel (hexane:EtOAc 2:1). State: yellow solid; mp 78-80 °C; yield:
1
1
33 mg, 72%; H NMR (400 MHz, CDCl
3
) δ 7.72 (d, J = 7.9 Hz, 1H), 7.36 – 7.23 (m, 3H), 7.20 (t, J = 7.3
1
3
Hz, 1H), 4.57 (s, 2H), 3.79 (s, 3H), 1.67 (s, 1H); C NMR (125 MHz, CDCl ) δ 136.2, 132.8, 129.2, 122.7,
3
+
1
1
20.5, 120.1, 109.7, 96.2, 89.0, 79.8, 52.12, 33.09; HRMS: Calcd for C H NO (M+H) 186.0919, found
1
2
12
86.0920.
Synthesis of compounds (5a and 5d): To a degassed solution of N-MOM protected 3-iodo indole (0.65
mmol) in dry Et N (5 mL), PdCl (PPh ) (3 mol %) , CuI (20 mol %) and compound 4a/4d ( 1.1 equiv) were
3
2
3 2,
added under N
poured into ethyl acetate, and the organic layer was washed with brine. The organic layer was then dried
over anhydrous Na SO and evaporated, and the purified product was obtained via column chromatography
by using hexane−ethyl acetate as eluent.
-(3-(3-(1-(methoxymethyl)-1H-indol-3-yl)prop-2-ynyloxy)prop-1-ynyl)-1-(methoxymethyl)-1H-indole (5a).
2
atmosphere and the mixture was allowed to stir at room temperature for 12 h. It was then
2
4
3
Following the general procedure, pure product 5a was isolated by flash chromatography on silica gel
1
(
hexane:EtOAc 3:1). State: yellow liquid; yield: 94 mg, 35%; H NMR (400 MHz, CDCl ) δ 7.79 (d, J = 7.7
3
Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.40 (s, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.242 (t, J = 7.2 Hz, 2H), 5.41 (s,
1
3
4
1
4
H), 4.69 (s, 4H), 3.23 (s, 6H); C NMR (100 MHz, CDCl
3
) δ 135.8, 132.0, 129.8, 123.4, 121.3, 120.6,
+
10.4, 98.1, 86.7, 80.1, 77.7, 57.8, 56.1. HRMS: Calcd for C26
35.1678.
H
24
N
2
O
3
Na (M+Na) 435.1685, found
1
9

ACCEPTED MANUSCRIPT
3
-(3-(3-(5-chloro-1-(methoxymethyl)-1H-indol-3-yl)prop-2-ynyloxy)prop-1-ynyl)-5-chloro-1-
(
methoxymethyl)-1H-indole (5d). Following the general procedure, pure product 5d was isolated by flash
1
chromatography on silica gel (hexane:EtOAc 3:1). State: yellow liquid; yield: 109 mg, 35%; H NMR (400
MHz, CDCl ) δ 7.72 (d, J = 1.5 Hz, 2H), 7.41-7.38 (m, 4H), 7.23 (dd, J = 8.7, 1.7 Hz, 2H), 5.39 (s, 4H), 4.65
3
1
3
(
s, 4H), 3.23 (s, 6H), C NMR (100 MHz, CDCl ) δ 134.1, 133.1, 130.9, 127.4, 123.8, 119.9, 111.6, 97.8,
3
+
8
7.1, 79.4, 77.9, 57.7, 56.2. HRMS: Calcd for C26
H23Cl
2
N
2
O
3
(M+H) 481.1086, found 481.1085.
General Procedure for O-Propargylation: Synthesis of compounds (4a-4i): To an ice-cold solution of
alcohol (0.5 mmol) in dry THF (6 mL) was added NaH (2 equiv, 60% suspension in mineral oil), and the
solution was stirred for 30 min at room temperature under N atmosphere. After the alkoxide was generated,
2
propargyl bromide (1.2 equiv) was added dropwise by maintaining the ice-cold temperature, and the mixture
was stirred for 1 h at room temperature. It was then partitioned between ethyl acetate and water. The organic
layer was washed with brine, and the organic layer was dried with anhydrous Na SO . The solvent was
2
4
removed, and the crude residue was purified by flash chromatography (Si-gel, hexane−ethyl acetate mixture
as eluent).
1
-(methoxymethyl)-3-(3-(prop-2-ynyloxy)prop-1-ynyl)-1H-indole (4a). Following the general procedure, pure
product 4a was isolated by flash chromatography on silica gel (hexane:EtOAc 5:1). State: yellow liquid;
1
yield: 101 mg, 78%; H NMR (400 MHz, CDCl ) δ 7.74 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.40
3
(
s, 1H), 7.32 – 7.21 (m, 2H), 5.42 (s, 2H), 4.58 (s, 2H), 4.38 (d, J = 2.4 Hz, 2H), 3.24 (s, 3H), 2.49 (t, J = 2.2
1
3
Hz, 1H); C NMR (100 MHz, CDCl ) δ 135.8, 132.1, 129.8, 123.5, 121.4, 120.3, 110.4, 97.9, 86.2, 80.3,
3
+
7
9.3, 77.7, 75.0, 57.8, 56.4, 56.2. HRMS: Calcd for C H NO Na (M+Na) 276.1000, found 276.1000.
1
6
15
2
5
-methoxy-1-(methoxymethyl)-3-(3-(prop-2-ynyloxy)prop-1-ynyl)-1H-indole (4b). Following the general
procedure, pure product 4b was isolated by flash chromatography on silica gel (hexane:EtOAc 5:1). State:
1
yellow liquid; yield: 106 mg, 75%; H NMR (400 MHz, CDCl ) δ 7.36- 7.34 (m, 2H), 7.16 (s, 1H), 6.93 (d,
3
1
3
J = 8.8 Hz, 1H), 5.33 (s, 2H), 4.59 (s, 2H), 4.38 (s, 2H), 3.88 (s, 3H), 3.20 (s, 3H), 2.51 (s, 1H); C NMR
2
0

ACCEPTED MANUSCRIPT
(
100 MHz, CDCl ) δ 155.4, 132.4, 130.6, 130.3, 113.7, 111.3, 101.5, 97.3, 86.2, 80.4, 79.3, 77.8, 74.9, 57.8,
3
+
5
6.3, 55.9, 55.8. HRMS: Calcd for C H NO Na (M+Na) 306.1106, found 306.1102
1
7
17
3
.
5-bromo-1-(methoxymethyl)-3-(3-(prop-2-ynyloxy)prop-1-ynyl)-1H-indole (4c). Following the general
procedure, pure product 4c was isolated by flash chromatography on silica gel (hexane:EtOAc 6:1). State:
1
yellow liquid; yield: 128 mg, 77%; H NMR (400 MHz, CDCl ) δ 7.86 (s, 1H), 7.39 – 7.33 (m, 3H), 5.39 (s,
3
13
2
H), 4.56 (s, 2H), 4.36 (d, J = 2.2 Hz, 2H), 3.22 (s, 3H), 2.50 (t, J = 2.3 Hz, 1H); C NMR (100 MHz,
CDCl
3
) δ 134.3, 132.9, 131.3, 126.3, 122.8, 114.9, 111.9, 97.5, 86.7, 79.4, 79.2, 77.8, 75.1, 57.7, 56.5, 56.1.
+
HRMS: Calcd for C H BrNO Na (M+Na) 356.0085, found 356.0084.
1
6
14
2
5
-chloro-1-(methoxymethyl)-3-(3-(prop-2-ynyloxy)prop-1-ynyl)-1H-indole (4d). Following the general
procedure, pure product 4d was isolated by flash chromatography on silica gel (hexane:EtOAc 5:1). State:
1
yellow liquid; yield: 112 mg, 78%; H NMR (400 MHz, CDCl ) δ 7.69 (d, J = 1.6 Hz, 1H), 7.37-7.36 (m,
3
2
H), 7.22 (dd, J = 8.7, 1.7 Hz, 1H), 5.35 (s, 2H), 4.56 (s, 2H), 4.36 (d, J = 2.2 Hz, 2H), 3.20 (s, 3H), 2.51 (t,
1
3
J = 2.2 Hz, 1H). C NMR (100 MHz, CDCl
3
) δ 134.0, 133.0, 130.7, 127.3, 123.8, 119.7, 111.6, 97.5, 86.6,
+
7
3
5
9.4, 79.2, 77.8, 75.1, 57.6, 56.5, 56.1. HRMS: Calcd for C16
10.0610.
-fluoro-1-(methoxymethyl)-3-(3-(prop-2-ynyloxy)prop-1-ynyl)-1H-indole (4e). Following the general
H
14ClNO
2
Na (M+Na) 310.0611, found
procedure, pure product 4e was isolated by flash chromatography on silica gel (hexane:EtOAc 5:1). State:
1
yellow liquid; yield: 99 mg, 73%; H NMR (400 MHz, CDCl ) δ 7.43 – 7.34 (m, 3H), 7.07 – 7.00 (m, 1H),
3
1
3
5
.37 (s, 2H), 4.56 (s, 2H), 4.36 (d, J = 2.2 Hz, 2H), 3.22 (s, 3H), 2.50 (t, J = 2.3 Hz, 1H); C NMR (100
MHz, CDCl ) δ 158.94 (d, J = 237.6 Hz), 133.4, 132.2, 130.38 (d, J = 10.2 Hz), 111.87 (d, J = 26.3 Hz),
3
1
5
1
11.38 (d, J = 9.6 Hz), 105.37 (d, J = 24.1 Hz), 97.87 (d, J = 4.2 Hz), 86.6, 79.6, 79.2, 77.9, 75.1, 57.7, 56.4,
+
6.1. HRMS: Calcd for C16
H14FNO
2
Na (M+Na) 294.0906, found 294.0905.
-(methoxymethyl)-7-methyl-3-(3-(prop-2-ynyloxy)prop-1-ynyl)-1H-indole (4f). Following the general
procedure, pure product 4f was isolated by flash chromatography on silica gel (hexane:EtOAc 5:1). State:
2
1

ACCEPTED MANUSCRIPT
1
yellow liquid; yield: 103 mg, 77%; H NMR (600 MHz, CDCl ) δ 7.59 (d, J = 7.8 Hz, 1H), 7.32 (s, 1H),
3
7
3
1
2
7
.14 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 7.1 Hz, 1H), 5.47 (s, 2H), 4.59 (s, 2H), 4.39 (d, J = 1.8 Hz, 2H), 3.23 (s,
1
3
H), 2.72 (s, 3H), 2.50 (s, 1H); C NMR (150 MHz, CDCl ) δ 134.1, 133.9, 131.0, 126.2, 122.4, 121.5,
3
+
18.1, 97.5, 86.2, 80.4, 79.5, 79.3, 74.9, 57.8, 56.4, 55.5, 19.1. HRMS: Calcd for C H NO Na (M+Na)
1
7
17
2
90.1157, found 290.1162.
-ethyl-1-(methoxymethyl)-3-(3-(prop-2-ynyloxy)prop-1-ynyl)-1H-indole (4g). Following the general
procedure, pure product 4g was isolated by flash chromatography on silica gel (hexane:EtOAc 5:1). State:
1
yellow liquid; yield: 112 mg, 80%; H NMR (400 MHz, CDCl ) δ 7.61 (d, J = 7.8 Hz, 1H), 7.33 (s, 1H),
3
7
3
1
.20 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 5.46 (s, 2H), 4.59 (s, 2H), 4.39 (d, J = 2.0 Hz, 2H), 3.23 (s,
1
3
H), 3.10 (q, J = 7.5 Hz, 2H), 2.50 (s, 1H), 1.34 (t, J = 7.5 Hz, 3H); C NMR (100 MHz, CDCl ) δ 134.1,
3
33.3, 131.3, 128.9, 124.1, 121.7, 118.0, 97.6, 86.2, 80.3, 79.8, 79.3, 74.9, 57.8, 56.4, 55.6, 24.7, 15.7;
+
+
HRMS: Calcd for C H NO Na (M+Na) 304.1313, found 304.1314.
1
8
19
2
1
-methyl-3-(3-(prop-2-ynyloxy)prop-1-ynyl)-1H-indole (4h). Following the general procedure, pure product
4
h was isolated by flash chromatography on silica gel (hexane:EtOAc 5:1). State: yellow liquid; yield: 78
1
mg, 70%; H NMR (400 MHz, CDCl
3
) δ 7.74 (d, J = 8.0 Hz, 1H), 7.33-7.26 (m, 3H), 7.21 (t, J = 7.3 Hz,
13
1
H), 4.58 (s, 2H), 4.38 (d, J = 2.2 Hz, 2H), 3.78 (s, 3H), 2.49 (t, J = 2.2 Hz, 1H); C NMR (100 MHz,
CDCl ) δ 136.2, 132.9, 129.3, 122.8, 120.5, 120.2, 109.7, 96.2, 85.6, 80.9, 79.4, 74.9, 57.9, 56.3, 33.2;
3
+
HRMS: Calcd for C H NO (M+H) 224.1075, found 224.1078.
1
5
14
1
-benzyl-3-(3-(prop-2-ynyloxy)prop-1-ynyl)-1H-indole (4i). Following the general procedure, pure product 4i
was isolated by flash chromatography on silica gel (hexane:EtOAc 8:1). State: yellow liquid; yield: 76 mg,
1
6
5
1
8%, H NMR (500 MHz, CDCl
3
) δ 7.81 (d, J = 6.5 Hz, 1H), 7.41 – 7.22 (m, 7H), 7.15 (d, J = 6.7 Hz, 2H),
1
3
.30 (s, 2H), 4.62 (s, 2H), 4.42 (s, 2H), 2.52 (s, 1H); C NMR (125 MHz, CDCl
3
) δ 136.6, 135.8, 132.3,
29.5, 129.0, 128.0, 127.0, 122.0, 120.7, 120.2, 110.1, 96.9, 85.9, 80.7, 79.4, 74.9, 57.8, 56.3, 50.4.
2
2

ACCEPTED MANUSCRIPT
4
-(3-(prop-2-ynyloxy)prop-1-ynyl)isoquinoline (10). Following the general procedure, pure product 10 was
1
isolated by flash chromatography on silica gel (hexane:EtOAc 3:1). State: liquid; yield: 76 mg, 68%; H
NMR (400 MHz, CDCl ) δ 9.21 (s, 1H), 8.70 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.80
3
(
t, J = 7.4 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 4.66 (s, 1H), 4.41 (d, J = 2.3 Hz, 1H), 2.52 (t, J = 2.3 Hz, 1H);
1
3
C NMR (100 MHz, CDCl ) δ 152.5, 147.0, 147.0, 135.8, 131.3, 128.0, 127.9, 125.1, 115.2, 91.7, 82.2,
3
+
7
9.0,75.4, 57.5, 56.9; HRMS: Calcd for C15
H
12NO (M+H) 222.0919, found 222.0917.
3
-(3-(prop-2-ynyloxy)prop-1-ynyl)quinoline (12). Following the general procedure, pure product 12 was
1
isolated by flash chromatography on silica gel (hexane:EtOAc 3:1). State: liquid; yield: 78 mg, 70%; H
NMR (400 MHz, CDCl ) δ 8.89 (d, J = 1.2 Hz, 1H), 8.22 (d, J = 1.5 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.82
3
13
–
7.63 (m, 2H), 7.55 (d, J = 7.8 Hz, 1H), 4.54 (s, 2H), 4.35 (d, J = 2.3 Hz, 2H), 2.50 (t, J = 2.3 Hz, 1H); C
NMR (100 MHz, CDCl ) δ 152.0, 146.9, 139.0, 130.4, 129.4, 127.7, 127.5, 127.2, 116.6, 87.7, 84.1, 78.9,
3
+
7
5.4, 57.3, 56.9; HRMS: C H NO (M+H) 222.0919, found 222.0919.
15
12
General Procedure for the Garratt–Braverman Cyclization: Synthesis of compounds (6a-6i, 7a-7i, 11,
t
1
3). To a solution of bispropargyl ether (0.2 mmol) in toluene (3 mL), KOBu (2.5 equiv) was added, and the
mixture was refluxed at 110ꢁ˚C for 6 h. The reaction mixture was then partitioned between ethyl acetate and
water. The organic layer was washed with brine, and the combined organic layer was dried with anhydrous
Na SO . The solvent was removed, and the crude residue was purified by flash chromatography (Si-gel,
2
4
hexane−ethyl acetate mixture as eluent).
,10-dihydro-5-(methoxymethyl)-4H-furo[3,4-b]carbazole (6a). Following the general procedure, pure
5
product 6a was isolated by flash chromatography on silica gel (hexane:EtOAc 8:1). State: white solid; mp
1
8
7
7-90 °C; yield: 40 mg, 80%; H NMR (600 MHz, CDCl
3
) δ 7.61 (d, J = 7.8 Hz, 1H), 7.50-7.48 (m, 3H),
1
3
.33 (t, J = 7.2 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 5.40 (s, 2H), 3.95 (s, 2H), 3.92 (s, 2H), 3.29 (s, 3H); C
NMR (150 MHz, CDCl ) δ 138.1, 138.0, 137.9, 132.9, 127.3, 121.9, 119.9, 119.7, 118.8, 118.1, 109.1,
3
+
1
09.0, 73.7, 55.6, 18.1, 17.0. HRMS: Calcd for C H NO Na (M+Na) 276.1000, found 276.1000.
1
6
15
2
2
3

ACCEPTED MANUSCRIPT
5
,10-dihydro-8-methoxy-5-(methoxymethyl)-4H-furo[3,4-b]carbazole (6b). Following the general procedure,
pure product 6b was isolated by flash chromatography on silica gel (hexane:EtOAc 8:1). State: white solid;
1
mp 112 °C; yield: 46 mg, 82%; H NMR (400 MHz, CDCl ) δ 7.44 (s, 2H), 7.34 (d, J = 8.8 Hz, 1H), 7.01 (d,
3
J = 1.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.39 (s, 2H), 3.93 (s, 2H), 3.90 (s, 3H), 3.86 (s, 2H), 3.24 (s, 3H);
1
3
C NMR (100 MHz, CDCl ) δ 154.4, 138.1, 138.1, 133.6, 133.1, 127.8, 119.8, 118.9, 111.2, 109.9, 108.8,
3
+
1
00.6, 73.9, 55.9, 55.7, 18.3, 17.2. HRMS: Calcd for C17
H17NO
3
Na (M+Na) 306.1106, found 306.1107.
8
-bromo-5,10-dihydro-5-(methoxymethyl)-4H-furo[3,4-b]carbazole (6c). Following the general procedure,
pure product 6c was isolated by flash chromatography on silica gel (hexane:EtOAc 9:1). State: white solid;
1
mp 90-95 °C; yield: 48 mg, 72%; H NMR (600 MHz, CDCl ) δ 7.64 (s, 1H), 7.42 (s, 2H), 7.31-7.29 (m,
3
1
3
13
2
H), 5.39 (s, 2H), 3.93 (s, 2H), 3.81 (s, 2H), 3.23 (s, 3H); C NMR (101 MHz, CDCl ) δ C NMR (150
3
MHz, CDCl ) δ 138.3, 138.2, 136.8, 134.4, 129.2, 124.7, 120.9, 119.41, 118.5, 113.2, 110.7, 108.9, 74.1,
3
+
5
5.9, 18.4, 17.0. HRMS: Calcd for C H BrNO K (M+K) 369.9845, found 369.9844.
1
6
14
2
8
-chloro-5,10-dihydro-5-(methoxymethyl)-4H-furo[3,4-b]carbazole (6d). Following the general procedure,
pure product 6d was isolated by flash chromatography on silica gel (hexane:EtOAc 8:1). State: white solid;
1
mp 102-104 °C; yield: 43 mg, 74%; H NMR (600 MHz, CDCl
3
) δ 7.48 (s, 1H), 7.43 (s, 2H), 7.33 (d, J = 8.6
1
3
Hz, 1H), 7.18 (dd, J = 8.6, 1.6 Hz, 1H), 5.38 (s, 2H), 3.92 (s, 2H), 3.81 (s, 2H), 3.24 (s, 3H); C NMR (150
MHz, CDCl ) δ 138.2, 138.2, 136.4, 134.5, 128.5, 125.7, 122.1, 119.4, 118.6, 117.8, 110.2, 108.9, 74.0, 55.8,
3
+
1
8.3, 17.0. HRMS: Calcd for C H ClNO K (M+K) 326.0350, found 326.0351.
1
6
14
2
8
-fluoro-5,10-dihydro-5-(methoxymethyl)-4H-furo[3,4-b]carbazole (6e). Following the general procedure,
pure product 6e was isolated by flash chromatography on silica gel (hexane:EtOAc 8:1). State: white solid;
1
mp 89-93 °C; yield: 38 mg, 70%; H NMR (600 MHz, CDCl
3
) δ 7.43 (s, 2H), 7.36-7.34 (m, 1H), 7.18 (dd, J
1
3
=
9.2, 2.3 Hz, 1H), 6.97 (td, J = 9.0, 2.3 Hz, 1H), 5.44 (s, 2H), 3.96 (s, 2H), 3.85 (s, 2H), 3.25 (s, 3H); C
NMR (150 MHz, CDCl ) δ 158.25 (d, J = 235.3 Hz), 138.24, 138.21, 134.8, 134.5, 127.92 (d, J = 9.4 Hz),
3
1
19.5, 118.7, 109.9, 109.9 (d, J = 25.35 Hz), 109.25 (d, J = 4.2 Hz), 103.5 (d, J = 23.4 Hz), 74.1, 55.8, 18.4,
2
4

ACCEPTED MANUSCRIPT
1
9
+
1
2
5
7.1; F NMR (376 MHz, D -acetone) δ −125.8759 (s, 1F). HRMS: Calcd for C H FNO (M+H)
6 16 15 2
72.1087, found 272.1082.
,10-dihydro-5-(methoxymethyl)-6-methyl-4H-furo[3,4-b]carbazole (6f). Following the general procedure,
pure product 6f was isolated by flash chromatography on silica gel (hexane:EtOAc 10:1). State: white solid;
1
mp 97-99 °C; yield: 42 mg, 79.1%; H NMR (400 MHz, CDCl ) δ 7.44 (s, 2H), 7.39 (d, J = 7.7 Hz, 1H),
3
7
.08 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 7.1 Hz, 1H), 5.55 (s, 2H), 3.96 (s, 2H), 3.88 (s, 2H), 3.28 (s, 3H), 2.75
1
3
(
s, 3H); C NMR (100 MHz, CDCl
3
) δ 138.2, 138.1, 136.3, 133.3, 128.6, 125.4, 121.3, 120.3, 119.8, 119.1,
+
1
2
6
16.1, 109.4, 74.8, 54.8, 19.8, 18.7, 17.2. HRMS: Calcd for C H NO Na (M+Na) 290.1157, found
1
7
17
2
90.1158.
-ethyl-5,10-dihydro-5-(methoxymethyl)-4H-furo[3,4-b]carbazole (6g). Following the general procedure,
pure product 6g was isolated by flash chromatography on silica gel (hexane:EtOAc 10:1). State: white solid;
1
mp 95-98 °C; yield: 44 mg, 77.8%; H NMR (400 MHz, CD Cl ) δ 7.44-7.38 (m, 3H), 7.13 (t, J = 7.4 Hz,
2
2
1
1
1
H), 7.07 (d, J = 7.2 Hz, 1H), 5.52 (s, 2H), 3.97 (s, 2H), 3.88 (s, 2H), 3.27 (s, 3H), 3.11 (q, J = 7.5 Hz, 2H),
13
.36 (t, J = 7.5 Hz, 3H).; C NMR (100 MHz, CDCl
3
) δ 138.2, 138.1, 135.5, 133.4, 128.9, 127.9, 123.5,
+
2
20.5, 119.8, 119.1, 116.0, 109.6, 75.1, 54.9, 25.4, 18.8, 17.2, 15.9. HRMS: Calcd for C18H19NO Na
+
(
M+Na) 304.1313, found 304.1313.
5
,10-dihydro-5-methyl-4H-furo[3,4-b]carbazole (6h). Following the general procedure, pure product 6h was
isolated by flash chromatography on silica gel (hexane:EtOAc 10:1). State: white solid; mp 89-92 °C; yield:
1
3
7
6 mg, 82%; H NMR (400 MHz, CDCl ) δ 7.59 (d, J = 7.7 Hz, 1H), 7.46 (s, 2H), 7.34 (d, J = 8.1 Hz, 1H),
3
1
3
.27 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 7.3 Hz, 1H), 3.92 (s, 2H), 3.90 (s,2H), 3.68 (s, 3H); C NMR (100 MHz,
CDCl
3
) δ 138.1, 138.0, 137.7, 133.1, 126.8, 121.2, 120.2, 119.0, 118.9, 118.0, 108.7, 107.0, 29.2, 18.4, 17.2;
+
HRMS: Calcd for C15
H
14NO (M+H) 224.1075, found 224.1109.
5
-benzyl-5,10-dihydro-4H-furo[3,4-b]carbazole(6i). Following the general procedure, pure product 6i was
isolated by flash chromatography on silica gel (hexane:EtOAc 12:1). State: white solid; mp 105-107 °C;
2
5

ACCEPTED MANUSCRIPT
1
yield: 38 mg, 83%; H NMR (400 MHz, CDCl ) δ 7.62 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 7.33 –
3
1
3
7
.24 (m, 4H), 7.22 – 7.12 (m, 2H), 7.02 (d, J = 7.1 Hz, 2H), 5.35 (s, 2H), 3.97 (s, 2H), 3.82 (s, 2H); C
NMR (100 MHz, CDCl ) δ 138.2, 138.1, 138.0, 137.7, 133.0, 129.0, 127.5, 127.1, 126.2, 121.6, 120.1,
3
+
1
3
3
19.3, 119.0, 118.2, 109.3, 108.0, 46.6, 18.5, 17.3; HRMS: Calcd for C H NOK (M+K) 338.0947, found
2
1
17
38.0854.
,5-dihydro-5-(methoxymethyl)-1H-furo[3,4-b]carbazole (7a). Following the general procedure, pure
product 7a was isolated by flash chromatography on silica gel (hexane:EtOAc 5:1). State: white solid; mp
1
1
15-118 °C; yield: 5 mg, 10%; H NMR (400 MHz, CDCl ) δ 8.05 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.54 (d,
3
J = 8.0 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.39 (s, 1H), 7.29 – 7.25 (m, 1H), 5.68 (s, 2H), 5.27 (s, 4H), 3.30 (s,
1
3
3
1
3
H); C NMR (100 MHz, CDCl ) δ 141.3, 140.8, 138.1, 131.5, 126.1, 123.6, 123.2, 120.3, 120.1, 112.5,
3
+
09.3, 101.8, 74.4, 73.8, 73.5, 56.3. HRMS: Calcd for C H NO Na (M+Na) 276.1000, found 276.1003.
1
6
15
2
,5-dihydro-8-methoxy-5-(methoxymethyl)-1H-furo[3,4-b]carbazole (7b). Following the general procedure,
pure product 7b was isolated by flash chromatography on silica gel (hexane:EtOAc 4:1). State: white solid;
1
mp 142 °C; yield: 4 mg, 7.8%; H NMR (400 MHz, CDCl
3
) δ 7.86 (s, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.43 (d,
J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.10 (dd, J = 8.8, 2.4 Hz, 1H), 5.64 (s, 2H), 5.26 (s, 4H), 3.93 (s, 3H), 3.28 (s,
1
3
3
1
3
8
H); C NMR (100 MHz, CDCl ) δ 154.5, 141.4, 138.2, 136.3, 131.2, 123.8, 123.5, 115.0, 112.4, 110.1,
3
+
03.5, 101.9, 74.6, 73.8, 73.4, 56.2, 56.2. HRMS: Calcd for C H NO Na (M+Na) 306.1106, found
1
7
17
3
06.1100.
-bromo-3,5-dihydro-5-(methoxymethyl)-1H-furo[3,4-b]carbazole (7c). Following the general procedure,
pure product 7c was isolated by flash chromatography on silica gel (hexane:EtOAc 5:1). State: white solid;
1
mp 124 °C; yield: 10 mg, 14.4%; H NMR (400 MHz, CDCl
3
) δ 8.14 (s, 1H), 7.82 (s, 1H), 7.53 (d, J = 8.4
13
Hz, 1H), 7.41 – 7.37 (m, 2H), 5.63 (s, 2H), 5.25 (s, 4H), 3.27 (s, 3H); C NMR (100 MHz, CDCl
3
) δ 141.1,
1
39.9, 139.1, 132.0, 128.7, 125.0, 123.1, 122.5, 113.0, 112.7, 110.8, 102.0, 74.4, 73.7, 73.4, 56.3. HRMS:
+
Calcd for C H BrNO Na (M+Na) 354.0106, found 354.0106.
1
6
14
2
2
6

ACCEPTED MANUSCRIPT
8
-chloro-3,5-dihydro-5-(methoxymethyl)-1H-furo[3,4-b]carbazole (7d). Following the general procedure,
pure product 7d was isolated by flash chromatography on silica gel (hexane:EtOAc 5:1). State: white solid;
1
mp 138-139 °C; yield: 9 mg, 15.2%; H NMR (400 MHz, CDCl ) δ 7.98 (d, J = 1.5 Hz, 1H), 7.82 (s, 1H),
3
1
3
7
1
.45 – 7.38 (m, 2H), 7.36 (s, 1H), 5.63 (s, 2H), 5.25 (s, 4H), 3.27 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
41.2, 139.6, 139.0, 131.9, 126.1, 125.7, 124.4, 122.7, 120.0, 112.7, 110.4, 102.0, 74.5, 73.7, 73.4, 56.3.
+
HRMS: Calcd for C16
H
14ClNO
2
K (M+K) 326.0350, found 326.0350.
8
-fluoro-3,5-dihydro-5-(methoxymethyl)-1H-furo[3,4-b]carbazole (7e). Following the general procedure,
pure product 7e was isolated by flash chromatography on silica gel (hexane:EtOAc 4:1). State: white solid;
1
mp 133 °C; yield: 7 mg, 13%; H NMR (400 MHz, CDCl ) δ 7.84 (s, 1H), 7.69 (dd, J = 8.7, 2.2 Hz, 1H),
3
7
3
9
.45 (dd, J = 8.8, 4.1 Hz, 1H), 7.37 (s, 1H), 7.19 (td, J = 8.9, 2.3 Hz, 1H), 5.65 (s, 2H), 5.26 (s, 4H), 3.29 (s,
1
3
H); C NMR (100 MHz, D -acetone) δ 158.63 (d, J = 234.3 Hz), 142.7, 140.1, 138.6, 132.6, 124.60 (d, J =
6
.6 Hz), 123.63 (d, J = 4.2 Hz), 114.06 (d, J = 25.4 Hz), 111.52 (d, J = 9.2 Hz), 111.5, 106.48 (d, J = 24.3
1
9
Hz)., 103.3, 74.9, 73.8, 73.4, 56.1; F NMR (376 MHz, D
6
-acetone) δ −125.559 (s, 1F). HRMS: Calcd for
+
C
16
H14FNO
2
Na (M+Na) 294.0906, found 294.0904
3
,5-dihydro-5-(methoxymethyl)-6-methyl-1H-furo[3,4-b]carbazole (7f). Following the general procedure,
pure product 7f was isolated by flash chromatography on silica gel (hexane:EtOAc 6:1). State:white solid;
1
mp 124-127 °C; yield: 5 mg, 9.5%; H NMR (400 MHz, D -acetone) δ 7.97-7.96 (m, 2H), 7.63 (s, 1H), 7.20
6
1
3
(
(
d, J = 7.2 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 5.87 (s, 2H), 5.16 (s, 4H), 3.29 (s, 3H), 2.81 (s, 3H); C NMR
100 MHz, D -acetone) δ 142.9, 140.3, 139.2, 132.5, 129.8, 125.0, 124.2, 122.4, 121.0, 118.6, 112.8, 102.8,
6
+
7
5.7, 73.8, 73.4, 55.7, 19.6. HRMS: Calcd for C H NO (M+H) 268.1338, found 268.1338.
1
7
18
2
6
-ethyl-3,5-dihydro-5-(methoxymethyl)-1H-furo[3,4-b]carbazole (7g). Following the general procedure, pure
product 7g was isolated by flash chromatography on silica gel (hexane:EtOAc 8:1). State: white solid; mp
31-133 °C; yield: 5 mg, 9.5%; 1H NMR (600 MHz, D -acetone) δ 7.976-7.969 (m, 2H), 7.64 (s, 1H), 7.28
1
6
(
d, J = 7.2 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 5.83 (s, 2H), 5.16-5.15 (m, 4H), 3.29 (s, 3H), 3.19 (q, J = 7.5
2
7

ACCEPTED MANUSCRIPT
1
3
Hz, 2H), 1.36 (t, J = 7.5 Hz, 4H); C NMR (150 MHz, d -acetone) δ 143.4, 139.6, 139.4, 132.7, 129.1,
6
1
28.2, 125.6, 124.5, 121.4, 118.7, 112.9, 103.0, 76.2, 74.0, 73.6, 55.9, 25.8, 16.4. HRMS: Calcd for
+
C H NO Na (M+Na) 304.1313, found 304.1313.
18
19
2
3
,5-dihydro-5-methyl-1H-furo[3,4-b]carbazole (7h). Following the general procedure, pure product 7h was
isolated by flash chromatography on silica gel (hexane:EtOAc 6:1). State: white solid; mp 133-135 °C;
1
yield: 4 mg, 9%; H NMR (400 MHz, CDCl
3
) δ 8.11 (d, J = 7.8 Hz, 1H), 8.00 (s, 1H), 7.52 (d, J = 8.2 Hz,
1
3
1
H), 7.48 – 7.41 (m, 2H), 7.19 (t, J = 7.4 Hz, 1H), 5.17 (s, 2H), 5.16 (s, 2H), 3.90 (s, 3H); C NMR (100
MHz, Acetone) δ 142.5, 142.2, 140.0, 131.4, 126.4, 123.6, 123.4, 120.8, 119.6, 113.0, 109.6, 102.0, 73.9,
+
7
3.5, 29.4; HRMS: Calcd for C H NO (M+H) 224.1075, found 224.1078.
1
5
14
5
-benzyl-3,5-dihydro-1H-furo[3,4-b]carbazole (7i). Following the general procedure, pure product 7i was
isolated by flash chromatography on silica gel (hexane:EtOAc 8:1). State: white solid; mp 128-132 °C;
1
yield: 5 mg, 12%; H NMR (400 MHz, CDCl ) δ 8.15 (d, J = 7.8 Hz, 1H), 8.04 (s, 1H), 7.54 (d, J = 8.2 Hz,
3
1
3
1
H), 7.45-7.39 (m, 8.3 Hz, 2H), 7.29-7.17 (m, 6H), 5.66 (s, 2H), 5.16 (s, 2H), 5.12 (s, 2H); C NMR (100
MHz, Acetone) δ 142.2, 142.0, 139.2, 138.8, 131.8, 129.5, 128.2, 127.5, 126.6, 123.8, 123.6, 120.9, 119.9,
+
1
13.2, 110.2, 102.7, 73.8, 73.5, 46.9; HRMS: Calcd for C21
H
17NONa (M+Na) 322.1208, found 322.1207.
3
,5-dihydro-5-(methoxymethyl)-4-(1-(methoxymethyl)-1H-indol-3-yl)-1H-furo[3,4-b]carbazole
(9a).
Following the general procedure, pure product 9a was isolated by flash chromatography on silica gel
1
(
hexane:EtOAc 5:1). State: white solid; mp 125-128 °C; yield: 68 mg, 82%; H NMR (400 MHz, CDCl ) δ
3
8
.09 (d, J = 7.8 Hz, 1H), 7.94 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.45-7.44 (m, 2H), 7.34-7.26 (m, 4H), 7.13 (t,
J = 7.5 Hz, 1H), 5.44 (ABq, JAB = 10.8, 2H), 5.35 (s, 2H), 5.15 (s, 2H), 5.02 (d, J = 12.4 Hz, 1H), 4.90 (d, J
1
3
=
3
12.4 Hz, 1H), 3.34 (s, 3H), 2.77 (s, 3H); C NMR (150 MHz, CDCl ) δ 142.0, 140.2, 139.3, 136.5, 131.2,
1
7
28.7, 126.8, 126.1, 125.2, 123.5, 123.2, 121.0, 120.4, 120.3, 119.9, 112.3, 111.7, 111.6, 110.4, 110.2, 77.7,
+
4.4, 74.3, 73.9, 56.1, 55.2. HRMS: Calcd for C H N O Na (M+Na) 435.1685, found 435.1684.
2
6
24
2
3
2
8