Transition-Metal-Free Cyclization of Propargylic Alcohols with Aryne: Synthesis of 3-Benzofuranyl-2-oxindole and 3-Spirooxindole Benzofuran Derivatives

Article abstract of DOI:10.1021/acs.orglett.8b01414

An unprecedented base-mediated cyclization of propargylic alcohols with aryne is reported, providing a novel method for the synthesis of 3-benzofuranyl-2-oxindole and 3-spirooxindole benzofuran scaffolds via a propargyl Claisen rearrangement/cycloaddition pathway. The nature of the substituent on acetylene group of propargylic alcohol influences the outcome of the reaction. The protocol offers a transition-metal-free and operationally simple methodology with broad substrate scope as a ready access to complex oxindole-linked heterocyclic compounds.

Full text of DOI:10.1021/acs.orglett.8b01414

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transition-Metal-Free Cyclization of Propargylic Alcohols with
Aryne: Synthesis of 3‑Benzofuranyl-2-oxindole and 3‑Spirooxindole
Benzofuran Derivatives⊥
Babachary Kalvacherla,†,‡,∇ Srinivas Batthula,†,∇ Sridhar Balasubramanian,§
and Radha Krishna Palakodety*,†
†D-211, Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR−Indian Institute of Chemical Technology,
Hyderabad−500007, India
‡Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
§Center for X-ray Crystallography, CSIR−Indian Institute of Chemical Technology, Hyderabad−500007, India
S
* Supporting Information
ABSTRACT: An unprecedented base-mediated cyclization of propargylic alcohols with aryne is reported, providing a novel
method for the synthesis of 3-benzofuranyl-2-oxindole and 3-spirooxindole benzofuran scaffolds via a propargyl Claisen
rearrangement/cycloaddition pathway. The nature of the substituent on acetylene group of propargylic alcohol influences the
outcome of the reaction. The protocol offers a transition-metal-free and operationally simple methodology with broad substrate
scope as a ready access to complex oxindole-linked heterocyclic compounds.
On the other hand, the complexity and structural diversity of
oxindole derivatives have gained prominence, because of their
presence as structural subunits of bioactive natural products
and pharmaceutical ingredients.5 Interestingly, furan and
oxindole derivatives are ubiquitous scaffolds that display
diverse pharmacological activities.5−7 For instance, while
Amiodarone I is an antiarrhythmic agent,7a,b compound II
exhibited antiproliferative activity,7a Obovaten III displayed
antitumor activity,7d and (−)-BPAP IV is an antidepressant
drug.7e In addition, oxindole-linked spirocyclic compounds are
privileged scaffolds, and, because of their unique three-
dimensional structures, possess broad biological activities in
several natural products and pharmacologically relevant
he development of novel synthetic methodologies is an
Tinteresting and challenging proposition for organic
chemists when complex scaffolds are to be built from simpler
precursors. Over the past decade, arynes have emerged as the
favored species that facilitated the construction of new
chemical bonds toward the ready access to functionalized
chemical entities.1 The transient and high reactivity of aryne
has paved the way to a manifold of reactions such as
multicomponent reactions (MCR),1d pericyclic reactions,1g
insertion reactions,2 and many more.1a,e,i,j Among them,
cycloaddition and insertion reactions of arynes allow the
insertion of benzene ring through the formation of new C−C
and C-X (X = H, O, N, S, etc.) bond in one step, and such a
manifestation prompted its varied exploitation.1k,2,3 The
resurgence of aryne chemistry was made possible mainly
because of the mild and expedient method developed by
Koyabashi4 in 1983, for the in situ generation of arynes from
the o-silylaryl triflates by fluoride-induced β-elimination
reaction at ambient temperatures, which tolerated a wide
range of functional groups.
5
8
d
drugs. , For example, XEN907 V, which is a tetracyclic 3-
spirooxindole benzoether, is a unique hNav1.7 blocker used for
the treatment of chronic pain8e and 3-spirooxindole ether VI is
a CB2 receptor antagonist8f (see Figure 1).
Received: May 4, 2018
© XXXX American Chemical Society
A
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Letter
arynes with tertiary allylamine to afford functionlized aniline
derivatives (see Scheme 1b).2e Thus, tuning aryne chemistry
for the synthesis of architecturally diverse heterocyclic
derivatives is worth exploring. We have a long-standing interest
in developing novel synthetic protocols for functionalized
heterocyclic compounds.14 In continuation, herein, we report a
novel and efficient protocol for the synthesis of 3-
benzofuranyl-2-oxindoles and 3-spiroox-indole benzofuran
motifs from propargylic alcohols and aryne under mild and
transition-metal-free conditions (see Scheme 1c).
Our investigation began by reacting propargylic alcohol
(1aa) as the model substrate with Koyabashi precursor (2a),
using CsF and 18-crown-6 as additive in the presence of
Cs2CO3 in anhydrous CH3CN at room temperature. A smooth
transformation under these conditions led to chromato-
graphically separable products 3-benzofuranyl-2-oxindole 3aa
and 3-spirooxindole benzofuran 4aa derivative in yields of 48%
and 23%, respectively. Next, we screened several bases,
solvents, F− sources, and various reaction conditions
(equivalents, time, and temperature) to increase the yield of
products. The optimization results are presented in the
Supporting Information (SI).15
With the optimized reaction conditions in hand, we explored
the substrate scope and versatility of this protocol. Generally,
substrates with aryl substituent on the propargylic alcohol
afforded a separable mixture of corresponding products. A
wide variety of propargylic alcohols with aryl substituents were
examined in the reaction, and the results are summarized in
Scheme 2. Broadly, this strategy displayed good functional
Figure 1. Representative bioactive benzofuran and spirooxindole
scaffolds.
Because of the aforementioned importance, numerous
emerging protocols provide viable alternatives to conventional
techniques, or sometimes offer direct construction of
heterocyclic systems via domino/cascade/tandem transforma-
tions.9a−d Moreover, some synthetic methodologies were
reported for the preparation of furan-containing heterocyclic
derivatives through transition-metal/noble-metal catalysts,9,10
Lewis/Brønsted acids,11 and base-promoted cyclizations12
using propargylic alcohols or their derivatives as starting
materials. However, accessing such preferred scaffolds using
aryne chemistry is less known.13 Recently, Larock and co-
workers described the synthesis of diaryl ethers and aryl esters
by the aryne insertion into the O−H bond of phenols and
carboxylic acids under transition-metal free conditions. In
addition, amines were also amenable to aryne insertion to
produce corresponding aryl amines (see Scheme 1a).2a,b More
recently, Biju et al. developed a temperature-dependent
reaction of aryne with aliphatic alcohols for the synthesis of
alkylaryl ethers via aryne insertion, followed by multi-
component coupling (MCC).2c,d Interestingly, Greany’s
group developed aryne-induced aza-Claisen rearrangement of
a
Scheme 2. Substrate Scope When R1 = Aryl
Scheme 1. Previous and Present Approaches
a
Reaction was carried out with 1a (1.0 mmol), 2a (2.0 mmol),
Cs2CO3 (3.0 mmol), CsF (2.5 mmol) and 18-crown-6 (2.5 mmol)
and 4 Å MS (60 mg) in CH3CN (2.0 mL) at room temperature for
1−2 h; isolated yields were reported.
group tolerance. Accordingly, the reaction of propargylic
alcohol possessing different substituents at the para position of
the phenyl ring 1aa−1ae with aryne 2a produced an isolable
mixture of corresponding products 3aa−3ae and 4aa−4ae in
moderate to good yields. Furthermore, the structures of 3ac
and 4aa have been unequivocally corroborated by single X-ray
crystallographic analysis (see the SI). The effect of the
electron-rich substituent at the para position of benzene ring
like p-Me exhibited minimal reactivity. The reaction of p-OMe
phenyl substrate (1af) provided the compound 3af (56%) and
the corresponding 4af could not be obtained in pure form.
Moreover, the halo group such as 4-Cl (1ad) underwent the
reaction in 2 h to yield 3ad (34%) and 4ad (17%). Next, we
B
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examined the electronic effects of substituents (−Me and −Br)
at the C5-position of the oxindole scaffold, which, under
established reaction conditions, provided the corresponding
products 3ag−3ah and 4ag−4ah in decent yields.
In order to probe if the substituents on the distal end of
acetylene group of propargylic alcohol have any bearing on the
product outcome, we selected substrates possessing alkyl/
cycloalkyl groups on the alkynyl carbon (see Scheme 3). First,
tolerated under these conditions, retaining the cyclopropane
ring. The substrate with propyl cyanide group (1bg) gave 3bg
in 66% yield. To expand the generality of the reaction, we set
out to explore both electron-rich (−Me and −OMe) and
electron-deficient (−F, −Cl, −Br, −I, and −OCF3) effects at
the 5-position of the oxindole moiety. The results indicated
that, while 1bh and 1bi gave 3bh and 3bi in 69% and 73%
yields, respectively, their counterparts 1bj−1bn gave corre-
sponding products 3bj−3bn in the range of 47%−65% yields.
The structure of the product 3bk was unambiguously
confirmed by X-ray analysis (see the SI). The alkyl/cycloalkyl
groups on substrates containing alkynyl carbon of the 5-Br-
oxindole moiety were subsequently investigated and found that
the reaction worked equally well on 1bo−1bs to afford
respective products 3bo−3bs in moderate to good yields.
Furthermore, the 6-Cl-oxindole derivative 1bt provided 3bt in
56% yield. These results demonstrate that very negligible
electronic effects were observed, irrespective of their position.
Finally, we investigated the regioselectivity and substituent
effects on substituted aryne precursors 2 with 1ba under the
optimal conditions (Scheme 3). Thus, the reaction of
unsymmetrical 3-methyl aryne precursor 2b with 1ba gave
an inseparable mixture of regioisomers 3bu and 3bu′ in a ratio
of 1:1 (62% yield). Moreover, the symmetrical 4,5-difluoro
aryne 2c with 1ba resulted in 3bv as the sole product in 51%
yield. Next, we selected 4-fluoro aryne (from 2d), which
produced a mixture of regioisomers 3bw and 3bw′ in 3:1 ratio
in a combined yield of 56%. In addition, we performed the
reaction with substrates containing tertiary propargylic alcohol
systems such as 2-methyl-4-phenylbut-3-yn-2-ol (5) and1-
(phenyethynyl)-cyclopentanol (7) with aryne precursor (2a)
to afford the corresponding aryl ethers 6 (25%) and 8 (30%).16
Thus, it was observed that the substituents on the alkynyl
carbon decided the outcome of the reaction. If the distal end of
the propargylic alcohol is substituted by an alkyl group (R1),
then 3-benzofuranyl-2-oxindole derivatives were the sole
products. Conversely, if aryl groups are the substituents (R1),
then both propargyl Claisen rearrangement and cycloaddition
products were obtained in one pot via 5-exo-dig cyclization. In
the case of the aryl group that is present at the distal end of the
triple bond, the cycloaddition process is the competing
reaction that is mainly facilitated because of the extended
conjugation.
a
Scheme 3. Substrate Scope When R1 = Alkyl/Cycloalkyl
and R2 = Variation of Arynes
Based on the experimental results and the literature
precedence2e−g,3,17,18 a tentative mechanism for the reaction
is depicted in Scheme 4. Initially, propargylic oxyanion A is
generated by abstraction of the proton from the propargylic
alcohol 1a/1b by Cs2CO3. The intermolecular nucleophilic
attack of O− in A onto aryne (2a) results in the intermediate B,
which undergoes intramolecular nucleophilic addition on
alkyne moiety, followed by protonation to produce 4a via
cycloaddition pathway. On the other hand, the intermediate B
can transform to the allene intermediate C by propargyl
Claisen rearrangement, followed by 5-exo-dig cyclization to
generate the intermediate D, which, upon subsequent
protonation, affords the product 3a/3b. The reaction pathway
involves a domino transformation of intermolecular C−O and
subsequent intramolecular C−C/C-O bond formation.
a
Reactions were carried out with 1ba (1.0 mmol), 2a (2.0 mmol),
Cs2CO3 (3.0 mmol), CsF (2.5 mmol) and 18-crown-6 (2.5 mmol),
and 4 Å MS (60 mg) in CH3CN (2.0 mL) at room temperature for
1−2 h; isolated yields were reported. bThe ratio of regioisomers were
1
determined by H NMR.
1ba (containing hexyl group) was chosen as the test substrate
and the reaction was conducted under established conditions
to afford 3ba as an exclusive product in 73% yield. To evoke
more understanding, the cycloalkyl analogue 1bf (cyclohexyl
group) was selected as the next example to give 3bf as a sole
product in matching yields (72%). We next sought to evaluate
the scope of similar substrates such as n-pentyl (1bb), n-butyl
(1bc), and n-propyl (1bd), which furnished corresponding
products 3bb−3bd in varying yields (69%−72%). Gratifyingly,
the cyclopropyl-group-bearing substrate (1be) was also well-
In summary, we have demonstrated an efficient Cs2CO3-
mediated propargyl Claisen rearrangement/cycloaddition
reaction between 3-alkynyl-3-hydroxy oxindole derivatives
and aryne, leading to the formation of 3-benzofuranyl-2-
oxindole and 3-spirooxindol benzofuran derivatives in one pot.
C
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Scheme 4. Proposed Reaction Mechanism
ACKNOWLEDGMENTS
■
The first two authors (B.K. and S.B.) thank the CSIR and the
UGC, New Delhi respectively for their financial support in the
form of a fellowship.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01414.
Typical experimental procedures, detailed screening of
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izations of compounds and spectroscopic data for 4aa,
3ac, and 3bk (PDF)
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Accession Codes
CCDC 1821924−1821926 contain the supplementary crys-
tallographic 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: prkgenius.iict@gov.in.
ORCID
Radha Krishna Palakodety: 0000-0002-3287-3477
Author Contributions
∇Both the authors contributed equally to this work.
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Notes
⊥IICT Communication No. IICT/Pubs/2018/071.
The authors declare no competing financial interest.
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