Cascade Radical Cyclization on Alkynyl Vinylogous Carbonates for the Divergent Synthesis of Tetrasubstituted Furans and Dihydrofurans

Article abstract of DOI:10.1021/acs.orglett.8b03668

A single alkynyl vinylogous carbonate was elaborated to tetrasubstituted furan or dihydrofuran via a cascade inter-intramolecular radical reaction by changing the radical being added. The strategy could be used in the synthesis of polycyclic heterocycles as well as bis-furan exhibiting atropisomerism. Installation of a new furan motif on the existing one was feasible by iteration. Stannyl dihydrofuran derivative was used in Stille coupling, whereas intramolecular Friedel-Crafts acylation on the furan gave furanonaphthol.

Full text of DOI:10.1021/acs.orglett.8b03668

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cascade Radical Cyclization on Alkynyl Vinylogous Carbonates for
the Divergent Synthesis of Tetrasubstituted Furans and
Dihydrofurans
Santosh J. Gharpure,* Padmaja, V. Prasath, and Yogesh G. Shelke
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
S
* Supporting Information
ABSTRACT: A single alkynyl vinylogous carbonate was elaborated to tetrasubstituted furan or dihydrofuran via a cascade
inter-intramolecular radical reaction by changing the radical being added. The strategy could be used in the synthesis of
polycyclic heterocycles as well as bis-furan exhibiting atropisomerism. Installation of a new furan motif on the existing one was
feasible by iteration. Stannyl dihydrofuran derivative was used in Stille coupling, whereas intramolecular Friedel−Crafts
acylation on the furan gave furanonaphthol.
ensely substituted furans constitute important congeners
present in many natural products and are fast emerging
for the synthesis of cyclic ethers,7 their utility for furan/
dihydrofuran synthesis remains unexplored. It is also pertinent
to mention that general strategies that give access to
tetrasubstituted dihydrofuran are uncommon. While radical
cyclization using thiyl or stannyl radical addition to terminal
alkynes has been explored exhaustively, the same is not true for
internal alkynes, perhaps due to regioselectivity problems
encountered in these reactions.8 Recently, we disclosed a
highly regioselective addition of thiyl radical to internal
alkynes, followed by cyclization for the synthesis of N-fused
indole and indoline derivatives.9 In another study, we had used
a tandem radical cyclization to vinylogous carbonates for the
stereoselective synthesis of angular triquinanes.10 Herein, we
disclose an approach for the divergent synthesis of
tetrasubstituted furan/dihydrofuran by a cascade radical
cyclization on alkynyl vinylogous carbonates, wherein the
outcome is dependent on the hydrogen abstraction ability of
the radical being added.
D
as an important class of therapeutic agents.1 These scaffolds are
also found in vital fragrances and in various biologically active
molecules (Figure 1).2 They have also proved to be efficient
Our initial studies began with the idea of synthesizing
tetrasubstituted dihydrofuran 1a using a cascade radical
cyclization from an alkynyl vinylogous carbonate 2a initiated
by an appropriate radical precursor (X = PhS and n-Bu3Sn)
(Table 1). It was envisaged that the problem of regioselectivity
could be circumvented by employing aryl alkynes. To test our
hypothesis, alkynyl vinylogous carbonate 2a was subjected to
radical cyclization using PhSH (1.0 equiv) and AIBN (0.3
equiv) in toluene at reflux. Interestingly, the tetrasubstituted
dihydrofuran 1a (X = SPh) was obtained as only minor
product along with the tetrasubstituted furan 3a (X = SPh)
Figure 1. Biologically active substituted furans.
synthons in the total synthesis of various natural products.3
Not surprisingly, synthesis of furans has attracted enormous
attention in recent past.4 However, transformation of furan to
afford tetrasubstituted furans is extremely challenging due to
regioselectivity issues, thus necessitating development of new
methods consisting of appropriately substituted precursors.5
In this context, vinylogous carbonates/esters have been used
in the synthesis of substituted furans, which typically involves a
metal-assisted Claisen rearrangement (or its variant), followed
by cyclization.6 Interestingly, even though the vinylogous
carbonates (β-alkoxy acrylates) are excellent radical precursors
Received: November 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03668
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Organic Letters
Letter
a
a
Table 1. Optimization of Cascade Radical Cyclization
Scheme 1. Synthesis of Tetrasubstituted Furans 3
b
sr. no.
XH
equiv equiv of AIBN
yield (%)
c
1
2
3
4
5
6
7
8
PhSH
PhSH
PhSH
PhSH
PhSH
PhSH
n-Bu3SnH
n-Bu3SnH
1.0
2.0
2.0
3.5
3.5
3.5
3.5
3.5
0.3
0.3
0.1
0.1
1.0
2.0
0.1
2.0
1a (10)
−
−
−
−
−
3a (42)
3a (52)
3a (33)
3a (46)
3a (57)
3a (82)
−
c
c
4a (24)
4a (81)
−
a
In all the cases 2a (0.39 mmol) was reacted with AIBN and
thiophenol/n-Bu3SnH at reflux in dry toluene (15 mL) for ca. 6 h.
b
c
Isolated yield. dr = 1:1, measured on the crude reaction mixture by
1H NMR.
(Table 1, entry 1). Increasing the amount of PhSH resulted in
an exclusive formation of furan 3a (Table 1, entry 2). Reducing
the amount of AIBN resulted in poorer yield, whereas
increasing equivalents of both PhSH and AIBN resulted in
an efficient formation of furan (Table 1, entries 3−6).
Interestingly, when n-Bu3SnH was used in place of PhSH, no
formation of furan derivative was observed, instead dihy-
drofuran 4a (X= SnBu3) was obtained as the only product
(Table 1, entries 7 and 8) (see, Supporting Information for
details). Given this divergence in the outcome, we decided to
explore both these reactions to study their scope and utility.
To begin with, attention was turned toward the synthesis of
furan derivatives 3. Various alkynyl vinylogous carbonates 2b−
g bearing aliphatic substitution at the α position of the oxygen
were subjected to optimized reaction conditions to furnish the
corresponding tetrasubstituted furans 3b−g in good to
excellent yield (Scheme 1). The structure of furan 3f was
also confirmed by single crystal X-ray diffraction studies.11 The
efficiency of the reaction was found to be unaffected by the
steric bulk of the substitution. On the other hand, aromatic
substitution at the α position led to tetrasubstituted furans
3h−i with slightly diminished yields. Electron-donating and
-withdrawing groups at the para position of the phenyl ring
tethered to the alkynyl vinylogous carbonate had little impact
on the formation of tetrasubstituted furans 3j−k. Heterocycles
namely, benzothiophene and N-methylindole bearing tetrasub-
stituted furans 3l−m could also be accessed readily.
Trimethylsilyl group too survived the radical cyclization and
gave the corresponding tetrasubstituted furans 3n−o in
excellent to good yield. Alkynyl thioethers participated in the
reaction with complete regioselectivity, and corresponding bis-
thiophenyl-substituted furan 3p was formed as the sole
product. Unfortunately, alkynes having alkyl, ester, or amino
groups (ynamide) when subjected to optimized radical
cyclization condition resulted in only decomposition of the
starting compounds, and the corresponding tetrasubstituted
furans 3q−s could not be isolated. Alkynyl vinylogous ester
and enol ethers too were found to be good substrates, and
corresponding furans 3t−u were obtained in good yield
highlighting that the scope of the reaction is not limited to
varied vinylogous carbonates. Moreover, ester-substituted
vinylogous carbonate gave the corresponding dihydrofuran
a
b
Isolated yield. Numbers in parentheses refer to dr measured by 1H
NMR on the crude reaction mixture.
1v with excellent diastereoselectivity. Interestingly, 2-naph-
thalenethiol and thiophenols bearing electron-donating as well
as -withdrawing substituents proved to be good radical
precursors, and the tetrasubstituted furans 3w−y were
obtained in moderate yields. This suggested that differentiation
can be brought about in the structure of the furan from very
same precursors.
Next, the cascade radical cyclization for the synthesis of
tetrasubstituted dihydrofuran was explored using tributyltinhy-
dride as the radical precursor. As anticipated, substitution at
the α position of the alkynyl vinylogous carbonate affected the
diastereoselectivity of the reaction. Thus, while ethyl-
substituted dihydrofuran 4a was formed with poor diaster-
eoselectivity (cf. Table 1), the cyclohexyl and t-butyl-
substituted dihydrofurans 4b−c were obtained with improved
diastereoselectivity, with the latter being better (Scheme 2).
However, the phenyl group as substitution furnished the
dihydrofuran 4d with reduced diastereoselectivity (dr = 1.6:1).
The silyl group survived the radical reaction to form the
tetrasubstituted dihydrofuran 4e−f in excellent yield. Interest-
ingly, the ester-substituted alkynyl vinylogous carbonate, which
failed to give furan 3r under thiyl radical conditions,
participated smoothly in stannyl radical-mediated cascade
cyclization to form dihydrofuran 4g in good yield and
diastereoselectivity (15:1). Further, alkynyl vinylogous carbo-
nate with ester substitution also gave the corresponding
stannyl-substituted dihydrofuran 4i in good yield as a single
B
DOI: 10.1021/acs.orglett.8b03668
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Organic Letters
Letter
a b
,
Scheme 2. Synthesis of Tetrasubstituted Dihydrofurans 4
Scheme 4. Support for the Proposed Mechanism
PhSH/AIBN in refluxing toluene, the corresponding oxidized
tetrasubstituted furan 3l was obtained quantitatively. On the
other hand, when the stannyl-substituted dihydrofurans were
resubjected to the radical conditions using n-Bu3SnH/AIBN
(or PhSH/AIBN), it only resulted in decomposition. Thus, it
was apparent that thiyl radical enables 5-exo-trig cyclization as
well as oxidation to give furan. It could be argued that since the
bond energy of PhS-H is greater than that of n-Bu3Sn-H, the
thiyl radical can participate in oxidation of dihydrofurans to the
corresponding furans.12
a
1
Numbers in parentheses refer to dr measured by H NMR on the
b
crude reaction mixture. Isolated yield.
In one of the experiments, when β-methoxy naphthyl-
substituted alkynyl vinylogous carbonate 2z was subjected to
cascade radical cyclization under optimized conditions,
formation of an inseparable mixture of the dihydrofuranyl
tetracyclic-fused framework 5 along with the corresponding
tetrasubstituted furan 3z was observed. The mixture upon
reduction with LiAlH4 furnished a separable mixture of
alcohols 6 and 7 in 95% over two steps (Scheme 5).
diastereomer. Dihydrofurans 4h−i are noteworthy as they
contain tertiary ether linkages, which are otherwise difficult to
access in good yields and diastereoselectivity by conventional
methods.
The divergent outcome of thiyl and stannyl radical initiated
radical cyclization leading to furan or dihydrofuran could be
explained as follows (Scheme 3): The intermolecular addition
Scheme 3. Plausible Mechanism
Scheme 5. Radical Cascade Cyclization Involving
Intramolecular Aryl Trapping
of initial thiyl or stannyl radical to alkyne in a regioselective
manner generates the aryl vinyl radical A. The regioselectivity
is perhaps the outcome of the relative stability of the vinyl
radical.8 Alternatively, the reversible addition of the thiyl or
stannyl radical to the alkyne followed by the favored 5-exo-trig
radical cyclization to vinylogous carbonate enables the
equilibrium to shift in the forward direction to furnish B.
This radical, formed α to the ester, B abstracts hydrogen from
n-Bu3SnH or PhSH to give the dihydrofuran derivative C.
When the reaction is carried out with excess of PhSH and
AIBN, another radical process is initiated in which PhS• picks
up hydrogen from the (either of the) second position of the
dihydrofuran C (only one side abstraction of H is shown) to
generate resonance stabilized allylic radical D. Abstraction of
another hydrogen from the (corresponding) fifth position of
the dihydrofuran D to gain aromaticity results in the formation
of a highly substituted furan skeleton 3.
Formation of the fused dihydrofuran 5 could be explained by
the fact that, due to the proximity of the aryl ring tethered onto
the alkyne, the radical α to the ester (cf. intermediate B,
Scheme 3) adds to the former giving a six-membered ring
stereoselectively. These experiments gave further support to
the proposed mechanism. Interestingly, based on 1H NMR, we
observed that compound 7 demonstrated atropisomerism.
To probe this atropisomeric behavior further, we subjected
diyne vinylogous carbonate 8a to cascade 5-exo-trig radical
cyclization and obtained the tetrasubstituted bis-furan 9a in
moderate yield. Surprisingly, this molecule 9a also exhibited
atropisomerism, which could be identified by the occurrence of
We carried out some experiments to test the proposed step
of conversion of the dihydrofuran to furan (cf. C → D → 3 in
Scheme 3). Thus, the vinylogous carbonate 2l was subjected to
radical condition, and reaction was stopped after 3 h to furnish
the tetrasubstituted dihydrofuran 1l (Scheme 4). When this
dihydrofuran 1l was further subjected to radical reaction using
1
an AB quartet for the CH2 protons α to the ester in H NMR
spectrum. To the best of our knowledge, such atropisomerism
displayed by a bis-furan molecule 9a is unprecedented to
date,13 thus enhancing the uniqueness and importance of the
method developed (Scheme 6). Further, 2,5-disubstituted
C
DOI: 10.1021/acs.orglett.8b03668
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Organic Letters
Letter
Scheme 6. Cascade Radical Cyclization on Diynes To Form
Polyheterocycles
Scheme 8. Functionalization of Furans 3 and Dihydrofurans
4
thiophene alkynyl vinologous carbonate 8b, under the standard
thiophenyl radical cascade condition, gave the tricyclic
tetrasubstituted furanyl thiophene 9b in moderate yield,
which did not exhibit atropisomerism.
We envisioned that the ester group of the product furan is a
good handle for allowing iteration of the reaction sequence. To
test this, the tetrasusbstituted furan 3a was reduced to the
corresponding alcohol 10 (Scheme 7). Oxidation of alcohol 10
In conclusion, we have developed a robust, chemodivergent,
cascade thiyl and stannyl radical cyclization on alkynyl
vinylogous carbonates to gain an expeditious access to
tetrasubstituted furans and dihydrofurans, respectively. The
reaction displayed broad substrate scope even with thiophe-
nols. Interestingly, PhSH not only acts as radical precursor but
also acts as an oxidant (along with AIBN) converting the
dihydrofurans to furans. Cascade radical cyclization on diynes
gave the first example of atropisomeric bis-furan and is
applicable to the synthesis of polyheterocyclic systems. The
reaction sequence could be iterated to install a new furan ring.
The dihydrofurans and furans could be elaborated to useful
derivatives such as furanonaphthols.
Scheme 7. Iterative Strategy for the Synthesis of Non-
Adjacent Tetrasubstituted Bis-furans
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03668.
Synthetic procedures and characterization data of
products (PDF)
followed by addition of lithiated phenylacetylene to the
resultant aldehyde furnished the secondary alcohol 11.
DABCO catalyzed Michael addition of the alcohol 11 to
ethyl propiolate (12) gave the corresponding vinylogous
carbonate 13, which when subjected to cascade radical
cyclization installed the second tetrasubstituted furan 14 in
moderate overall yield.
We also explored functionalization of the furans 3 and
dihydrofurans 4. Thus, desulfurization of the furan 3o led to
the disubstituted silyl-furan 15, which could be a potential
synthon for rosefuran or its sila-analogue.2 In another
direction, acid-mediated destannylation of 4f gave trisubsti-
tuted dihydrofuran 16, a potential synthon for Hagen’s gland
lactone.14 Stannyl-dihydrofuran 4a also proved to be an
excellent Stille coupling partner, and the tetrasubstituted
dihydrofuran 17 was obtained in good yield (Scheme 8).
Finally, base-mediated hydrolysis of the ester 3c gave the acid
18. Conversion of the acid 18 to its acid chloride followed by
intramolecular Friedel−Crafts acylation gave a furanonaphthol
derivative 19.
Accession Codes
CCDC 1878359 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sjgharpure@iitb.ac.in
ORCID
Santosh J. Gharpure: 0000-0002-6653-7236
Padmaja: 0000-0001-8988-2553
Yogesh G. Shelke: 0000-0003-3157-1159
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.8b03668
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(10) Gharpure, S. J.; Niranjana, P.; Porwal, S. K. Org. Lett. 2012, 14,
5476.
(11) CCDC 1878359 3f contains the supplementary crystallographic
data for this paper. This data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
datarequest/cif.
ACKNOWLEDGMENTS
■
We thank SERB, New Delhi, for financial support. We
acknowledge the efforts of Mr. Pradeep Billas (M.Sc., IIT
Bombay) for carrying out the initial experiments in this
project. We thank Mr. Darshan Mhatre of the X-ray facility of
the Department of Chemistry, IIT Bombay, for collecting the
crystallographic data and IRCC, IIT Bombay, for funding. We
are grateful to IIT Bombay for the award of research fellowship
to Padmaja and CSIR, New Delhi, to V.P. and Y.G.S.
(12) Crich, D.; Grant, D.; Krishnamurthy, V.; Patel, M. Acc. Chem.
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see: Raut, V. S.; Jean, M.; Vanthuyne, N.; Roussel, C.; Constantieux,
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2017, 139, 2140.
(14) Gharpure, S. J.; Nanda, L. N.; Shukla, M. K. Eur. J. Org. Chem.
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