Facile synthesis of 4H-chromene derivatives via base-mediated annulation of orffro-hydroxychalcones and 2-bromoallyl sulfones

Article abstract of DOI:10.3762/bjoc.12.3

The cesium carbonate-mediated reaction of 2-bromoallyl sulfones and ortho-hydroxychalcones furnished 3-arylsulfonyl-4H-chromene derivatives in 58-67% yield (18 examples). 2-Bromoallyl sulfones functioned as synthetic surrogates for allenyl sulfones in the reaction.

Full text of DOI:10.3762/bjoc.12.3

Facile synthesis of 4H-chromene derivatives via
base-mediated annulation of ortho-hydroxychalcones
and 2-bromoallyl sulfones
Srinivas Thadkapally, Athira C. Kunjachan and Rajeev S. Menon*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 16–21.
Medicinal Chemistry and Pharmacology Division, CSIR-Indian
Institute of Chemical Technology, Hyderabad 500 007, India
doi:10.3762/bjoc.12.3
Received: 31 October 2015
Accepted: 21 December 2015
Published: 06 January 2016
Email:
Rajeev S. Menon* - rajeevmenon@iict.res.in
* Corresponding author
Associate Editor: T. J. J. Müller
Keywords:
© 2016 Thadkapally et al; licensee Beilstein-Institut.
License and terms: see end of document.
allenes; chromenes; cyclocondenzation; sulfones; vinylic substitution
Abstract
The cesium carbonate-mediated reaction of 2-bromoallyl sulfones and ortho-hydroxychalcones furnished 3-arylsulfonyl-4H-
chromene derivatives in 58–67% yield (18 examples). 2-Bromoallyl sulfones functioned as synthetic surrogates for allenyl sulfones
in the reaction.
Findings
Benzo[b]dihydropyran, commonly known as 4H-chromene (1), The utility of some of these methods are limited by drawbacks
is a privileged heterocyclic scaffold that is found in a variety of such as lengthy substrate synthesis, high cost of catalysts and
biologically active natural and synthetic products (Figure 1) tedious procedures. Therefore, general synthetic methods for
[1-3]. For example, the synthetic chromene derivative HA14-1 accessing substituted chromene derivatives from readily avail-
(Figure 1) has been shown to bind to the cellular protein Bcl-2 able materials are still in demand.
and to induce apoptotic cell death [4]. The natural chromene
rhodomyrtone (Figure 1) is known to exhibit potent antibacte- During the course of our recent investigations on annulation
rial activity [5]. As a consequence, a number of methods have reactions of unsaturated sulfones [16,17], we became interested
been developed for the synthesis of substituted 4H-chromenes in the possibility of exploiting allenyl sulfones as a building
[6]. This includes, inter alia, transition metal-mediated cycliza- block for heterocyclic sulfones. The synthetic potential of
tions [7], multicomponent reactions [8], ring-closing metathesis allenyl sulfones remains largely unexploited. This is in sharp
approaches [9,10], tandem reactions of 1,3-dicarbonyl com- contrast with the widespread use of electronically similar
pounds [11,12] and cyclocondenzation reactions of salicylic allenyl esters (allenoates) in numerous useful reactions (see for
aldehydes with α,β-unsaturated carbonyl compounds [13-15]. examples [18-20]). The propensity of allenyl sulfones to
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Beilstein J. Org. Chem. 2016, 12, 16–21.
Figure 1: 4H-chromene (1) and some of its biologically active derivatives.
oligomerise and display anomalous reactivity profiles in pres- aldehyde furnished the 3-sulfonyl-2H-chromene derivative 4 in
ence of base has, to some extent, dissuaded chemists from 69% yield (Scheme 1, path c) [24]. The formation of allenyl
devising synthetic applications of allenyl sulfones [21,22]. We sulfone 5 and propargyl sulfone 6 in the reaction of 2a with
envisaged that such problems may be circumvented by devel- cesium carbonate indicated that 5 is an intermediate in the
oping a synthetic surrogate for the sensitive allenyl sulfones. above-mentioned reactions (Scheme 1, path d) [24].
Investigations along this direction led to the discovery that the
easily prepared 2-bromoallyl sulfones 2a,b function as allenyl The facile cyclocondenzation of salicylaldehyde with 2a
sulfone surrogates in the presence of cesium carbonate (Scheme 1, path c) prompted us to explore analogous annula-
(Scheme 1, path a). Bromoallyl sulfones 2a,b partake in a tion reactions for the synthesis of functionalized chromene
cesium carbonate-mediated formal vinylic substitution reaction derivatives. The biological activities exhibited by many
with heteronucleophiles to afford valuable multifunctional 4H-chromene derivatives provided an added incentive for this
building blocks [23]. For example, the reaction of 2a with investigation [1]. We envisaged that the presence of a Michael
4-chlorophenol afforded the enol ether 3 in 84% yield acceptor double bond at the ortho position of a phenol would
(Scheme 1, path b) [24]. Similarly, treatment of 2a with salicyl- offer avenues for carbon–carbon bond forming annulation in its
Scheme 1: a) Preparation of 2-bromoallyl sulfones 2a,b; b) reaction of 2a with 4-chlorophenol and Cs2CO3; c) reaction of 2a with salicylaldehyde and
Cs2CO3 and d) reaction of 2a with Cs2CO3.
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Beilstein J. Org. Chem. 2016, 12, 16–21.
reaction with 2a,b. In view of their well-known reactivity The cesium carbonate-mediated reaction of 2-bromoallyl
profiles, diversity options, stability, and ease of preparation, sulfones 2a,b with o-hydroxychalcones 7a–i proceeded
ortho-hydroxychalcones were considered to be a suitable choice uneventfully to afford the corresponding 2-methyl-3-arylsul-
for this purpose. A pilot reaction between the o-hydroxychal- fonyl-4H-chromene derivatives 8aa–8ib (Scheme 4).
cone 7a and bromoallyl sulfone 2a in the presence of 2 equiva-
lents of cesium carbonate in acetonitrile afforded the The annulation reaction appears to be general as evident from
4H-chromene derivative 8aa in 61% yield (Scheme 2). It may the results in Scheme 4. The chalcone component can accom-
be noted that these reaction conditions were developed for the modate chloro, bromo and methoxy groups as aromatic
reaction of 2a with phenols (see Scheme 1, paths b and c) [24]. substituents. Polycyclic aromatic hydrocarbon frameworks
(naphthalene and anthracene rings) as well as a representative
heterocyclic ring (furan) may be incorporated into the
4H-chromene skeleton product by using chalcones (7c, 7d, and
7e, respectively) functionalized with these moieties. Disappoint-
ingly, attempts to extend the annulation reaction to phenols with
other Michael acceptors at the ortho-position (such as unsatu-
rated esters, enals and nitroolefins) were not successful. Addi-
tionally, a very low yield (ca. 10%) of the product 8aa was
obtained when the chalcone formation (7a) and its annulation
Scheme 2: Base-mediated cyclization reaction of o-hydroxychalcone
7a and 2-bromoallyl sulfone 2a.
reaction with 2a were combined into a one-pot operation (medi-
ated by KOH in ethanol).
In the 1H NMR spectrum of 8aa, three sets of doublet of A plausible mechanistic rationalization of the 4H-chromene for-
doublets were visible at δ 4.52 (1H, J = 2.3 and 9.0 Hz), δ 3.58 mation is presented in Scheme 5. Cesium carbonate mediates
(1H, J = 2.3 and 17.1 Hz) and δ 3.33 (1H, J = 9.0 and 17.1 Hz) the dehydrobromination of 2a to produce the allenyl sulfone 5
arising from the -CH2–CH- fragment. The methyl group protons (see Scheme 1, path d). Additionally, deprotonation of 7a by
resonated as a singlet at δ 2.51. A peak at δ 197.4 in the Cs2CO3 generates the phenoxide anion 9. A hetero-Michael
13C NMR spectrum along with the absorption peak at addition of 5 and 9 results in the formation of a stabilized
1680 cm−1 in the IR spectrum confirmed the presence of the carbanion which may be represented as the resonance struc-
keto group. All other signals were in agreement with the tures 10 or 11. The α-sulfonyl carbanion 11 then undergoes an
assigned structure.
intramolecular Michael addition to the β-carbon of the enone
unit to afford the enolate 12. Isomerization of the exocyclic
In order to explore the scope and generality of this facile olefin moiety of 12 into the endocyclic position may be assisted
4H-chromene synthesis, a variety of o-hydroxychalcones were by internal proton transfer. Tautomerization of the resultant
prepared as previously described (Scheme 3) [6].
enol 13 to its keto form affords the final product 8aa. It may be
Scheme 3: Preparation of ortho-hydroxychalcones 7a–i.
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Beilstein J. Org. Chem. 2016, 12, 16–21.
Scheme 4: Synthesis of 4H-chromenes via base-mediated reactions of 7a–i and 2a,b. Reaction conditions: 7a–i (0.25 mmol), 2a,b (0.30 mmol),
Cs2CO3 (0.60 mmol), CH3CN (3 mL), 25 °C, 4 h. Yields of isolated products are shown.
noted that the key carbon–carbon bond forming event (conver- Conclusion
sion of 11 to 12) here is completely regioselective as the In conclusion, a base-mediated, facile synthesis of 3-sulfonyl-
Michael addition of the stabilized carbanion 11 occurs selec- 4H-chromenes from o-hydroxychalcones and 2-bromoallyl
tively at the α-sulfonyl position (not at the less hindered sulfones was developed. The starting materials are easily avail-
terminal of the allylic carbanion 11).
able and the reaction conditions are mild. 2-Bromoallyl sulfones
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Beilstein J. Org. Chem. 2016, 12, 16–21.
Scheme 5: A plausible mechanistic rationalization for the formation of 4H-chromene derivative 8aa from 7a and 2a.
2. Kidwai, M.; Saxena, S.; Khan, M. K. R.; Thukral, S. S.
2a,b functions as stable surrogates for the sensitive allenyl
sulfones in this reaction. Functionalities such as carbonyl and
sulfonyl groups are easily incorporated into the privileged scaf-
fold of 4H-chromene via this method.
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Acknowledgements
Financial support from Science and Engineering Research
Board, (SERB), Department of Science and Technology (DST),
India in the form of a Ramanujan fellowship (SR/S2/RJN-05/
2011) and a fast-track project (CS-141/2011) to RSM is
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