: NBu4NPF6 promoted regioselective cascade synthesis of functionally embellished naphthofurans under acid, metal & solvent free conditions

Article abstract of DOI:10.1039/c6ra17411f

ⁿBu₄NPF₆ mediated highly regioselective synthesis of functionally embellished naphthofurans has been achieved from easily available naphthols and propargyl alcohols through a cascade benzylation, oxacyclisation (5-exo dig) and isomerization under solvent free conditions. The reaction works in a short time through dibenzyl ether formation followed by the decomposition to the carbocation to furnish the high yielding products with large substrate scope. The synthetic utility of the products is demonstrated through C(sp³)-H functionalization. In addition, we investigated selected naphthofurans for their anti-amyloidogenic properties. Preliminary studies suggest that these are excellent inhibitors for amyloid formation, a hallmark for several neurodegenerative diseases.

Full text of DOI:10.1039/c6ra17411f

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DOI: 10.1039/C6RA17411F
Journal Name
COMMUNICATION
nBu4NPF6 Promoted Regioselective Cascade Synthesis of
Functionally Embellished Naphthofurans under Acid, Metal &
Solvent Free Conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Abhishek Pareek, Ravikrishna Dada, Monika Rana, Anuj K. Sharma and Srinivasarao Yaragorla*
DOI: 10.1039/x0xx00000x
www.rsc.org/
derivatives.9
A base promoted naphthofuran synthesis was
nBu4NPF6 mediated highly regioselective synthesis of functionally
embellished naphthofurans has been achieved from easily
available naphthols and propargyl alcohols through a cascade
benzylation, oxacyclisation (5-exo dig) and isomerization under
solvent free conditions. The reaction works in a short time
reported in chloroform starting from naphthols and nitroallylic
acetates.10 Although there are a number of methods reported for
the synthesis of 2,3-disubstituted benzofurans, only a limited
number of methods are available for the synthesis of 2,3-
disubstituted naphthofurans. Some of them suffer from the
drawbacks such as multistep procedures, inert conditions, longer
reaction times, poor substrate scope, use of chlorinated solvents,
transition metal catalysts, acid catalysts and the use of starting
materials which are not easily available. Hence it is highly desired to
develop a regioselective, metal, acid and solvent free, one-pot
(single step) synthesis of functionally embellished naphthofurans
starting from easily available materials under simple reaction
procedures.
through
a
dibenzyl ether formation followed by the
decomposition to the carbocation to furnish the high yielding
products with large substrate scope. The synthetic utility of the
products are demonstrated through C(sp3)-H functionalization. In
addition, we investigated selected naphthofurans for their anti-
amyloidogenic properties. Prelimininary studies suggest that these
are excellent inhibitors for amyloid formation, a hallmark for
several neurodegenrative diseases.
Previous approaches
OH
Naphthofurans and benzofurans belong to the important class of
oxygen containing heterocyclic compounds that possess a spectrum
of biological and pharmacological properties.1-3 They are integral
TsOH, DCM
r.t., 2-24 h
t-BuOK,
OH
O
Ph
16a
OH
Ar
+
r.t., 5-20 h
Ph
Ar
Ar
Ar
Ph
part of several natural
Furomollugin, Viniferifuran, Anigopreissin
&
synthetic molecules (for example
7-methoxy-2-
A
&
OH
FeCl3, MeCN
r.t., 3-72 h
K2CO3
OH
O
Ph
nitronaphtho[2,1-b]furan (R7000) etc. and serve as building blocks
in the organic synthesis.2 Naphthofuran moiety is proved as
“privileged structure”4 to design potential anticancer agents1a and
regulators of the nuclear receptors HNFa7.5 Owing to these
Ar
OH
26d
sealed tube,
80 oC, 2-26 h
+
Ph
Ar
Ph
O
OH
+
(1). K2CO3, toluene, r.t., 1- 5 h
CO2Et
NO2
Ar
AcO
important features several synthetic approaches have been
emerged for the synthesis of naphthofurans.1h,
37, 410
or
6-10.
CO2Et
Most of the
Ar
(2). Cs2CO3, CHCl3, r.t., 4 h
methods were involved in two to three step syntheses starting from
suitable propargyl alcohols and naphthols such as a metal/ acid
catalyzed benzylation followed by the base mediated oxacyclization
and isomerization (Figure 1, eq. 1 & 2).6, 1h It is also reported that
arenols react with Morita-Baylis-Hillman (MBH) acetates in
presence of a base and toluene as the reaction medium to form
naphthofurans (Figure 1, eq. 3 & 4) though the method goes
through a single step, the use of MBH acetates makes this method
less amenable.7 In(OTf)3 catalyzed coupling of naphthols with
nitroalkenes in DCE has also been reported.8 Organometallic cross
coupling reactions also used to synthesize the benzo/naphthofuran
This work
COOEt
* METAL-FREE
* ACID-FREE
* BASE-FREE
* SOLVENT-FREE
OH
Bu4NPF6,
120 oC, 1.5-3 h
O
CO2Et
*
ONE POT
Ar
HO
Ar
Figure 1.
Previous reports on the synthesis of 2-alkyl, 3-aryl naphthofurans.
Naphthofuran derivatives are well known as imaging agents for β-
amyloid plaques in the brain.5 Amyloid formation is related to
several devastating diseases including the most common
neurodegenerative disease, Alzheimer’s disease (AD).12 AD is
characterized by deposits of amyloid β-peptide (Aβ) in the brain and
the disease still lacks a specific treatment.13 In fact, there is a great
demand for compounds that can interact with early stage oligomers
Department of Chemistry,
Central University of Rajasthan, NH-8, Bandersindri,
Ajmer-district, Rajasthan, 305817, India
E-mail: srinivasarao@curaj.ac.in & ysriict@gmail.com
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Journal Name
or amyloid plaques and/or either inhibit their formation or cause
their dissolution into monomeric peptide.14 Only a few of the
polyphenolic compounds, benzothiazole based small molecules are
known to inhibit the amyloid formation.15 Interestingly, our
preliminary analysis suggest that these naphthofuran derivatives
exhibit excellent anti-amyloidogenic properties as they very
efficiently inhibit fibrilization of lysozyme from chicken egg white, a
readily available protein that undergo fibrilization. The detailed
investigation is still in progress and the results will be published
elsewhere.
neat conditions (entry 15). Considering the importanVcieewoAfrtBicule4ONnPlinFe6
we carried out the reaction with 10 mol% of Bu4NPF6
DOI: 10.1039/C6(RwAi1t7h4o1u1Ft
Ca(OTf)2) and were delighted to see the formation of 3a in 72%
after 7 h (entry 4, Table 1). Increase in the catalyst (Bu4NPF6)
loading from 10-15 and 15-20 mol% has showed the remarkable
effect on the reaction time and yield (entries 4-6). The reaction
gave 90% of 3a with in 2.5 h with 20 mol% of Bu4NPF6 at 120 oC
(entry 6).20
Table 1. Optimization of reaction condition for the one-pot cascade
synthesis of 2-alkyl3-aryl naphthofurana
On the other side the alarming calls of the global warming
emphasize “the role of chemistry in investigating a sustainable
future.”16 In response to the global demand to develop the green
synthetic protocols,17 we are working towards the development of
novel green synthetic procedures for various biologically relevant
18
Temperature
(oC)b
Solve
nt
Yield
(%)c
Entry Catalyst (mol%)
Time (h)
molecules
(Privileged Structures) including our recent work
towards the synthesis of fused benzofurans using an alkaline earth
catalyst.1f In continuation, here in we report a Bu4NPF6 catalysed,
highly regioselective, acid, metal & solvent free synthesis of 2-
Ca(OTf)2/
1
120 ᵒC
120 ᵒC
neat
70
4.5 h
Bu4NPF6 (10/10)
Ca(OTf)2/
alkyl-3-aryl-naphthofurans
using
a
cascade
2
neat
neat
neat
62
24
72
4.5 h
5 h
Bu4NPF6 (10/5)
benzylation/oxacyclisation/isomerization strategy.
120 ᵒC
120 ᵒC
120 ᵒC
3
4
Ca(OTf)2 (10)
Bu4NPF6 (10)
7 h
5
6
7
Bu4NPF6 (15)
Bu4NPF6 (20)
Bu4NPF6 (20)
neat
neat
neat
81
4 h
120 ᵒC
90
2.5 h
24 h
rt
trace
15
8
9
Bu4NPF6 (20)
Bu4NPF6 (20)
60 ᵒC
80 ᵒC
neat
neat
24 h
24 h
21
10
11
Bu4NPF6 (20)
Bu4NPF6 (20)
100 ᵒC
90 ᵒC
neat
71
<5
12 h
10 h
EtOH
12
13
Bu4NPF6 (20)
Bu4NPF6 (20)
50 ᵒC
70 ᵒC
DCM
56
10 h
10 h
The schematic representation of our concept for the
regioselectivity has been described in the Figure 2. The benzyl
intermediate (I) will have two possible pathways of cyclization,
either a nucleophilic (phenolic oxygen) addition at β-carbon
through a 5-exo dig fashion to furnish the naphthofuran, or the
nucleophilic addition at α-carbon through a 6-endo dig fashion to
furnish the naphthopyran. We believe that the R group will play a
MeOH trace
Benze
12
ne
14
Bu4NPF6 (20)
-
90 ᵒC
10 h
10 h
15
16
17
120 ᵒC
120 ᵒC
120 ᵒC
neat
neat
neat
nr
<5
15
NH4Cl (20%)
Bu4NF (20%)
8 h
8 h
critical role to differentiate
α & β carbons and thus the
regioselectivity could be achieved.
18
120 ᵒC
neat
KPF6 (20%)
trace
8
8 h
8 h
Our investigations began by treating the stoichiometric amount of
2-naphthol (1a) and 4-hydroxy-4-phenylbut-2-ynoate (2a) with 10
o
mol% of Ca(OTf)2/Bu4NPF6 under solvent free conditions at 120 C
19
20
21
Proline 10%
120 ᵒC
120 ᵒC
120 ᵒC
neat
neat
neat
45d
60
8 h
8 h
(entry 1, Table 1).[19] As expected the reaction gave the desired
ethyl 2-(3-phenylnaphtho[1,2-b]furan-2-yl)acetate (3a) in 70%
after 4.5 h. When the same reaction was repeated with 10 mol%
of Ca(OTf)2 & 5 mol% of Bu4NPF6 only 62% of 3a was isolated. This
indicated that Bu4NPF6 has an important role in increasing the yield
of 3a. Further to confirm this, we performed the reaction in the
absence of Bu4NPF6 (entry 3, Table 1) and were surprised to note
that only 24% of 3a was formed after 5 h. The absence of
catalyst/additive could not proceed even after 10 h at 120 oC under
PTSA 10%
NbCl5 10%
[a] 1a (1.1 eq), 2a (1 eq). [b] Oil bath temperature. [c] Isolated yields. [d]
Combined yield for the mixture of furan/pyran
To check the temperature effect we performed the same
o
reaction at various temperatures such as rt, 60 C, 80 C, 100
oC & 120 oC and found that 120 oC is the optimum temperature
o
2 | J. Name., 2012, 00, 1-3
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(Table 1, entries 6-10). The role of solvents in this reaction has Encouraged by the reactivity of 2-naphthol derivatives towards
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DOI: 10.1039/C6RA17411F
been studied using ethanol, dichloromethane, methanol and the synthesis of naphtho[2, 1-b]furans, we looked forward to
benzene under the reflux conditions (entries 11-14) and found make the complimentary class of furans i.e. naphtho[1, 2-
that the reaction works better under solvent free conditions. b]furans for which we used the 1-naphthol (
4) against benzylic-
The catalytic activity of the other ammonium derivatives such propargylic alcohols ). The initial product ethyl 2-(3-
(2
as NH4Cl (20 mol%) & nBu4NF was studied and found that none phenylnaphtho[1, 2-b]furan-2-yl)acetate (5a) was realized in
of them proved to be useful (entries 16, 17). A phosphorous 92 % yield after 2.5 h when 2a was treated with 1-naphthol
salt, KPF6 was tried but only traces of 3a could be detected under the optimum conditions (Table 3). In the similar fashion
(entry 18). Proline (an organocatalyst) could not produce more other benzylic-propargylic alcohols (2) bearing 4-methyl, 4-
that 8% of 3a (entry 19). PTSA (a Bronsted acid) gave the methoxy, 4-bromo, 4-chloro and 4-fluoro substitutions on the
mixture of furan/pyran (45%, no regioselectivity) after 8 h phenyl ring smoothly reacted with 1-naphthol to provide the
(entry 20). NbCl5 (an oxophilic transition metal catalyst) could corresponding naphtho[1, 2-b]furans in good yields (Table 3,
yield maximum of 60% of 3a at 120 oC (entry 21).
Having the conditions set for the Bu4NPF6 catalysed reacted with 1-naphthol to furnish the 2-alkyl-3-
regioselective cascade synthesis of naphthofurans, we further arylnaphthofurans 5g 5h 5i in 84%, 93, 81% yields. Similarly
studied the scope of the various naphthols (1, 4) and benzylic 6-methoxy-1-naphthol furnished the naphthofurans 5j
propargylic alcohols ( ) in the methodology. The benzylic 75, 77% yields (Table 3).
alcohol bearing 4-methyl substitution on the phenyl ring (2b
products 5b, 5c, 5d, 5e & 5f). Methyl ester derivatives of 2 also
,
&
&
5k in
2
)
Table 3.
naphtho[1, 2-b]furansa
Substrate scope of Bu4NPF6 catalyzed one-pot cascade synthesis of 2-alkyl, 3-aryl
was reacted with 2-naphthol for 3 h 10 min to yield the
OH
naphthofuran 3b in 81% yield. Similarly 4-methoxy, 4-bromo
OH
COOR'
Bu4NPF6 (20 mol%),
Solvent-free, 120 oCb
O
and 4-fluoro derivatives (2c
respective naphthofurans 3c
,
2d and 2e) furnished the
3d and 3e in 84, 92 & 80%
+
COOR'
R
R
,
X
X=H; 4a
X=OMe;
2
5
4b
X
respective yields (Table 2, first row). The second row of the
Table 2 shows that naphthofuran derivatives 3f 3g and 3h
,
COOEt
COOEt
COOEt
COOEt
with methyl esters were synthesized in 86, 81 & 80% yields.
6-bromo-2-naphthol reacted with both the propargyl alcohols
bearing ethyl & methyl esters to yield the corresponding
naphtho[2,1-b]furans 3i-3n in good yields (Table 2, entries 3i-
3n).
O
O
O
O
Me
OMe
Br
5a
5b
5c
93%, 2.3 h
5d
92%, 2.5 h
88%, 1.5 h
85%, 2.5 h
COOEt
COOEt
COOMe
COOMe
O
O
O
O
Table 2. Substrate scope of Bu4NPF6 catalyzed one-pot cascade synthesis of 2-alkyl, 3-aryl naphtho
[2,1-b]furans [a]
Cl
F
OMe
Me
R
COOR1
OH
OH
5e
75%, 3 h
5f
5h
93%, 2.5 h
5g
nBu4NPF6 (20 mol%),
Solvent free, 120 oCb
85%, 2.5 h
84%, 2.5 h
O
X
+
COOR1
R
1a
X=H;
X
COOMe
COOEt
COOEt
2
X=Br; 1b
3
O
O
O
F
Me
MeO
COOEt
Br
F
OMe
5j
75%, 2.5 h
OMe
COOEt
COOEt
COOEt
COOEt
5i
5k
81%, 3 h
77%, 2.5 h
O
O
O
O
O
[a] reaction conditions: 1 (1.1 eq), 2 (1 eq) Bu4NPF6 (0.2 eq), 120 oC; [b] Oil bath temperature
3a
3e
80%, 2 h
3b
81%, 3 h
3c
84%, 2 h
3d
92%, 2.3 h
90%, 2.5 h
Further alkynol 10a (R=TMS) reacted with 2-naphthol under
same conditions and yielded the 2-methyl, 3-phenyl
naphthofuran 11 in 65% after 5h (Scheme 1). Probably due to
the presence of fluorine in the reaction (in the form of
catalyst) the silyl group could have deprotected.[1f] 1-
phenylprop-2-yn-1-ol (10b, a terminal alkyne) gave the same 2-
methyl, 3-phenyl naphthofuran 11 in 69% yield.
F
Me
MeO
COOMe
COOMe
O
COOEt
COOEt
COOMe
Br
O
O
O
O
Br
3h
3i
3j
82%, 2 h
3f
3g
81%, 3 h
80%, 3 h
79%, 1.5 h
86%, 2 h
MeO
Me
Me
MeO
O
COOEt
COOEt
COOMe
COOMe
OH
OH
Me
Bu4NPF6 (20 mol%)
neat, 120 oC, 5 h
O
O
O
O
+
R
Br
Br
Br
Br
3k
1a
3l
3m
88%, 2 h
3n
11
10a
; R= TMS
10b
; R=H
84%, 2.3 h
85%, 2 h
84%, 2.3 h
65% with 10a
10b
69% with
[a] reaction conditions: 1 (1.1 eq), 2 (1 eq) Bu4NPF6 (0.2 eq), 120 oC; [b] Oil bath temperature
Scheme 1. Regioselectve studies of 1-naphthol with trimethylsilyl & terminal alkynes.
This journal is © The Royal Society of Chemistry 20xx
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Further 7a1 undergoes 5-exo dig oxa-cyclisation V(i7ewa2Ar)t,iclaesOntlhinee
The scope of various phenols also has been investigated β-carbon is more electrophilic to be aDttOaIc: k10e.d103b9y/C6pRhAe1n74o1l1iFc
under the same reaction conditions (Scheme 2). When the oxygen and the resultant α-carbanion is stabilized by the ester
reaction of alkynol 2a was performed with simple phenol, it group. Protonation of 7a2 will lead to the formation of
could not yield the expected benzofuran but the naphthofuran with exo cyclic double bond 7a3 (isolated and
corresponding benzyl ether was obtained. But in case of m- characterized), which further isomerizes to the final compound
hydroxyanisole (which has two ortho-nucleophilic sites) 3a
and benzylic alcohol 2a, the reaction gave the regioisomeric
.
To authenticate the mechanism proposed in the Scheme 3,
ether 7 was isolated and separately treated with 2-
naphthol under the same reaction conditions to obtain the
naphthofuran 3a in 88% yield after 1.5 h (Figure 3).
benzofurans 6a
& 6b in 33%, 39% isolated yields
respectively after 4 h (Scheme 1). p-cresol and o-cresol
reacted with 2a and yielded benzofurans 6c and 6d in 83%,
81% yields. p-cresol was also furnished the benzofuran 6e
in 85% yield after 2 h (Scheme 2).
Bu4NPF6
(20 mol%)
HO
OH
+
COOR
120 o
C
R1
R2
2
COOEt MeO
O
COOEt
O
R=Et, R1=H, R2=H
7
only formed
+
no further reaction
OMe
6b
6a
As we proposed in our regioselective conceptualization in
Figure 2, if ester group is replaced by a phenyl group the
reaction should yield naphthopyrans instead of naphthofurans.
This could be explained based on the mechanism proposed in
the Scheme 3, the benzylated intermediate 7a1 (-CO2Et=Ph)
will undergo a 6-endo dig cylisation as the benzylic position (α-
carbon) is more electrophilic to be cyclised by the phenolic
oxygen. In this case the 5 exo dig cyclisation is not preferred as
R=Et, R1=H, R2=3-OMe,
regio-isomeric mixture
6a/6b in 6a,
of
33% & 39% in 4 h.
O
Me
O
O
OEt
O
OEt
OMe
O
O
Me
Me
F
R=Me, R1=H, R2=4-Me,
6d,
R=Et, R1=H, R2=4-Me,
6c
R=Et, R1=F, R2=4-Me
6e
2.3 h, 81%
, 1.5 h, 83%
the benzylic anion is less stable
(7a2, -CO2Et=Ph). To
, 2 h, 85%
experimentally validate this, We performed a reaction with 2-
naphthol and 1,3-diphenylprop-2-yn-1-ol derivatives (Scheme
Scheme 2. Scope of various substituted phenols.
3, 8a-8c
conditions. Interestingly, all three alkynols 8a
the naphthopyrans 9a 9b
)
at 120 oC using 20 mol% of Bu4NPF6 under neat
The Plausible mechanism for this cascade regioselective
synthesis has been demonstrated in the Scheme 3. Initially
,
8b
& 8c gave
,
& 9c (Scheme 4) in moderate yields
benzylic alcohol
presence of Bu4NPF6 to afford the dibenzyl ether
and characterized). At this temperature ether will collapse to
2
will undergo heat induced dehydration in
after 4 h.21 Yields could not increase even after continuing the
reactions till 12 h.
7
(isolated
7
form the benzyl carbocation 7a and alcohol in a reversible
pathway. Once the carbocation is available in the reaction
mixture it will undergo nucleophilic substitution with naphthol
(1a) to form the benzyl intermediate 7a1 (which was isolated
and characterized).
The utility of the 2-alkyl-3-aryl naphthofurans as the useful
building blocks in the organic synthesis has been successfully
delineated by functionalizing the sp3 C-H bond which is α to
the ester functionality. Naphthofuran 3a was subjected to the
22
DDQ mediated oxidative etherification
(Scheme 5) with
propargyl alcohol at room temperature for 12 h to yield the
respective propargyl ether 12a in 72% yield. Naphthofuran 3c
was also reacted with propargyl alcohol under same conditions
and yielded the ether 12b in 70% yield. The resultant propargyl
ethers (12a and 12b) were further subjected to the “click
reaction” conditions with benzyl azides under standard
4 | J. Name., 2012, 00, 1-3
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[23]
conditions
derivatives 13a
(CuI, NEt3, DMSO, rt) to isolate the triazole monitor the progress of aggregation.27 InteresVtiienwgAlyrti,cletOhnelisnee
DOI: 10.1039/C6RA17411F
,
13b
,
13c
&
13d in 81-86% yields (Scheme 5).
three compounds inhibit lysozyme aggregation by 85, 92 and
90%, respectively (Figure 4). The results suggest that
naphthofuran framework is a good inhibitor of amyloid
formation and minor substitution may not bring any big
change. Although we anticipated some inhibition by these
compounds given previous reports, a complete inhibition of
lysozyme fibrilization is unprecedented and deserves more
investigation in future.
140
e
m
y
120
z
o
s
y
L
100
80
60
f
3
+
e
j
k
5
5
m
40
20
0
+
y
+
e
z
e
o
m
s
m
y
y
y
z
z
L
o
o
s
s
y
y
L
L
Encouraged by the successful functionalization of sp3 C-H bond
of 2-alkyl, 3-aryl naphthofurans to prepare propargyl ethers
and triazoles, we decided to further look into the preparation
of α-bromoesters which are well known building blocks & feed
stock materials in the organic synthesis.24 α-bromination of 3c
was achieved by refluxing with N-bromosuccinamide (NBS) in
CCl4 for 10 h to furnish the α-bromoester 14 in 71% yield
(Scheme 6).
250
200
150
100
50
Lysozyme
Lysozyme+3f
Lysozyme+5j
Lysozyme+5k
0
460 480 500 520 540 560 580 600
Wavelength(nm)
Anti-amyloid Activity. Since naphthofuran derivatives and
Figure 4. (Top) Normalized ThT fluorescence intensities for
lysozyme fibrils without inhibitors and with inhibitors 3f, 5j and 5k,
respectively; (bottom) Thioflavin-T (ThT) fluorescence spectra with
lysozyme fibrils without inhibitors and lysozyme fibrils containing
inhibitors 3f, 5j, and 5k, respectively.
related compounds have been shown to interact with amyloid
plaques,11 we were curious to explore their effect on amyloid
formation. Selected three compounds were investigated for
their anti-amyloidogenic properties. Compound 3f from 2-
alkyl, 3-aryl naphtho[2,1-b]furans series and 5j, 5k from 2-
alkyl, 3-aryl naphtho[1, 2-b]furans series were selected as
representatives of the two categories of compounds reported
in this work. Compound 5k was also selected to see if fluoro-
substitution brings any additional change in these studies.
Amyloid binding compounds having a fluoro-substitution can
be of potential application for positron emitting tomography
(PET).25
EXPERIMENTAL SECTION
General information: Unless otherwise noted, all reagents were
used as received from commercial suppliers. Bu4NPF6 catalyst were
obtained from Sigma-Aldrich and used without further purification.
THF was dried in the presence of sodium metal using
benzophenone as indicator and distilled prior to use. Reactions
were monitored using thin-layer chromatography (TLC) with
aluminium sheets silica gel 60 F254 from Merck. TLC plates were
visualized with UV light (254 nm), iodine treatment or using p-
We performed the inhibition assays using lysozyme enzyme
from chicken egg white as it is a readily available amyloid
forming protein.26 Thioflavin-T (ThT) assay were used to
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Journal Name
anisaldehyde or KMNO4 stain. Column chromatography was carried 2H), 3.90 (s, 3H), 3.75 (s, 2H), 1.25 (t, J = 7 Hz, 3H) ppm; 13C NMR
View Article Online
DOI: 10.1039/C6RA17411F
out using silica gel 60-120 mesh as stationary phase. NMR spectra (125 MHz, CDCl3): δ 169.4, 159.4, 151.8, 146.9, 131.6, 130.8, 128.9,
were recorded at 500 MHz (H) and at 125 MHz (C), respectively on 128.2, 125.9, 125.4, 125.2, 124.2, 123.1, 122.2, 121.3, 114.2, 112.4,
Avance Bruker spectrometer. Chemical shifts (δ) are reported in 61.4, 55.4, 33.0, 14.2 ppm; IR (KBr): υ 3048, 2923, 2834, 1735, 1598,
ppm, using the residual solvent peak in CDCl3 (H: δ = 7.26 and C: δ = 1576, 1510, 1462, 1392, 1248, 1179, 1027, 806 cm-1, HRMS (ESI)
77.0 ppm) as internal standard, and coupling constants (J) are given m/z calcd. for C23H20O4 [M +Na]+ 383.1259; found 383.1255.
in Hz. HRMS was recorded using ESI-TOF techniques. Melting points Ethyl
2-(1-(4-bromophenyl)naphtho[2,1-b]furan-2-yl)acetate
were measured with Büchi Melting Point B-540 apparatus.
(3d)10a: Sticky white solid; (71.0 mg 92%); 1H NMR (500 MHz, CDCl3):
General Experimental procedure for the synthesis of propargylic δ 7.96 (d, J = 8 Hz, 1H), 7.76 (t, J = 9.5 Hz, 2H), 7.7 (d, J = 8 Hz, 3H),
alcohol derivatives (2, 8 &10)1h: LHMDS (1.2 mmol) was added to a 7.46 (d, J = 8.5 Hz, 3H), 7.37 (d, J = 8 Hz, 1H), 4.24 - 4.20 (m, 2H),
stirred solution of alkyl propiolate or phenyl acetylene (1.1 mmol) in 3.77 (s, 2H), 1.29 (t,
J
= 7.5 Hz, 3H) ppm; 13C NMR (125 MHz,
o
dry THF (15 ml.) at -78 C and stirred for 30 minutes at the same CDCl3): δ 169.1, 151.9, 146.9, 132.3, 132.1, 132.0, 130.8, 129, 127.8,
temperature. Aryl aldehyde (1 mmol) was added slowly to the 126.1, 125.8, 124.4, 122.9, 122.3, 121.6, 120.6, 112.3, 61.5, 33.0,
reaction mixture at -78 oC and the reaction progress was monitored 14.2 ppm; IR (KBr): υ 3055, 2982, 2923, 1735, 1576, 1488, 1388,
by TLC. After completion, the reaction was brought to rt, quenched 1362 cm-1, HRMS (ESI) m/z calcd. for C22H17BrO3 [M +Na]+ 431.0258;
with aq-saturated NH4Cl and extracted into EtOAc thrice. The found 431.0250.
combined organic layers were washed with brine solution and dried Ethyl 2-(1-(4-fluorophenyl)naphtho[2,1-b]furan-2-yl)acetate (3e):
over anhydrous Na2SO4. The solvent was removed under reduced Pale green viscous; (62.6 mg 80%); 1H NMR (500 MHz, CDCl3): δ 7.95
pressure and the crude product was purified by silica gel column (d, J = 8 Hz, 1H), 7.77 (d, J = 9 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.57 -
chromatography (8-10 % EtOAc in pet-ether) to obtain the desired 7.54 (m, 2H), 7.46 - 7.43 (m, 1H), 7.37 - 7.35 (m, 1H), 7.25 (dd, J =
products 2, 8 or 10.
1.5 Hz, J = 6.5 Hz, 2H), 4.24 - 4.21 (m, 2H), 3.77 (s, 2H), 1.29 (t, J = 7
General procedure for the Bu4NPF6 catalyzed synthesis of 2-alkyl, - Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 169.2, 163.7, 161.7,
aryl naphthofurans (3, 5, 9, & 11): A mixer of suitable propargylic 151.8, 147.0, 132.2, 132.1, 130.8, 129.0, 128.0, 126.0, 125.7, 124.3,
alcohol (2, 8 or 10, 1.0 mmol) and naphthol 1 or 4 (1.1 mmol) was 122.9, 115.9, 115.8, 112.4, 61.5, 33.0, 14.2 ppm; IR (KBr): υ 3063,
heated at 120 oC in presence of Bu4NPF6 (20 mol%) for 1.5 - 5h. 2974, 2915, 1738, 1572, 1447, 1395, 1318, 1189 cm-1 ; HRMS (ESI)
After completion of reaction (monitored by TLC), the reaction m/z calcd. for C22H17FO3 [M + Na]+ 371.1059; found 371.1062.
mixture was diluted with water, extracted with EtOAc thrice, the Methyl 2-(1-(p-tolyl)naphtho[2,1-b]furan-2-yl)acetate (3f): Light
1
combined organic layers were washed with brine solution and dried yellow viscous liquid; (69.6 mg 86%); H NMR (500 MHz, CDCl3): δ
over anhydrous Na2SO4. Solvent was removed under reduced 7.94 (d, J = 8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 9 Hz, 1H),
pressure and the crude product was purified by silica gel column 7.70 (d, J = 9 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.36 (t, J = 9.5 Hz, 1H),
chromatography (3-5 %, EtOAc in pet ether) to obtain the desired 7.28 (s, 3H), 3.81 (s, 2H), 3.76 (s, 3H), 2.52 (s, 3H) ppm; 13C NMR
product 3, 5, 9 & 11.
Ethyl 2-(1-phenylnaphtho[2,1-b]furan-2-yl)acetate (3a)10a
(125 MHz, CDCl3): δ 169.9, 151.9, 146.6, 137.8, 130.8, 130.3, 130.0,
:
Light 129.5, 128.9, 128.2, 125.9, 125.5, 124.2, 123.2, 122.0, 121.7, 112.3,
o
1
yellow solid; (76.6 mg, 72%); mp 79 - 80.5 C; δ H NMR (500 MHz, 52.5, 32.8, 21.4 ppm; IR (KBr): υ 3060, 2974, 2915, 1738, 1572,
CDCl3): δ 7.95 (d, J = 8 Hz, 1H), 7.79 - 7.76 (m, 2H), 7.71 (d, J = 9 Hz, 1447, 1395, 1318, 1180 cm-1; HRMS (ESI) m/z calcd. for C22H18O3 [M
1H), 7.59 - 7.52 (m, 5H), 7.43 (t, J = 7.5 Hz, 1H), 7.33 (t, J = 7.5 Hz, + Na]+ 353.1157; found 353.1165.
1H), 4.23 - 4.12 (m, 2H), 3.78 (s, 2H), 1.29 (t, J = 7 Hz, 3H) ppm; 13C Methyl 2-(1-(4-methoxyphenyl)naphtho[2,1-b]furan-2-yl)acetate
1
NMR (125 MHz, CDCl3): δ 169.3, 151.9, 146.9, 133.2, 130.8, 130.4, (3g): Pale orange viscous liquid; (63.7 mg 81%); H NMR (500 MHz,
128.9, 128.8, 128.5, 128.3, 128.0, 125.9, 125.5, 124.2, 123.1, 121.9, CDCl3): δ 7.94 (d, J = 8 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.81 (d, J =
112.4, 61.4, 33.0, 14.2 ppm; IR (KBr): υ 3063, 2974, 2915, 1738, 8.5 Hz, 1H), 7.75 (d, J = 9 Hz, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.48 (dd, J
1572, 1447, 1395, 1318, 1189 cm-1, HRMS (ESI) m/z calcd. for = 2 Hz, J = 6.5 Hz, 1H), 7.10 - 7.08 (m, 2H), 7.08 - 7.02 (m, 1H), 3.94
C22H18O3 [M + Na]+ 353.1157; found 353.1165.
(s, 3H), 3.8 (s, 2H), 3.76 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ
Ethyl 2-(1-(p-tolyl)naphtho[2,1-b]furan-2-yl)acetate (3b)7: Light 169.7, 159.4, 151.9, 146.7, 132.0, 131.5, 130.8, 128.9, 128.2, 125.9,
o
1
orange solid; (64.1 mg 81%); mp 70.5 - 72.5 C; H NMR (500 MHz, 125.5, 125.1, 124.2, 123.1, 121.3, 114.3, 112.3, 55.4, 52.5, 32.7
CDCl3): δ 7.95 (d, J = 8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8 ppm; IR (KBr): υ 3063, 2974, 2915, 1738, 1572, 1447, 1395, 1318,
Hz, 1H), 7.7 (d, J = 9 Hz, 1H), 7.42 - 7.47 (m, 3H), 7.38 - 7.32 (m, 3H), 1189 cm-1; HRMS (ESI) m/z calcd. for C22H18O4 [M + H]+ 347.1283;
4.24 - 4.20 (m, 2H), 3.79 (s, 2H), 2.52 (s, 3H), 1.29 (t, J = 7 Hz, 3H) found 347.1282.
ppm; 13C NMR (125 MHz, CDCl3): δ 169.4, 151.8, 146.8, 137.7, Methyl 2-(1-phenylnaphtho[2,1-b]furan-2-yl)acetate (3h): Yellow
130.8, 130.3, 130.1, 129.5, 128.8, 128.1, 125.9, 125.4, 124.2, 123.2, viscous liquid; (66.3 mg, 80%); 1H NMR (500 MHz, CDCl3): δ 7.93 (d,
121.6, 118.0, 112.4, 61.4, 33.0, 21.4, 14.2 ppm; IR (KBr): υ 3020 , J = 8.5 Hz, 1H), 7.77 - 7.68 (m, 3H), 7.56 - 7.51 (m, 5H), 7.43 - 7.33
2925, 1735, 1216, 759, 669 cm-1, HRMS (ESI) m/z calcd. for C23H20O3 (m, 2H), 1.99 (s, 2H), 3.75 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ
[M +H]+ 345.1490; found 345.1494.
Ethyl 2-(1-(4-methoxyphenyl)naphtho[2,1-b]furan-2-yl)acetate 124.3, 123.0, 121.9, 121.6, 120.6, 120.5, 111.1, 51.2, 31.5 ppm; IR
168.5, 150.6, 145.4, 131.9, 129.5, 129.1, 127.6, 127.5, 126.8, 124.7,
1
(3c)10a: Light orange viscous liquid; (64.8 mg 84%); δ H NMR (500 (KBr): υ 3063, 2974, 2915, 1738, 1572, 1447, 1395, 1318, 1180 cm-1;
MHz, CDCl3): δ 7.90 (d, J = 8 Hz, 1H), 7.79 (d, J = 8 Hz, 1H), 7.71 (d, J HRMS (ESI) m/z calcd. for C21H16O3 [M + H]+ 317.1177; found
= 8.5 Hz, 1H), 7.65 (d, J = 9 Hz, 1H), 7.46 - 7.44 (m, 2H), 7.37 - 7.41 317.1179.
(m, 1H), 7.39 - 7.31 (m, 1H), 7.05 (d, J = 8.5 Hz, 2H), 4.16 - 4.20 (m,
6 | J. Name., 2012, 00, 1-3
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COMMUNICATION
Ethyl 2-(7-bromo-1-phenylnaphtho[2,1-b]furan-2-yl)acetate (3i): 8 Hz, 1H), 7.81 - 7.78 (m, 2H), 7.7 (d, J = 9 Hz, 1H), 7.57 - 7.54 (m,
View Article Online
1
Orange viscous liquid; (61.0 mg 79%); H NMR (500 MHz, CDCl3): δ 4H), 7.45 - 7.41 (m, 2H), 7.34 - 7.31 (m, 1HD),O4I:.2104.1-0349.2/C06R(mA1,7241H1)F,
8.09 (d, J= 2 Hz, 1H), 7.72 (d, J= 9 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.55 3.79 (s, 2H), 1.29 (t, J = 7 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ
(d, J = 9 Hz, 5H), 7.40 - 7.38 (m, 1H), 4.24 - 4.20 (m, 2H), 3.79 (s, 2H), 169.3, 151.9, 146.9, 130.8, 130.4, 128.9, 128.8, 128.5, 128.3, 128.1,
1.30 (t, J = 14 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 169.2, 126.8, 125.9, 125.5, 124.2, 123.1, 118.0, 112.4, 61.4, 33.0, 14.2
151.9, 147.4, 132.8, 132.1, 130.8, 130.3, 129.1, 128.9, 128.2, 126.5, ppm; IR (KBr): υ 3055, 2982, 2922, 1735, 1580, 1443, 1377, 1252,
124.8, 124.5, 122.1, 121.5, 118.0, 113.4, 61.5, 33.0, 14.2 ppm; 1182, 1027, 982 cm-1, HRMS (ESI) m/z calcd. for C22H18O3 [M + Na]+
HRMS (ESI) m/z calcd. for C22H17BrO3 [M +Na]+ 431.0258; found 353.1157; found 353.1164.
431.0237.
Ethyl 2-(3-(p-tolyl)naphtho[1,2-b]furan-2-yl)acetate (5b)7: Light
1
2-(7-bromo-1-(4-fluorophenyl)naphtho[2,1-b]furan-2- yellow viscous liquid; (69.7 mg 88%); H NMR (500 MHz, CDCl3): δ
Ethyl
1
yl)acetate (3j): Orange viscous liquid; (61.9 mg 82%); H NMR (500 7.94 (d, J = 9 Hz, 1H), 7.82 (d, J = 7 Hz, 1H), 7.75 (d, J = 9 Hz, 1H),
MHz, CDCl3): δ 8.09 (d, J = 2 Hz, 1H), 7.71 (d, J = 9 Hz, 2H), 7.67 (s, 7.69 (d, J = 8.5 Hz, 1H), 7.44 (t, J = 8 Hz, 3H), 7.34 (m, 3H), 4.24 –
1H), 7.50 - 7.53 (m, 2H), 7.42 (s, 1H), 7.26 (t, J = 9 Hz, 2H), 4.20 - 4.20 (m, 2H), 3.78 (s, 2H), 2.51 (s, 3H), 1.28 (t, J = 7 Hz, 3H) ppm; 13
C
4.24 (m, 2H), 3.77 (s, 2H), 1.29 (t, J = 7 Hz, 3H) ppm; 13C NMR (125 NMR (125 MHz, CDCl3): δ 169.42, 151.8, 146.8, 137.7, 130.7, 130.3,
MHz, CDCl3): δ 169.1, 163.8, 161.8, 151.8, 147.6, 132.1, 132.0, 130.1, 129.5, 128.8, 128.1, 125.8, 125.4, 124.2, 123.2, 122.0, 121.6,
130.9, 129.2, 126.4, 124.6, 124.5, 120.5, 118.1, 116.1, 115.9, 113.4, 112.4, 61.4, 33.0, 21.4, 14.2, ppm; IR (KBr): υ 3022, 2983, 2926,
61.5, 32.9, 14.1 ppm; HRMS (ESI) m/z calcd. for C22H16BrFO3 [M 1737, 1513, 1382, 1258, 1216, 812, 758 cm-1, HRMS (ESI) m/z calcd.
+Na]+ 449.0164; found 449.0145.
Ethyl
for C23H20O3 [M +Na]+ 367.1310; found 367.1314.
2-(7-bromo-1-(4-methoxyphenyl)naphtho[2,1-b]furan-2- Ethyl
2-(3-(4-methoxyphenyl)naphtho[1,2-b]furan-2-yl)acetate
yl)acetate (3k): Light orange viscous liquid; (62.8 mg 84%); H NMR (5c)10a: Orange solid; (71.8 mg 93%); mp 85 - 87 ⁰C; H NMR (500
(500 MHz, CDCl3): δ 8.06 (d, J = 2 Hz, 1H), 7.69 - 7.62 (m, 3H), 7.43 MHz, CDCl3): δ 7.95 (d, J = 8 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.76 (d,
(d, J = 8.5 Hz, 2H), 7.38 (dd, J = 2 Hz, J = 7 Hz, 1H), 7.06 (d, J = 8.5 Hz, J = 9 Hz, 1H), 7.71 (d, J = 9 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.46 -
2H), 4.43 - 4.19 (m, 2H), 3.94 (s, 2H), 3.77 (s, 3H), 1.29 (t, J = 7 Hz, 7.43 (m, 1H), 7.37 – 7.32 (t, J = 7 Hz, 1H), 7.10 (d, J = 8 Hz, 2H), 4.26
1
1
3H) ppm; 13C NMR (125 MHz, CDCl3): δ 169.3, 159.5, 151.8, 147.4, - 4.21 (m, 2H), 3.95 (s, 3H), 3.80 (s, 2H), 1.3 (t, J = 7 Hz, 3H) ppm; 13
C
132.1, 131.5, 130.8, 129.1, 126.6, 124.8, 124.4, 122.4, 121.1, 117.9, NMR (125 MHz, CDCl3): δ 169.4, 159.4, 151.8, 146.9, 131.6, 130.8,
114.3, 113.8, 113.4, 61.4, 55.4, 33.0, 14.2 ppm; HRMS (ESI) m/z 128.9, 128.2, 125.9, 125.4, 125.2, 124.2, 123.13, 122.2, 121.3,
calcd. for C23H19BrO4 [M +H]+ 439.0544; found 439.0540.
114.2, 112.4, 61.4, 55.4, 33.0, 14.2 ppm; IR (KBr): υ 2915, 2836,
Ethyl 2-(7-bromo-1-(p-tolyl)naphtho[2,1-b]furan-2-yl)acetate (3l): 1741, 1515, 1459, 1381, 1250, 1179 cm-1, HRMS (ESI) m/z calcd. for
Light yellow viscous liquid; (62.6 mg 85%); 1H NMR (500 MHz, C23H20O4 [M +Na]+ 383.1259; found 383.1255.
CDCl3): δ 8.08 (d, J = 2 Hz, 1H), 7.70 (t, J = 10 Hz, 2H), 7.64 (d, J = 9 Ethyl
2-(3-(4-bromophenyl)naphtho[1,2-b]furan-2-yl)acetate
Hz, 1H), 7.42 - 7.40 (m, 3H), 7.36 (d, J = 7.5 Hz, 2H), 4.24 - 4.20 (m, (5d)10a: Orange solid; (65.6 mg 85%); mp 87 - 89.5 ⁰C; H NMR (500
2H), 3.79 (s, 2H), 2.51 (s, 3H), 1.29 (t, J = 7.5 Hz, 3H) ppm; 13C NMR MHz, CDCl3): δ 7.95 (d, J = 8.5 Hz, 1H), 7.77 (t, J = 9 Hz, 2H), 7.70
(125 MHz, CDCl3): δ 169.2, 151.9, 147.4, 138.0, 132.1, 130.8, 130.2, (dd, J = 2 Hz, J = 7.5 Hz, 3H), 7.48 - 7.45 (m, 3H), 7.38 (dd, J = 1.5 Hz,
129.7, 129.6, 129, 126.6, 124.9, 124.4, 122.2, 121.4, 117.9, 113.4, J = 8.5 Hz, 1H), 4.24 - 4.20 (m, 2H), 3.77 (s, 2H), 1.3 (t, J = 7.5 Hz,
61.4, 33.0, 21.4, 14 ppm; IR (KBr): υ 3063, 2974, 2915, 1738, 1572, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 169.1, 151.9, 146.9, 132.3,
1447, 1395, 1318, 1189 cm-1; HRMS (ESI) m/z calcd. for C23H19BrO3 132.1, 132.0, 130.1, 129.0, 127.9, 126.1, 127.9, 126.1, 125.8, 124.4,
1
[M + Na]+ 445.0415; found 445.0395.
Methyl
2-(7-bromo-1-(p-tolyl)naphtho[2,1-b]furan-2-yl)acetate 3055, 2923, 2843, 1735, 1488, 1377, 1253, 1189 cm-1; HRMS (ESI)
(3m): Light yellow solid; (67.9 mg 88%); mp 139 – 141 C; H NMR m/z calcd. for C22H17BrO3 [M +Na]+ 431.0258; found 431.0259.
(500 MHz, CDCl3): δ 8.08 (d, J = 2 Hz, 1H), 7.72 - 7.64 (m, 3H), 7.43 - Ethyl 2-(1-(4-chlorophenyl)naphtho[2,1-b]furan-2-yl)acetate
122.9, 122.3, 121.6, 120.6, 112.4, 61.5, 33.0, 14.2 ppm; IR (KBr): υ
o
1
1
7.39 (m, 3H), 7.36 (d, J = 8 Hz, 2H), 3.80 (s, 2H), 3.76 (s, 3H), 2.51 (s, (5e)10a: Yellow solid; (57.3 mg 75%); mp 62 - 63.5 ⁰C; H NMR (500
3H) ppm; 13C NMR (125 MHz, CDCl3): δ 169.7, 151.9, 147.1, 138, MHz, CDCl3): δ 7.83 (d, J = 8 Hz, 1H), 7.64 (t, J = 9 Hz, 2H), 7.58 (d, J =
132.1, 130.8, 130.1, 129.7, 129.6, 129.1, 126.6, 124.9, 124.5, 122.2, 8.5 Hz, 3H), 7.35 - 7.31 (m, 3H), 7.26 - 7.23 (m, 1H), 4.1 (q, J = 7 Hz,
121.5, 118.0, 113.4, 52.5, 32.7, 21.4 ppm; HRMS (ESI) m/z calcd. for 2H), 3.65 (s, 2H), 1.17 (t, J = 7 Hz, 3H) ppm; 13C NMR (125 MHz,
C22H17BrO3 [M + Na]+ 431.0258; found 431.0250.
CDCl3): δ 169.1, 159.1, 146.6, 131.3, 130.5, 128.6, 127.9, 125.6,
Methyl 2-(7-bromo-1-(4-methoxyphenyl)naphtho[2,1-b]furan-2- 125.1, 124.9, 123.9, 122.8, 121.9, 121.0, 113.9, 112.1, 61.1, 55.1,
yl)acetate (3n): Light orange viscous liquid; (63.6 mg 84%); 1H NMR 32.7, 13.9 ppm; IR (KBr): υ 3055, 2923, 2841, 1735, 1490, 1377,
(500 MHz, CDCl3): δ 8.08 (d, J = 2 Hz, 1H), 7.87 (d, J = 9 Hz, 1H), 7.71 1255, 1189, 1086 cm-1; HRMS (ESI) m/z calcd. for C22H17ClO3 [M
- 7.64 (m, 3H), 7.46 - 7.41 (m, 2H), 7.08 (dd, J = 2 Hz, J = 6.5 Hz, 2H), +Na]+ 387.0764; found 387.0773.
3.94 (s, 3H), 3.8 (s, 2H), 3.75 (s, 3H) ppm; 13C NMR (125 MHz, Ethyl
2-(3-(4-fluorophenyl)naphtho[1,2-b]furan-2-yl)acetate
CDCl3): δ 169.7, 159.5, 151.8, 147.2, 132.1, 131.4, 130.8, 129.1, (5f): Orange viscous liquid; (66.5 mg 85%); 1H NMR (500 MHz,
126.6, 124.8, 124.4, 122.3, 121.2, 118, 114.3 (2C), 113.4, 55.4, 52.5, CDCl3): 7.95 (d, J = 8 Hz, 1H), 7.77 (d, J = 9 Hz, 1H), 7.74 – 7.69 (m,
32.7 ppm; IR (KBr): υ 3063, 2974, 2915, 1738, 1570, 1447, 1395, 2H), 7.56 – 7.54 (m, 2H), 7.53 (s, 1H), 7.44 (t, J = 7 Hz, 1H), 7.34
1318, 1180 cm-1; HRMS (ESI) m/z calcd. for C22H17BrO4 [M + Na]+ (t, J = 7 Hz, 1H), 7.29 – 7.26 (m, 1H), 4.24 – 4.20 (m, 2H), 3.77 (s,
447.0207; found 447.0193.
2H), 1.29 (t, J = 7 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 169.2,
Ethyl 2-(3-phenylnaphtho[1,2-b]furan-2-yl)acetate (5a)10a: Orange 163.7, 161.7, 151.8, 147.0, 132.2, 132.1, 130.8, 129.0, 128.0, 126.0,
sticky solid; (74.4 mg 92%); 1H NMR (500 MHz, CDCl3): δ 7.95 (d, J = 125.7, 124.3, 122.9, 115.9, 115.8, 112.4, 61.5, 33.0, 14.2 ppm;
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HRMS (ESI) m/z calcd. for C22H17FO3 [M + Na]+ 371.1059; found 4.18 (m, 4H), 1.3 - 1.25 (m, 6H) ppm; 13C NMR (125 MHz, CDCl3): δ
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DOI: 10.1039/C6RA17411F
153.1, 153, 135.9, 135.6, 129.5, 129.2, 129, 128.8, 127.9, 127.7,
371.1062.
Methyl 2-(3-(4-methoxyphenyl)naphtho[1,2-b]furan-2-yl)acetate 83.5, 83.2, 79.9, 79.3, 69.6, 69, 62.4, 62.3, 14.05, 14.03 ppm. HRMS
(5g): Light orange viscous liquid; (66.1 mg 84%); 1H NMR (500 MHz, (ESI) m/z calcd. for C24H22O5 [M + Na]+ 413.1364; found 413.1360.
CDCl3): δ 7.87 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 6.5 Hz, 1H), 7.76 (d, J = Ethyl 4-(2-hydroxynaphthalen-1-yl)-4-phenylbut-2-ynoate (7a1):
9 Hz, 1H), 7.69 (d, J = 9 Hz, 1H), 7.48 (d, J = 2 Hz, 2H), 7.45 - 7.41 (m, Pale yellow liquid; 1H NMR (500 MHz, CDCl3): δ 7.77 (s, 1H), 7.73 (d,
1H), 7.36 - 7.32 (m, 1H), 7.11 - 7.03 (m, 2H), 3.95 (s, 3H), 3.80 (s, J = 9.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 7.5 Hz, 3H), 7.38 -
2H), 3.76 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 169.9, 159.4, 7.30 (m, 3H), 7.12 (d, J = 7.5 Hz, 2H), 5.41 (s, 1H), 5.27 (s, 1H), 4.31-
151.8, 146.6, 131.5, 130.8, 128.9, 128.2, 125.9, 125.5, 125.1, 124.2, 4.27 (m, 2H), 1.35 (d, J = 7.5 Hz, 3H) ppm; 13C NMR (125 MHz,
123.1, 122.1, 114.3, 114.2, 112.3, 55.4, 52.5, 32.8 ppm; HRMS (ESI) CDCl3): δ 153.8, 139.4, 134.4, 133.8, 129.9, 128., 128.7, 128, 127.6,
m/z calcd. for C22H18O4 [M + H]+ 347.1283; found 347.1281.
127.5, 127.2, 126.6, 126.4, 118.3, 109.4, 88.2, 62.2, 43, 14.1 ppm.
Methyl 2-(3-(p-tolyl)naphtho[1,2-b]furan-2-yl)acetate (5h): Light HRMS (ESI) m/z calcd. for C22H18O3 [M + Na]+ 353.1157; found
1
yellow viscous liquid; (75.2 mg 93%); H NMR (500 MHz, CDCl3): δ 353.1165.
7.95 (d, J = 8 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), Ethyl-2-(1-(p-tolyl)naphtho[2,1-b]furan-2(1H)-ylidene)acetate
7.7 (d, J = 8.5 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.38 (s, 1H), 7.37 - 7.33 (7a3): Yellow viscous liquid; (48.5 mg 68%); 1H NMR (500 M Hz,
(m, 3H), 3.82 (s, 2H), 3.77 (s, 3H), 2.52 (s, 3H) ppm; 13C NMR (125 CDCl3): δ 7.85 - 7.83 (m, 2H), 7.65 (d, J = 8 Hz, 1H), 7.39 (d, J = 9 Hz,
MHz, CDCl3): 169.9, 151.9, 146.6, 137.8, 130.8, 130.3, 130.0, 129.5, 2H), 7.34 (t, J = 8 Hz, 1H), 7.27 (d, J = 8 Hz, 2H), 7.08 (d, J = 8 Hz,
128.9, 128.2, 125.9, 125.5, 124.2, 123.2, 122.0, 121.7, 112.4, 52.5, 2H), 6.07 (s, 1H), 5.85 (d, J = 2 Hz, 1H), 4.13 (q, J = 7.5 Hz 2H), 2.28
32.8, 21.4 ppm; HRMS (ESI) m/z calcd. for C22H18O3 [M + Na]+ (s, 3H), 1.26 (t, J = 7 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ
353.1153; found 353.1138.
177.3, 166.4, 153.1, 137.1, 136.5, 130.8, 130.3, 130.2, 129.5, 129.3,
Methyl 2-(3-phenylnaphtho[1,2-b]furan-2-yl)acetate (5i): Light 129.1, 129, 128.5, 127.4, 124.2, 123.2, 122.9, 111.2, 95.7, 59.8,
1
yellow viscous liquid; (67.1 mg 81%); H NMR (500 MHz, CDCl3): δ 51.1, 21.1, 14.4 ppm; HRMS (ESI) m/z calcd. for C23H20O3 [M +H]+
7.95 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 6 Hz, J = 9 Hz, 3H), 7.57 - 7.56 345.1490; found 345.1494.
(m, 4H), 7.55 - 7.52 (m, 1H), 7.44 - 7.41 (m, 1H), 7.34 - 7.31 (m, 1H), 2, 4-diphenyl-4H-benzo[h]chromene (9a)28: Yellow solid; (48.8 mg
3.81 (s, 2H), 3.76 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 169.8, 60%); mp 200 - 203 ⁰C; 1H NMR (500 MHz, CDCl3): δ 7.83 (d, J = 8.5
151.9, 146.3, 135.8, 133.2, 130.8, 130.4, 128.9, 128.8, 128.1, 125.9, Hz, 2H), 7.78 (t, J = 1.5 Hz, 3H), 7.46 - 7.38 (m, 4H), 7.39 - 7.37 (m,
125.6, 124.3, 123.1, 121.9, 121.7, 112.3, 52.5, 32.8 ppm; HRMS (ESI) 2H), 7.33 - 7.31 (m, 3H), 7.29 (d, J = 2.5 Hz, 2H), 5.85 (d, J = 5 Hz,
m/z calcd. for C21H16O3 [M + H]+ 317.1177; found 317.1176.
1H), 5.4 (d, J = 5 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ 149.6,
Ethyl 2-(5-methoxy-3-phenylnaphtho[1,2-b]furan-2-yl)acetate (5j): 146.6, 146.3, 133.9, 131.7, 131, 130.6, 129, 128.8, 128.4, 128.3,
1
Pale green gummy; (59 mg 75%); H NMR (500 MHz, CDCl3): δ 8.33 127.7, 125.5, 125, 124.7, 124.1, 123.7, 118.1, 114.3, 102.2, 39.2
(d, J = 8 Hz, 1H), 8.29 (dd, J = 1 Hz, J = 7.5 Hz, 1H), 7.63 - 7.61 (m, ppm.
3H), 7.57 (d, J = 7.5 Hz, 2H), 7.54 - 7.45 (m, 3H), 4.24 - 4.28 (m, 2H), 1-(4-methoxyphenyl)-3-phenyl-1H-benzo[f]chromene
(9b)28:
4.01 (s, 3H), 3.96 (s, 2H), 1.31 (t, J = 7 Hz, 3H) ppm; 13C NMR (125 White solid; (46.7 mg 61%); mp 198 - 200 ⁰C; H NMR (500 MHz,
MHz, CDCl3): δ 169.5, 152.4, 146.0, 132.4, 129.1, 128.6, 127.5, CDCl3): δ 7.8 (t, J = 1.5 Hz, 1H), 7.72 - 7.70 (m, 2H), 7.64 (s, 1H), 7.56
126.9, 125.2, 124.6, 124.1, 123.0, 122.9, 121.6, 121.2, 119.9, 95.6, (d, J = 8 Hz, 1H), 7.36 (s, 1H), 7.32 - 7.26 (m, 3H), 7.16 (t, J = 8 Hz,
61.4, 55.9, 33.6, 14.2 ppm; HRMS (ESI) m/z calcd. for C23H20O4 [M 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 8.5 Hz, 2H), 5.71 (d, J = 5 Hz,
1
+Na]+ 383.1259; found 383.1255.
1H), 5.22 (d, J = 5 Hz, 1H), 3.65 (s, 3H) ppm; 13C NMR (125 MHz,
Ethyl 2-(3-(4-fluorophenyl)-5-methoxynaphtho[1,2-b]furan-2- CDCl3): δ 158.1, 149.2, 145.1, 138.3, 136.1, 131.6, 131.3, 129.8, 129,
1
yl)acetate (5k): Brown solid; (58.8 mg 77%); mp 100 - 102˚ C; H 128.7, 127.7, 126.6, 124.2, 123.6, 123.2, 122.6, 118, 114.4, 114.2,
NMR (500 MHz, CDCl3): δ 8.30 (dd, J = 1.5 Hz, J = 8.5 Hz, 2H), 7.66 - 103.5, 55.2, 38.2 ppm.
7.64 (m, 1H), 7.63 - 7.58 (m, 2H), 7.54 - 7.51 (m, 1H), 7.27 - 7.24 (m, 1-(4-bromophenyl)-3-phenyl-1H-benzo[f]chromene (9c): Light
1
2H), 6.88 (s, 1H), 4.28 - 4.24 (m, 2H), 4.01 (s, 3H), 3.92 (s, 2H), 1.32 yellow solid; (41.8 mg 60%); mp 176 - 178 ⁰C H NMR (500 MHz,
(t, J = 7 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 169.4, 152.5, CDCl3): δ 7.73 (d, J = 3Hz, 2H), 7.58 - 7.56 (m, t, J = 10 Hz, 1H), 7.52 -
146.0, 144.8, 130.8, 130.7, 127.0, 124.7, 124.1, 123.0, 122.9, 121.6, 7.51 (m, 2H), 7.45 - 7.43 (m, 2H), 7.32 - 7.29 (m, J = 6H), 7.02 - 7.05
120.3, 119.9, 116.1, 115.9, 95.3, 61.5, 55.9, 33.5, 14.2 ppm; HRMS (m, 2H), 5.67 (d, J = 5 Hz, 1H), 5.24 (d, J = 10 Hz, 1H) ppm; 13C NMR
(ESI) m/z calcd. for C23H19FO4 [M +H]+ 379.1345; found 379.1345.
(125 MHz, CDCl3): δ 149.4, 146.1, 145.1, 132.7, 132, 131.5, 131.4,
Ethyl 2-(6-methoxy-3-phenylbenzofuran-2-yl)acetate (6b): Light 131.1, 129.4, 129.3, 128.5, 126.8, 126.3, 124.4, 123.4, 122.7, 120.4,
1
yellow viscous liquid; (26.9 mg 39%); H NMR (500 MHz, CDCl3): δ 117.9, 113.5, 102, 38 ppm. ppm ; (ESI) m/z for C25H17BrO [M + H]+
7.48 - 7.44 (m, 3H), 7.31 (t, J = 8 Hz, 2H), 7.76 (d, J = 2.5 Hz, 1H), 413.0540; found 413.0526.
6.91 - 6.89 (m, 1H), 4.24 - 4.22 (m, 2H), 3.88 (s, 3H), 3.85 (s, 2H), 2-methyl-1-phenylnaphtho[2,1-b]furan (11)8: Brown liquid; (40.3
2.44 (s, 3H), 1.30 (t, J = 7 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ mg, 65%); 1H NMR (500 MHz, CDCl3): δ 7.95 (d, J = 8 Hz, 1H), 7.82 (d,
169.5, 158.1, 155.3, 145.4, 137.3, 129.6, 129.0, 128.8, 121.8, 120.1, J = 8.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.55
119.5, 111.7, 95.9, 61.4, 55.8, 33.4, 21.3, 14.2 ppm; HRMS (ESI) m/z (t, J = 8 Hz, 4H), 7.51 (d, J = 2 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.33 (d,
calcd. for C20H20O4 [M +Na]+ 347.1259; found 347.1243.
J = 7.5 Hz, 1H), 2.47 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ
Diethyl 4,4'-oxybis(4-phenylbut-2-ynoate) (7): Colourless liquid; 150.2, 134.3, 130.7, 130.5, 129.2, 128.8, 128, 127.9, 127.6, 125.6,
(37 mg 88%); 1H NMR (500 MHz, CDCl3): δ 7.49 - 7.48 (m, 2H), 7.43 - 124.5, 124, 123.2, 122.3, 119, 112, 12.3 ppm.
7.42 (m, 2H), 7.37 - 7.32 (m, 6H), 5.64 (s, 1H), 5.29 (s, 1H), 4.24-
8 | J. Name., 2012, 00, 1-3
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General procedure for the oxidative C(sp3)-H functionalization of 1H), 7.82 (d, J = 9 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.5 Hz,
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2,3-disubstituted naphthofurans (12):5 To a stirred solution of 1H), 7.61 (d, J = 6.5 Hz, 1H), 7.55 (s, 4H), 7.45D(tO,IJ: 1=07.1.053H9/zC,61RHA)1,774.1316F
propargyl alcohol 2 (2 ml) and naphthofuran 3a or 3c (1 mmol) in -7.33 (m, 5H), 7.72 - 7.22 (m, 2H), 5.77 - 5.71 (m, 1H), 5.17 (s, 1H),
dichloromethane was added DDQ (2, 3-Dichloro-5,6-dicyano-1,4- 4.75 -4.71 (m, 2H), 4.28 - 4.21 (m, 2H), 1.91 (dd, J = 17 Hz, J = 17.5
benzoquinone) (2 mmol) at rt. The mixture was continued for 12 h. Hz 3H), 1.27 (t, J = 4.5 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
After completion of reaction (monitored by TLC), reaction mixture partially rotamers, δ 168.3, 152.2, 146.8, 144.1, 144.0, 139.8, 139.7,
was diluted with water, neutralized with Na2CO3 and extracted with 132.1, 132.1,130.8, 130.6, 130.3, 129, 128.9, 128.8, 128.6, 128.56,
dichloromethane thrice. The combined organic layers were washed 128.55, 128.4, 128.2, 126.9, 126.6, 126.5, 126.3, 124.6, 124.43,
with brine solution and dried over anhydrous Na2SO4. The solvent 124.41, 123.1, 121.7, 121.5, 121.4, 112.7, 72, 71.9, 63.4, 63.3, 62,
was removed under reduced pressure and the crude product was 60.3, 60.2, 21.3, 21.2, 14.1 ppm; HRMS (ESI) m/z calcd. for
purified by silica gel column chromatography (12 - 14%, EtOAc in C33H29N3O4 [M +H]+ 532.2236; found 532.2246.
pet ether) to obtain desired product 12.
Ethyl
2-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-2-(1-(4-
Light
Ethyl 2-(1-phenylnaphtho[2,1-b]furan-2-yl)-2-(prop-2-yn-1- methoxyphenyl)naphtho[2,1-b]furan-2-yl)acetate (13c):
1
1
yloxy)acetate (12a): Pink oily liquid; (45.5 mg 72%); H NMR (500 yellow sticky solid; (93.1 mg 88%); H NMR (500 MHz, DMSO-d6): δ
MHz, CDCl3): δ 7.96 (d, J = 8 Hz, 1H), 7.84 - 7.78 (m, 2H), 7.73 (d, J = 8.03 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 9 Hz, 1H), 7.81 (d, J = 9 Hz, 1H),
9 Hz, 1H), 7.66 (t, J = 8 Hz, 2H), 7.6 -7.56 (m, 3H), 7.48 - 7.44 (m, 7.65 (d, J = 8.5 Hz, 1H), 7.47 - 7.25 (m, 9H), 7.14 -7.06 (m, 2H), 5.53
1H), 7.38 - 7.35 (m, 1H), 5.39 (s, 1H), 4.36 - 4.2 (m, 4H), 2.23 (s, 1H), (s, 2H), 5.11(s, 1H), 4.57 (q, J = 17.5 Hz, 2H), 4.08 (q, J = 7 Hz, 2H),
1.23 (t, J = 7 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 168.1, 3.86 (s, 3H), 1.11 (t, J = 7 Hz, 3H) ppm; 13C NMR (125 MHz, DMSO-
152.4, 146.3, 132.1, 130.8, 130.7, 130.6, 129, 128.8, 128.7, 128.4, d6): δ 173.1, 164.5, 156.6, 152.6, 148.4, 141.1, 136.8, 136.5, 135.7,
128.2, 127, 126.3, 125.1,124.6, 123.1, 121.3, 112.7, 78, 75.8, 70.3, 133.9, 133.4, 133.1, 132.8, 132.1, 131.7, 129.9, 128.4, 128.1, 127.4,
62, 56.4, 14.1 ppm; HRMS (ESI) m/z calcd. for C25H20O4 [M +Na]+ 126, 119.6, 117.8, 76.1, 67.3, 66.6, 60.4, 57.9, 19.1 ppm; HRMS (ESI)
407.1259; found 407.1231.
m/z calcd. for C33H29N3O5 [M + Na]+ 570.1999; found 570.2045.
Ethyl 2-(1-(4-methoxyphenyl)naphtho[2,1-b]furan-2-yl)-2-(prop-2- Ethyl 2-(1-(4-methoxyphenyl)naphtho[2,1-b]furan-2-yl)-2-((1-(1-
yn-1-yloxy)acetate (12b): Pink viscous liquid; (43.1 mg 70%); 1H phenylethyl)-1H-1,2,3-triazol-4-yl)methoxy)acetate (13d): Yellow
NMR (500 MHz, CDCl3): δ 7.95 (d, J = 8 Hz, 1H), 7.82 (t, J = 9.5 Hz, sticky solid; (83.9 mg 86%); 1H NMR (500 MHz, CDCl3): δ 7.95 (d, J =
2H), 7.71 (d, J = 9 Hz, 1H), 7.56 (t, J = 7 Hz, 2H), 7.46 (t, J = 8 Hz, 1H), 8.5 Hz, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 9 Hz, 1H), 7.51 (d, J =
7.36 (t, J = 8 Hz, 1H), 7.56 (m, 2H), 5.38 (s, 1H), 4.35 – 4.23 (m, 4H), 8 Hz, 1H), 7.45 (t, J = 7 Hz, 2H), 7.38 - 7.32 (m, 5H), 7.24 - 7.21 (m,
3.96 (s, 3H), 2.27 (s, 1H), 1.28 (t, J = 7 Hz, 3H) ppm; 13C NMR (125 2H), 7.09 (t, J = 8.5 Hz, 2H), 5.77 - 5.69 (m, 1H), 5.17 (s, 1H), 4.71 (s,
MHz, CDCl3): δ 168.1, 159.7, 152.3, 146.2, 131.9, 131.7, 130.8, 129, 2H), 4.24 (q, J = 4 Hz, 2H), 3.96 (s, 3H), 1.9 (dd, J = 21 Hz, J = 21 Hz
128.3, 126.8, 126.3, 124.7, 124.5, 124.1, 123.1, 121.6, 114.3, 113.9, 3H), 1.26 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
112.7, 78.1, 75.8, 70.4, 62, 56.4, 55.4, 14.1 ppm. (ESI) m/z. for partially rotamers, δ 168.4, 152.2, 146.7, 144.2, 131.8, 130.8, 129,
C26H22O5 [M +H]+ 415.1545; found 415.1534.
129, 128.5, 128.5, 128.3, 126.8, 126.6, 126.5, 126.2, 124.5, 124.1,
General procedure for the synthesis of triazole formation from 12 124, 123.1, 121.6, 121.4, 114.4, 112.7, 72, 63.4, 63.3, 61.9, 60.3,
(13): To a stirred solution of terminal alkyne 12a or 12b (1 mmol) 60.1, 55.4, 21.3, 21.2, 14.1 ppm; HRMS (ESI) m/z calcd. for
and benzyl azide (1.5 mmol) in DMSO (1.5 ml) was added Et3N (0.4 C34H31N3O5 [M +H]+ 562.2341; found 562.2354.
mmol) and CuI (10 mol%) at rt. After completion (monitored by TLC) Ethyl 2-bromo-2-(1-(4-methoxyphenyl) naphtha [2,1-b]furan-2-
1
of the reaction, the reaction mixture was diluted with cold water yl)acetate (14): Light brown viscous liquid; (42.9 mg 71%) H NMR
and extracted with EtOAc thrice. The combined organic layers were (500 MHz, CDCl3): δ 8.28 (d, J = 7.5 Hz, 1H), 7.59 - 7.45 (m, 8H), 7.35
washed with brine solution and dried over anhydrous Na2SO4. (t, J = 7 Hz, 1H), 6.13 (s, 1H), 4.07 (q, J = 4 Hz 2H), 3.44 (s, 3H), 1.14
Solvent was removed under reduced pressure and the crude (t, J = 7.5 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 170.8, 167.3,
product was purified by silica gel column chromatography (30 - 40 145, 131.6, 131.3, 130.3, 129.9, 129.4, 128.7, 128.3, 127.9, 127.4,
%, EtOAc in pet ether) to obtain desired triazole products 13.
127.2, 125.2, 123.2, 122.8, 114.9, 100.8, 60.9, 50.6, 40.9, 14.1 ppm;
Ethyl
2-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-2-(1- HRMS (ESI) m/z calcd. for C23H19BrO4 [M +H]+ 439.0544; found
phenylnaphtho[2,1-b]furan-2-yl)acetate (13a): Yellow sticky solid; 439.0540.
(81.2 mg 81%); 1H NMR (500 MHz, CDCl3): δ 7.95 (d, J = 8 Hz, 1H), Lysozyme Fibrilization Experiment: Lysozyme from chicken egg
7.81 (d, J = 9 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.7 (d, J = 8 Hz, 1H), white was purchased from Sigma Aldrich (Catalog Number L6876).
7.59 - 7.54 (m, 5H), 7.42 (t, J = 7 Hz, 1H), 7.37 -7.33 (m, 5H), 7.24 (t, Lysozyme fibrils were prepared by dissolving monomeric lysozyme
J = 3 Hz, 2H), 5.44 (q, J = 18.5 Hz, 2H), 5.17 (s, 1H), 4.71 (q, J = 11.5 films in DMSO, diluting into the PBS buffer to a final concentration
Hz, 2H), 4.24 (q, J = 6.5 Hz, 2H), 1.26 (t, J = 7 Hz, 3H) ppm; 13C NMR of 20 µM. The resulting solutions were incubated for 72 h at 60 C
(125 MHz, CDCl3): δ 168.3, 152.3, 146.7, 144.5, 134.4, 132.2, 130.8, with continuous agitation (final DMSO concentration was <2%). For
130.7, 130.4, 129.1, 129, 128.9, 128.8, 128.4, 128.2, 128.1, 126.9, aggregation inhibition studies, inhibitors (20 µM final concentration
126.3, 124.6, 124.4, 123.1, 122.8, 121.3, 112.7, 71.8, 63.2, 61.9, using a 2 mM stock solution in DMSO) were added to lysozyme
54.1, 14.1 ppm; HRMS (ESI) m/z calcd. for C32H27N3O4 [M +H]+ solutions and then incubated for 72 hr at 60 C with constant
518.2079; found 518.2088.
agitation.
Ethyl 2-((1-(1-phenylethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(1- Fluoroscence Measurements: All fluorescence measurements were
phenylnaphtho[2,1-b]furan-2-yl)acetate (13b): Light yellow sticky performed using a Perkin Elmer fluorescence spectrometer (Model
solid; (76.8 mg 83%); 1H NMR (500 MHz, CDCl3): δ 7.96 (d, J = 8 Hz, No. LS55). For ThT fluorescence studies, samples were diluted to a
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J. Name., 2013, 00, 1-3 | 9
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3. (a) G. Schulte, P. J. Schener, and O. McConnel, Helv. Chim.
final lysozyme concentration of 2.5 µM in PBS containing ThT (10
µM) and the fluorescence intensities were measured at 485 nm (λex
= 435 nm).
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Acta., 1980, 63, 2159; (b) F. MD.ODI:e10a.n1,03A9/dCv6aRnAc1e7s411inF
Heterocyclic Chemistry, ed. A. R. Katritzky, Academic
Press, New York, 1982, 30, 167; (c) H. Wagner and B.
Fessler, Planta Med., 1986, 52, 374; (d) P. A. Jacobi and H.
G. Selnick, J. Org. Chem., 1990, 55, 202; (e) J. Lee, J.-H. Li,
S. Oya and J. K. Snyder, J. Org. Chem., 1992, 57, 5301; (f)
K. Kobayashi, H. Shimizu, A. Sasaki and H. Suginome, J.
Org. Chem., 1992, 57, 1170; (g) A. F. Furstner and H.
Weintritt, J. Am. Chem. Soc., 1998, 120, 2817; (h) A. F.
Furstner, K. Reinecke and H. H. Waldmann, Chem. Bio.
Chem., 2004, 5, 1575.
Conclusions
In conclusion, we have developed an Bu4NPF6 catalyzed, acid,
metal and solvent free, regioselective one pot cascade
synthesis of 2-alkyl, 3-aryl naphthofurans from the easily
available reactants under simple reaction conditions. Control
experiments have been performed to justify the mechanism.
The utility of the synthetic compounds has also been
illustrated successfully by synthesizing the α-bromo esters,
ethers and triazole derivatives. Atom and step economy, large
substrate scope, high yields and short reaction time make this
methodology superior to the existing metal catalysed and
multistep procedures. In addition, the biological relevance of
these compounds has been established for selected
compounds. ThT fluorescence data for the lysozyme
aggregation clearly suggest that complete arrest of
aggregation process occurred when these compounds were
added in fibrilization conditions. This preliminary anti-
amyloidogenic feature of these compounds is being explored
further in our laboratories.
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Acknowledgement
Science and Engineering Research Board (DST-SERB) India is
acknowledged for the financial support through Fast Track Young
Scientist programme (No-SB/FT/CS-149/2012). AP, RD & MR thank
Central University of Rajasthan for their fellowships. AKS thank DST-
INSPIRE programme for research grant IFA-13, CH-97. The authors
are thankful to Dr. Rambabu Chegondi for the technical support.
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This journal is © The Royal Society of Chemistry 20xx
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RSC Advances
Journal Name
COMMUNICATION
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DOI: 10.1039/C6RA17411F
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DOI: 10.1039/C6RA17411F
nBu4NPF6 Promoted Regioselective Cascade Synthesis of Functionally
Embellished Naphthofurans under Acid, Metal & Solvent Free Conditions
Abhishek Pareek,† Ravikrishna Dada,† Monika Rana,† Anuj K. Sharma† and Srinivasarao Yaragorla,*,†
†Department of Chemistry, Central University of Rajasthan, NH-8, Bandersindri, Ajmer-district,
Rajasthan, 305817, India
E-mail: srinivasarao@curaj.ac.in & ysriict@gmail.com
nBu4NPF6 mediated highly regioselective synthesis of functionally embellished naphthofurans has
been achieved from easily available naphthols and propargyl alcohols through a cascade benzylation,
oxacyclisation (5-exo dig) and isomerization under solvent free conditions. The reaction works in a
short time through a dibenzyl ether formation followed by the decomposition to the carbocation to
furnish the high yielding products with large substrate scope. The synthetic utility of the products
are demonstrated through C(sp3)-H functionalization. In addition, we investigated selected
naphthofurans for their anti-amyloidogenic properties. Prelimininary studies suggest that these are
excellent inhibitors for amyloid formation, a hallmark for several neurodegenrative diseases.